Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]23[CH2:24][CH2:23][CH2:22][CH:21]=[C:8]2[N:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:10](=[O:12])[NH:11]3)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]23[CH2:24][CH2:23][CH2:22][CH:21]=[C:8]2[N:9]([C:13]2[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:10](=[O:12])[N:11]3[CH3:29])=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1NC2(Cc3ccc(Br)cc3)CCCC=C2N1c1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C2=CCCCC21Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3a-(4-Bromo-benzyl)-1-(3,5-dichlorophenyl)-1,3,3a,4,5,6-hexahydro-benzimidazol-2-one (3.0 g) (0.0066 mol) in DMF (50 ml) was carefully dropped on a suspension of NaH 60% (0.32 g) (1.2 eq) in DMF (20 ml) at RT. The reaction mixture was stirred 1 h at RT then methyl iodide (0.6 ml) (1.5 eq) was added. After one night, the reaction mixture was partitioned between water and tBuOMe. The obtained precipitate was filtered, washed with water and tBuOMe, and dried to give 3a-(4-Bromo-benzyl)-1-(3,5-dichlorophenyl)-3-methyl-1,3,3a,4,5,6-hexahydro-benzimidazol-2-one (1.8 g) as a white solid. 1H NMR (CDCl3): 7.39 (2H, d), 7.10 (1H, m), 7.0 (2H, d), 6.77 (2H, m), 4.90 (1H, m), 3.0 (3H, s), 2.95 (2H, s), 2.5-2.2 (2H, m), 2.2-1.9 (3H, m), 1.8-1.6 (1H, m).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=[C:14]([C:19](=[O:21])[CH:20]=2)[C:15]([O:17]C)=[O:16])=[CH:7][CH:6]=1)C(C)=O.C(O)(=O)C>CO.[OH-].[Na+]>[NH2:1][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=[C:14]([C:19](=[O:21])[CH:20]=2)[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1
Reactant: COC(=O)c1cn(-c2cccnc2)c(-c2ccc(NC(C)=O)cc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2cccnc2)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
In 3 ml of methanol and 5 ml of 10% by weight aqueous sodium hydroxide solution was dissolved 0.5 g of methyl 6-(4-acetaminophenyl)-1-(3-pyridyl)-4-oxo-1,4-dihydronicotinate, and they were reacted at 60° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals were collected by filtration, washed with 10 ml of water, and then dried to obtain 0.34 g of 6-(4-aminophenyl)-1-(3-pyridyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 207°-208° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C(OCC)(=O)C.O.O1CCOCC1>[NH2:38][C:35]1[CH:34]=[CH:33][C:32]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][C:17]=2[F:30])=[N:37][CH:36]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Nc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ccc(N)cn2)c(F)c1
Reaction time: 0.17 h

Procedure:
N-(tert-Butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide (37 mg, 0.085 mmol) and 6-bromopyridin-3-amine (22 mg, 0.13 mmol) were added to a 5 mL sealable vial equipped with a stir bar. 1,4-Dioxane (0.2 mL) and 2 M Na2CO3 (0.2 mL) were added. Argon was bubbled through the solvent while it was rapidly stirred for 10 min then Pd(dppf)Cl2.CH2Cl2 (3 mg, 0.004 mmol) was added, and the mixture stirred for 15 hours at 80° Celsius under an argon atmosphere. The reaction was diluted with 2 mL of ethyl acetate and 2 mL of water and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic extracts were then dried with Na2SO4 and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C21H22FN3O2S, 399.14; m/z found, 400.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.25-8.16 (dd, J=8.0, 1.4, 1H), 7.83-7.76 (dd, J=8.8, 1.7, 1H), 7.77-7.68 (m, 1H), 7.66-7.58 (m, 1H), 7.58-7.48 (m, 2H), 7.46-7.39 (m, 2H), 7.37-7.30 (dd, J=7.4, 1.5, 1H), 4.31 (s, 1H), 1.09 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[NH2:15])[C:4]([CH3:16])=[N:3]1.C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:15][C:9]1[CH:10]=[C:11]([NH:14][C:31]([C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:32])[CH:12]=[CH:13][C:8]=1[C:5]1[C:4]([CH3:16])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: Cc1nn(C)c(C)c1-c1ccc(N)cc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c(C)c1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a solution of 76 (119.4 mg, 0.55 mmol) in CH2Cl2 (20 ml) was added N,N-diisopropylethylamine (DIEA, 258 mg, 348 μL, 2 mmol), 4-dimethylaminopyridine (DMAP, 0.6 mg, 0.05 mmol). The 4-chlorobenzoyl chloride (96 mg, 0.55 mmol) was dropped into above solution. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (40 ml) and extracted with EtOAc. The dicarboxamide was hydrolyzed with 1M NaOH in THF and MeOH (1:1). The product was purified by HPLC and afforded 77 (49 mg, 25%) as yellow solid. LC-MS: calcd. for C19H19ClN4O: 355 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=1)=[O:17]>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:38]2[CH:37]=[C:15]([CH:14]=[CH:13][C:39]=2[CH3:40])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=2)=[O:17])[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]=12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc2cnccn12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-a]pyrazine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 1. The product was obtained as a solid: 533 m/z (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40].[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH:42]3[CH2:43][CH2:44][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:46][CH2:47]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH:32]=[CH:33][C:34]=3[CH3:35])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.08 g, 0.14 mmol) was dissolved in CH2Cl2 (5 mL) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.0365 g, 0.175 mmol) and triethylamine (0.0284 g, 0.28 mmol) were added. The mixture was stirred under argon at room temperature overnight with only minor product formation. The reaction mixture was then heated to reflux for 24 h. The reaction still was not complete, so additional 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.146 g, 0.7 mmol) was added and the mixture stirred at reflux for 5 days. The solvents were pumped off in vacuo. The residue was taken up in EtOAc washed with 1M NaOH (2×), brine (1×), dried over anhydrous Na2SO4, filtered and evaporated The residue was flash chromatographed on silica gel (20 g) eluted with 0-50% EtOAc/CH2Cl2 to give the title compound as a white amorphous solid. mp (dec) 167-172° C.; LC-MS m/z 684 (M+H)+, 2.13 min (ret. time).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH2:12].[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][CH:23]1[CH2:24][CH2:25][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21][CH2:22]1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 143.5 %

Procedure:
Added 2-methoxy-5-nitro phenylamine (8.0 grams, 47.61 mmol) to a round bottomed flask, followed by the addition of 1-boc-4-piperidone (28.42 grams, 142.83 mmol), sodium sulfate (67.6 grams, 476 mmol) and acetic acid (80 mL). The above reaction mass was stirred for 8 hours at ambient temperature. Then added sodium triacetoxyborohydride (30.28 grams, 142.83 mmol) at 20-25° C. in 5 minutes and stirred the reaction mass for further 3 hours. The reaction mass was quenched into water (100 mL) and basified to pH: 9 with 50% aqueous sodium hydroxide solution. The product was extracted with ethyl acetate (4×50 mL). Combined organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated to obtain oily product. The product was further purified by column chromatography, the eluent being ethyl acetate, n-hexane and triethylamine, to obtain 24.01 grams of pure product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:28])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:32]=1)[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: O[C:2]1([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O=S(Cl)Cl>N1C=CC=CC=1>[C:11]1([C:8](=[C:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[C:9]#[N:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CC(c1ccccc1)C1(O)CCOCC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: N#CC(=C1CCOCC1)c1ccccc1
Reaction time: 0.42 h

Procedure:
(4-hydroxytetrahydro-2H-pyran-4-yl)(phenyl)acetonitrile (500 mg, 2.301 mmol) was dissolved in pyridine (10 ml). SOCl2 (1.680 ml, 23.01 mmol) was added and the reaction was stirred for 25 minutes then concentrated in vacuo. The crude material was purified by silica gel chromatography on an Isco Companion (5 to 35% EA/hexanes over 20 min, 40 g silica column). The desired fractions were combined and concentrated in vacuo. 450 mg, 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O>>[NH2:10][C:11]1[CH:12]=[C:13]([C:14]2[O:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[N:1]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: Nc1cccc(C(=O)O)c1
Product: Nc1cccc(-c2nc3cc(Cl)ccc3o2)c1

Procedure:
Prepared by the method of Example 1a), from 2-amino-4-chlorophenol (522 mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitle compound was obtained, 114 mg (13%). 1H NMR (CDCl3) δ 7.81(bs, 1H), 7.69–7.60(m, 3H), 7.49(t, J=7.1 Hz), 7.41–7.27(m, 2H), 6.96(dd, J=2.6, 7.9 Hz, 1H). MS 245, 247 m/z (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1>O1CCOCC1.[Pd]>[NH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: CNc1ncccc1N
Yield: 96.2 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 5.00 g of 2-methylamino-3-nitropyridine (prepared as described in Preparation 104) were hydrogenated in 80 ml of 1,4-dioxane in the presence of 1.00 g of 10 % w/w palladium-on-charcoal. After working up the product as described in Example 6, 3.87 g of the title compound, melting at 90°-92° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:13].[Cl:14][C:15]1[CH:16]=[C:17]([NH:25][C:26](OC2C=CC=CC=2)=[O:27])[C:18](=[CH:23][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([S:9]([NH:12][C:26]([NH:25][C:17]2[CH:16]=[C:15]([Cl:14])[CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[O:27])(=[O:11])=[O:10])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1c(Cl)cc(S(N)(=O)=O)cc1Cl
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1cc(Cl)c(N)c(Cl)c1
Yield: 45.4 %

Procedure:
1.06 g (4.40 mmol) of 4-amino-3,5-dichlorobenzenesulfonamide and 1.34 g (4.40 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as Example 1 to obtain 905 mg (yield 44%) of methyl 2-{[(4-amino-3,5-dichlorobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 3.87 (3H, s), 6.59 (2H, br), 7.22 (1H, dd), 7.72 (2H, s), 7.93 (1H, d), 8.24 (1H, d), 10.17 (1H, s).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:10](=[O:13])[CH2:11][CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].II>C1COCC1.[Zn]>[OH:13][CH:10]([CH2:11][CH3:12])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCC=O
Agent: II
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCC(O)CC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A mixture of zinc (4.25 g, 0.26 mol, granular), a small crystal of iodine and THF (200 ml, freshly distilled over LAH) was refluxed with stirring under a nitrogen atmosphere for 30 min. A portion of the solution (20 ml) of t-butyl α-bromoacetate (35.2 ml, 0.22 mol) and propionaldehyde (10.4 ml, 0.152 mol in THF, 200 ml, freshly distilled over LAH) was added to the above mixture. Within a few minutes the solution became cloudy and the iodine color disappeared. The remainder of the solution was added to the zinc during 30 min, after which the reactants were stirred and heated under reflux for 1 h. The cooled solution was poured into 0.1 N HCL (800 ml) and the pH was adjusted to ~2 with 2 N HCL. The excess of zinc was filtered off and the crude products were extracted into ethyl acetate (3×200 ml). The organic extracts were combined and washed with 8% NaHCO3 (2×200 ml), with water (2×200 ml) and dried over anhydrous MgSO4. The ethyl acetate was evaporated off under reduced pressure to give the crude ester which was purified by distillation, bp 71°-73° C./15 mm, to give colorless liquid (21.3 g, 54.5%). ir (neat) νmax : 3460 (--OH) and 1730 cm-1 (C=O of ester), 1Hmr (CDCl3) δ: 093 (3H, t), 1.23-1.83 (2H, m), 1.43 (9H, s), 2.32 (2H, d), 3.67 (H, s, OH) and 3.73 ppm (H, m).
Reaction SMILES: C1(C)C=CC=CC=1.CC(C)([O-])C.[Na+].[CH:14]1[C:26]2[NH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O.CCOCC>[Br:34][C:31]1[C:32]2[C:23]3[C:24](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:25]([C:26]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:33]=2[CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc(Br)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Brc1cccc2c1c1ccccc1n2-c1ccccc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A reaction vessel was charged with 4.37 mmol (4.00 g) Pd2dba3, (dba=dibenzoylacetone), 6.55 mmol (3.63 g) dppf (dppf=diphenylphosphine ferrocene), and 400 ml dry toluene. Using a magnetic stir bar and hot plate, the mixture was stirred for 15 minutes under argon. Then 436 mmol (48.92 g) sodium t-butoxide was added against counter flow of argon and the reaction was stirred another 30 minutes. Then 291 mmol (48.66 g) carbazole with 873 mmol (205.96 g) 1,4-dibromobenzene were added and the reaction was heated to 100° C. for 16 hours. The reaction progress was followed by TLC until no carbazole could be detected. At end of reaction, the reaction mixture was taken up into water/ether (2:1). The mixture was then washed with water until the organic layer was colorless, then the solution was concentrated. The residue was dissolved in a mixture of toluene/hexane and passed through a short column of silica gel. The solvent was then removed from the column filtrate which yielded the product.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=O)=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].S(Cl)(Cl)=O.[CH3:30][N:31]([CH2:33][CH2:34][NH2:35])[CH3:32]>CN(C)C=O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH:35][CH2:34][CH2:33][N:31]([CH3:32])[CH3:30])(=[O:21])=[O:22])=[CH:17][CH:18]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Reactant: CN(C)CCN
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)NCCN(C)C)cc3)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid, (7.0 g, 0.019 moles) and N,N-dimethylformamide (125 ml) is cooled to 0°, and treated with thionyl chloride (4.6 g, 0.038 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature, and stirred vigorously for one hour. The resulting slurry is cooled to 0°, and treated with unsym dimethylethylenediamine (8.8 g, 0.10 mole) and allowed to warm to ambient temperature. The reaction mixture is concentrated on a rotary evaporator, the residue is taken up in cool water and filtered. The solid thus obtained is recrystallized from ethanol and dried at 78° in a drying pistol to give 5.87 grams of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)-N-[2-(dimethylamino)ethyl]benzene-sulfonamide, mp 264°-265° C.(d).
Reaction SMILES: CC1N=C([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[O:10])ON=1.[N:32]1[N:33](C2C=CC=CC=2C(O)=O)[N:34]=[CH:35][CH:36]=1.Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1>>[N:32]1[N:33]([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=2)=[O:10])[N:34]=[CH:35][CH:36]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 8) from 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 57 mg, 0.28 mmol) and (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 72 mg, 0.26 mmol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH:3]=1.[C:16](OC)(=[O:21])[CH2:17][C:18]([CH3:20])=O>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[NH:1][C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[C:3]=2[C:4](=[O:15])[CH2:5]1
Reactant: COC(=O)CC(C)=O
Reactant: NC1=CC(=O)CC(c2ccccc2Cl)C1
Product: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 170 °C
Reaction time: 2.5 h
Yield: 4.9 %

Procedure:
A mixture of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (6.66 g) and methyl acetoacetate (5.8 g) was stirred at 170° C. for 2.5 hours, and to the mixture was added methyl acetoacetate (3 g). The mixture was stirred for 1.5 hours and cooled, and precipitated crystals were filtered and washed with ethanol to give 7-(2-chlorophenyl)-4-methyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.42 g) as pale yellow crystals.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[OH:6])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NCC(O)c1ccc(F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: NCC(O)c1ccc(F)c(F)c1
Reaction time: 8 h

Procedure:
A suspension of Pd (10 wt % on carbon; 232 mg, 0.22 mmol) in a solution of afforded 2-azido-1-(3,4-difluorophenyl)ethanol (435 mg, 2.2 mmol) in ethanol (20 mL) was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through Celite, acidified with hydrogen chloride (1 M in diethyl ether) and concentrated in vacuo to afford 2-amino-1-(3,4-difluorophenyl)ethanol, which was used without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC.[F-].[NH4+]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:14]([F:17])([F:16])[F:15])[O:8]2)=[CH:3][C:2]=1[CH:23]=[CH2:24]
Reactant: CCOC(=O)C1=Cc2cc(I)c(OC)cc2OC1C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=Cc1cc2c(cc1OC)OC(C(F)(F)F)C(C(=O)OCC)=C2
Temperature: 115 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.3 g (0.7 mmol) ethyl 6-iodo-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate and 16 mg (0.0139 mmol) tetrakis(triphenyl-phosphine)-palladium(0) in 4.2 mL of anhydrous toluene under nitrogen atmosphere was added 228 uL (0.785 mmol ) tributyl(vinyl)tin. The resulting solution was heated to 115° C. for three h. To the cooled reaction mixture was added 20 ml of 20% ammonium fluoride. After stirring for 15 min, the product was extracted three times with ethyl acetate. The combined organic extracts were washed twice with 20% ammonium fluoride, washed with brine and dried over anhydrous magnesium sulfate. The crude product was purified by silica chromatography with EtOAc/hexane (1:9) and used directly in the next step.