Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[N:17]\[S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])=[CH:12][CH:11]=1>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:2]([F:4])([F:3])[F:1])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
Add neat (trifluoromethyl)trimethylsilane (109 mL, 0.74 mol) at 0° C. to a stirred solution of tetrabutylammonium acetate (88 g, 0.29 mol) and (N—Z)—N-[(4-bromophenyl)methylene]-(R)-2-methyl-propane-2-sulfinamide (85 g, 0.29 mol) in DMF (1.2 L) at 0° C. Stir the mixture at 0-5° C. for 90 min. Add saturated aqueous ammonium chloride solution (1.2 L) and extract with EtOAc (4×400 mL). Combine the extracts and sequentially wash the extracts with water then brine (2×1 L); dry over magnesium sulphate; filter; and concentrate the filtrate under reduced pressure. Triturate the residue with hexane (200 mL) for 10 minutes, filter and dry the filtrate under reduced pressure to afford the title compound as a yellow solid (81 g, 76% yield, >98 de). MS (m/z): 358 (M+1).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([NH:20][C:21]([C:23]2[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:25][CH:24]=2)=[O:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(OCC)(=O)C.CO>[NH2:8][C:9]1[C:10]([NH:20][C:21]([C:23]2[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:25][CH:24]=2)=[O:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of pyridin-3-ylmethyl {4-[({4-[(tert-butoxycarbonyl)amino]-1-phenyl-1H-pyrazol-3-yl}amino)carbonyl]benzyl}carbamate (0.075 g, 0.14 mmol) in ethyl acetate (2 mL) and methanol (1 mL) was treated with 4M HCl in dioxane (3.11 mL, 12.4 mmol) and stirred at ambient temperature for 12 hours. The reaction was evaporated in vacuo and purified by flash column chromatography (0-5% methanol/methylene chloride w/0.1% ammonia) to give the title compound as an off-white solid. 1H NMR (CD3OD) δ 8.58 (s, 1H), 8.48 (m, 1H), 7.96 (d, J=8.22 Hz, 2H), 7.87 (d, J=8.22 Hz, 1H), 7.79 (s, 1H), 7.65 (d, J=8.22 Hz, 2H), 7.42 (m, 5H), 7.22 (t, J=7.30 Hz, 1H), 5.18 (s, 2H), 4.38 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:30])[C:7]=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N+:24]([O-])=O)[CH:21]=3)[N:16]([CH3:27])[C:15]=2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=1)=[O:10].CO>CN(C=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:30])[C:7]=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:24])[CH:21]=3)[N:16]([CH3:27])[C:15]=2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc([N+](=O)[O-])ccc3n(C)c12
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Reaction time: 18 h

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxamide (250 mg) was suspended in DMF (20 ml) and methanol (10 ml) and added with raney nickel (25 mg, 10% w/w) and reduced under pressure (60 psi) for 18 hrs at room temperature. The reaction mixture was filtered through celite and DMF was evaporated to get a green solid which was washed with water to give N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide. Confirmed by ninhydrin. The compound was taken directly without purification to synthesize the following example no 54, 55, 56 and 57
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[C:31]1([CH:37]2[CH2:42][N:41]3[CH:43]=[C:44]([C:46]([OH:48])=O)[N:45]=[C:40]3[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[F:49][C:50]([F:64])([F:63])[C:51]1[CH:52]=[C:53]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH:54]=[CH:55][CH:56]=1>CN(C=O)C>[C:31]1([CH:37]2[CH2:42][N:41]3[CH:43]=[C:44]([C:46]([N:60]4[CH2:59][CH2:58][N:57]([C:53]5[CH:54]=[CH:55][CH:56]=[C:51]([C:50]([F:63])([F:64])[F:49])[CH:52]=5)[CH2:62][CH2:61]4)=[O:48])[N:45]=[C:40]3[CH2:39][CH2:38]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1cn2c(n1)CCC(c1ccccc1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1cn2c(n1)CCC(c1ccccc1)C2)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (276 mg; 0.86 mmol) and N-methylmorpholine (237 μl; 218 mg; 2.15 mmol) were added to a solution of 6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (200 mg; 0.72 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (162 μl; 198 mg; 0.86 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, then poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 191 mg (59%).
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[F:16])/[C:5]([C:7]1[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:15])=[N:9][CH:8]=1)=O.[C:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[CH:30][CH:29]=2)[C@@H:23]([CH3:38])[CH2:22]1)(=[O:20])[CH3:19]>>[C:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]3[N:37]=[C:5]([C:7]4[N:11]([CH:12]([CH3:13])[CH3:14])[C:10]([CH3:15])=[N:9][CH:8]=4)[C:4]([F:16])=[CH:3][N:36]=3)=[CH:30][CH:29]=2)[C@@H:23]([CH3:38])[CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1C[C@H](C)N(c2ccc(NC(=N)N)cc2)C[C@H]1C
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Product: CC(=O)N1C[C@H](C)N(c2ccc(Nc3ncc(F)c(-c4cnc(C)n4C(C)C)n3)cc2)C[C@H]1C

Procedure:
The title compound was prepared from (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 335 mg, 1.40 mmol) and N-[4-((2S,5R)-4-acetyl-2,5-dimethylpiperazin-1-yl)phenyl]guanidine (Method 35; 737.1 mg, 2.10 mmol) by the procedure of Example 116. The reaction mixture was evaporated under reduced pressure and the residue purified by chromatography on silica gel with MeOH:DCM:EtOAc (1:49.5:49.5 to 6:47:47) to give a solid which required further purification with MeOH:DCM (1:99 to 6:94). After trituration with ether and evaporation of the solvent, the title compound was obtained as a solid which was dried in vac oven overnight at 50° C. (330 mg, 51%). NMR: (500 MHz) 0.95 (d, 3H), 1.33 (d, 3H), 1.40 (d, 6H), 2.03 (s, 3H), 2.50 (s, 3H+DMSO), 3.17 (m, 2H), 3.43 (brs, 1H), 3.83 (brs, 1H), 4.00 (m, 1H), 4.47 (brs, 1H), 5.40 (septet, 1H), 6.83 (d, 2H), 7.32 (d, 1H), 7.37 (d, 2H), 8.35 (d, 1H), 8.7 (s, 1H); 19F NMR (500 MHz MHz) −149.95 (t, 1F); m/z 466.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(O)C>[C:9]1([CH:8]=[C:2]2[CH2:3][CH2:4][CH2:5][C:6](=[CH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Yield: 61.9 %

Procedure:
A solution of 32.0 g (0.33 mole) of cyclohexanone, 70.0 g (0.66 mole) of benzaldehyde, 200 ml of ethanol and 20 ml of concentrated HCl is heated and then refluxed for one hour. Crystallization from the deep red solution occurs and after cooling the crystallized 2,6-bis(phenylmethylene)cyclohexanone is filtered and washed with cold ethanol and dried yielding 72.0 g; m.p. 114°-116° . This material is recrystallized from 120 ml of DMF (dimethylformamide) yielding 56.0 g (63%) of yellow 2,6-bis(phenylmethylene)cyclohexanone; m.p. 114°-116° .
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5]Cl)=[CH2:4].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]>CCOCC.CN(C=O)C>[CH2:24]([CH:28]1[CH2:33][CH2:32][N:31]([CH2:4][C:3](=[CH2:2])[CH2:5][N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:7][CH2:8][C:9]2=[O:17])[CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C1COc2ccccc2N1
Reactant: CCCCC1CCNCC1
Reactant: C=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(CN1CCC(CCCC)CC1)CN1C(=O)COc2ccccc21
Temperature: 65 °C
Reaction time: 5 h
Yield: 59.2 %

Procedure:
3-Chloro-2-chloromethyl-1-propene (0.20 g, 1.5 mmol), 4H-benzo[1,4]oxazin-3-one (0.15 g, 1.0 mmol) and Cs2CO3 (0.65 g, 2.0 mmol) were mixed with 1 mL DMF and were shaken at 65° C. for 5 h. The mixture was diluted with ether (20 mL) and washed with water (20 mL) and the water phase was extracted with ether (20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered concentrated under reduced pressure and the residue was purified by flash CC (SiO2; heptane/EtOAc 70:30). This product (0.080 g, 0.34 mmol) was dissolved in DMF (1 mL), thereafter 4-butylpiperidine (0.053 g, 0.37 mmol) and Cs2CO3 (0.23 g, 0.71 mmol) were added and the mixture was shaken at 65° C. for 24 h. The mixture was then poured into ether (25 mL) washed with water (10 mL) and the water phase was extracted with ether (20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by cation exchange CC, followed by flash CC (SiO2; EtOAc/MeOH/NH4OH (25% NH3 in water) 97.5:2:0.5), to yield the title compound (0.075 g, 21%). 1H NMR (CDCl3) δ 7.05-2.92 (m, 4H), 5.01 (brs, 1H), 4.82 (brs, 1H), 4.64 (brs 2H), 4.57 (brs, 2H), 2.94 (brs, 2H), 2.86 (brd, J=10.4 Hz, 2H), 1.93-1.82 (m, 2H), 1.71-1.62 (m, 2H), 1.34-1.15 (m, 9H), 0.89 (t, J=6.2 Hz, 3H); 13C NMR (CDCl3) δ 1.64.5, 145.4, 129.2, 123.9, 122.8, 116.9, 113.2, 67.9, 63.2, 54.4, 44.8, 36.6, 36.0, 32.8, 29.3, 23.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+=343.3.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20](OC2C=CC([N+]([O-])=O)=CC=2)=[O:21])[C:3]1=[O:32].[CH2:33]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1)[CH3:34].C(N(CC)CC)C>CN(C=O)C>[CH2:33]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:20]([NH:19][C@@H:4]2[N:5]=[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:32])=[O:21])[CH:38]=1)[CH3:34]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CN1C(=O)[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
(R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (150 mg, 0.35 mmol), 3-aminobenzoic acid ethyl ester (61 mg, 0.37 mmol), and triethylamine (52.5 mg, 0.52 mmol) were combined in DMF (2 ml) and heated at 45° overnight. The DMF was removed in vacuo and the residue crystallized from ethyl acetate to provide the title compound: (mp 140°-142° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16](N(C)C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].C[O-:29].[Mg+2].C[O-].Br[CH2:34][CH2:35][CH2:36][CH2:37]Cl.Cl>CO.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]3[CH2:37][CH2:36][CH2:35][CH2:34][O:17][C:16](=[O:29])[C:12]3=2)[C:7]1=[O:23]
Reactant: ClCCCCBr
Reactant: C[O-]
Reactant: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Cl
Agent: [Mg+2]
Solvent: CO
Solvent: CS(C)=O
Product: O=C1OCCCCn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (0.80 g, 2.19 mmol; Example 1, step 9) and magnesium methoxide in methanol (10.6 mL, 6-10% methanol solution available from Aldrich) in DMSO (22 mL) was heated at 60° C. for 30 minutes. Methanol was exhaustively removed under vacuum over 45 minutes. The residual DMSO solution was treated with 1-bromo-4-chlorobutane (1.80 g, 10.50 mmol) and stirred at 60° C. under an atmosphere of nitrogen overnight. The reaction mixture was heated at 100° C. for 3 hrs. The reaction mixture was treated with dilute HCl. The solid precipitated was filtered, dissolved in DMSO, and subjected to reverse phase HPLC purification. Collection and lyophization of appropriate fractions provided the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](Br)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:28][C:29]([CH3:39])([CH2:37][CH3:38])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[NH:34][CH:35]=1>C(Cl)Cl>[CH3:28][C:29]([CH3:39])([CH2:37][CH3:38])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[N:34]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:35]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C)(C)Cc1c[nH]c(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (34 mL, 0.24 mol) followed by trityl bromide (62 g, 0.19 mol) (portionwise) were added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazole (26.4 g, 0.16 mol) in methylene chloride (300 mL). After stirring at ambient temperature overnight, the reaction mixture was filtered and washed with water and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 10-40% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[N:21]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:21])=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c(N)c(N)n(C)c1=O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To the stirring solution of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (1.13 g, 4.0 mmol) in glacial acetic acid (22.5 ml) and water (7.5 ml) at 65° C. was added sodium nitrite (345 mg, 5.0 mmol) in portions. The pink mixture was stirred at 65° C. for 1 hour and then cooled to 0-5° C. After filtration, the violet solid was washed with water (2x 10 ml) and then suspended in water (20 ml) and heated at 65° C. while sodium hydrosulfite (2.78 g, 16.0 mmol) was added in portions. The pale yellow solution was stirred at 65° C. for an additional 1 hour, cooled to room temperature and extracted with chloroform (3x 25 ml). The combined extracts were dried over magnesium sulfate and filtered to provide crude (R)-3-(5-acetoxyhexyl)-5,6-diamino-1-methyluracil in chloroform. To this clear solution was added 1,1′-carbonyldiimidazole (650 mg, 4.0 mmol). After stirring overnight at room temperature, the mixture was washed with water (2x 25 ml), with 1 N aqueous hydrochloric add (2x 25 ml), with water (2x 25 ml), with saturated aqueous sodium chloride solution (25 ml) and then dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided the crude product which was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-3-methyluric acid (280 mg) as a beige solid which was dissolved in 20 ml of ethanol. To this solution was added hydrogen chloride in ethyl ether (1 M, 2.0 ml, 2.0 mmol). After refluxing overnight, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-hydroxyhexyl)-3-methyluric acid (210 mg, 19% yield) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[I:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[OH:41]>>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:41][C:32]2[CH:33]=[CH:34][C:35]([C:37]([F:38])([F:39])[F:40])=[CH:36][C:31]=2[I:30])=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: Oc1ccc(C(F)(F)F)cc1I
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(C(F)(F)F)cc3I)cc2F)c(OC)c1
Yield: 67 %

Procedure:
Prepared according to Preparation 255 using N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 647, 1000 mg, 2.26 mmol) and 2-iodo-4-(trifluoromethyl)phenol (Preparation 224, 975 mg, 3.38 mmol) to afford the title compound, 1080 mg, 67% yield.
Reaction SMILES: [CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[O:11])[C:7]=2I)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[O:11])[C:7]=2[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]=[O:14])[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(C2CCCC2)=C1I
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=Cc1cccc(C2=C(C3CCCC3)CCC2=O)c1
Yield: 63.3 %

Procedure:
A mixture of 120 mg 3-cyclopentyl-2-iodo-2-cyclopenten-1-one, 80 mg 3-formylphenylboronic acid and 20 mg tetrakis(triphenylphosphine)palladium was stirred at 80° C. overnight in 8 ml toluene, 4 ml ethanol and 4 ml 2 N aqueous sodium carbonate. Then the reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=2:1) to yield 70 mg of 3-cyclopentyl-2-(3-formylphenyl)-2-cyclopenten-1-one. 3-cyclopentyl-2-(3-formylphenyl)-2-cyclopenten-1-one in benzene was stirred with one drop of acetic acid and 100 mg sodium triacetoxyborohydride at 70-80° C. for 2 hours. Then the reaction mixture was poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=2:1) to yield 40 mg of 3-cyclopentyl-2-(3-hydroxymethylphenyl)-2-cyclopenten-1-one, which was then condensed with hydroxylamine hydrochloride according to a procedure similar to that described in STEP 4 for Example 1 to afford 20 mg of 3-cyclopentyl-2-(3-hydroxymethylphenyl)-2-cyclopenten-1-one oxime as a solid. 1H NMR (CDCl3, 300 MHz): δ 8.75 (bs, 1H), 7.40-7.29 (m, 3H), 7.12 (d, J=7.2 Hz, 1H), 4.66 (s, 2H), 2.98 (m, 1H), 2.75 (m, 2H), 2.61 (m, 2H), 1.71 (m, 4H), 1.55 (m, 4H).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH:18]=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2].[CH3:20]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)[CH2:16][CH2:17][CH:18]=[CH2:20]
Reactant: COC(C)(C)C
Reactant: N#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C#N)CC2)CC1
Temperature: 0 °C

Procedure:
3.28 g of methyltriphenylphosphonium bromide were suspended in 40 ml of tert.butyl methyl ether while gassing with argon. The suspension was treated at room temperature within 1 minute with 962 mg of potassium tert.butylate and stirred for I hour. The mixture was subsequently cooled to 0° C., treated dropwise within 3 minutes with a solution of 1.5 g of 4-[trans-4-(trans-4-cyanocyclohexyl)cyclohexyl]butyraldehyde in 20 ml of tert.butyl methyl ether and stirred at 0° C. for a further 45 minutes. Thereafter, the reaction mixture was diluted with 80 ml of water and extracted three times with 100 ml of petroleum ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the crude product (2.1 g) on silica gel at 0.5 bar with ethyl acetate/petroleum ether (vol. 2:98) and recrystallization from 20 ml of methanol gave 1.26 g of trans-4-[trans-4-(4-pentenyl)cyclohexyl]-cyclohexanecarbonitrile as colorless crystals with m.p. (C-SB) 20.1° C, SB -N 36.9° C., cl.p. (N-I) 54.8° C.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[CH:22]([NH2:25])([CH3:24])[CH3:23].[F:26][C:27]1[CH:45]=[CH:44][C:30]([CH2:31][N:32]([CH3:43])[C:33]([C:35]2[CH2:36]N(C)[C:38](=[O:41])[C:39]=2[OH:40])=[O:34])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:45]=[CH:44][C:30]([CH2:31][N:32]([CH3:43])[C:33]([C:35]2[CH2:36][N:25]([CH:22]([CH3:24])[CH3:23])[C:38](=[O:41])[C:39]=2[OH:40])=[O:34])=[CH:29][CH:28]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Reactant: CC(C)N
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CC(C)N1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (compound 1-D) was treated with paraformaldehyde and isopropylamine as described in the preparation of Compound 1. 1H NMR (500 MHz, CDCl3) δ: 1.23 (d, 6, J=7), 3.02 (s, 3), 4.10 (s, 2), 4.45 (heptet, 1, J=7), 4.62 (s, 2), 7.03 (m, 2), 7.24 (m, 2). 13C NMR (125 MHz, CDCl3) δ: 20.61, 34.72, 44.09, 44.34, 110.21, 115.57, 115.75, 129.43, 129.50, 132.28, 132.30, 149.92, 161.35, 163.31, 164.76, 165.80.
Reaction SMILES: C[C:2]1[NH:3][C:4]2[C:9]([C:10]=1C(OCC1C=CC=CC=1)=O)=[CH:8][C:7](O)=[CH:6][CH:5]=2.C([O-])([O-])=O.[Cs+].[Cs+].[Br:28]CCCBr>C(#N)C>[Br-:28].[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:2]1
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: [Br-]
Product: c1ccc2[nH]ccc2c1
Yield: 62.5 %

Procedure:
2-Methyl-3-benzyloxycarbonyl-5-hydroxyindole (0.558 g, 1.980 mmol, 1 eq) was suspended in acetonitrile (10 mL) under Ar. Cs2CO3 (0.645 g, 1.980 mmol, 1 eq) and KI (0.328 g, 1.980 mmol, 1 eq) were added followed by 1,3-dibromopropane (0.523 g, 2.590 mmol, 1.3 eq). The reaction mixture was stirred and heated to reflux for 20 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/hexane (1/5). 0.244 g (31%) of the indole-bromide was obtained as a colorless oil.