Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][N:27]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1,4-dibenzyl-2-(hydroxymethyl)piperazine (1.51 g), phthalimide (0.790 g) and triphenylphosphine (1.40 g) in tetrahydrofuran (20 ml) was added a 40% toluene solution (2.34 ml) of diethyl azodicarboxylate under ice cooling. The resulting mixture was stirred at room temperature for 6 hours. Furthermore, 1,4-dibenzyl-2-(hydroxymethyl)piperazine (0.87 g), phthalimide (0.486 g), triphenylphosphine (0.81 g) and tetrahydrofuran (5 ml) were added to the reaction mixture, followed by the addition of a 40% toluene solution (1.34 ml) of diethyl azodicarboxylate under ice cooling. The resulting mixture was stirred at room temperature for 18.5 hours. Phthalimide (0.405 g) and a 40% toluene solution (1.10 ml) of diethyl azodicarboxylate were added under ice cooling, followed by stirring at room temperature for 20 hours. The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography twice (3% methanol—methylene chloride for the first time and ethyl acetate/hexane=1/3 for the second time) using as a carrier silica gel, whereby a crude product was obtained. The crude product was crystallized from hexane - methylene chloride, collected by filtration and washed with hexane, whereby the title compound (0.243 g) was obtained as colorless powder.
Reaction SMILES: [CH2:1]=[O:2].[N+:3]([C:6]1[N:10]([CH3:11])[C:9]([CH3:12])=[N:8][C:7]=1[CH3:13])([O-:5])=[O:4].[OH-].[NH4+]>CS(C)=O.O>[CH3:11][N:10]1[C:6]([N+:3]([O-:5])=[O:4])=[C:7]([CH3:13])[N:8]=[C:9]1[CH2:12][CH2:1][OH:2]
Reactant: C=O
Reactant: Cc1nc(C)n(C)c1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(CCO)n(C)c1[N+](=O)[O-]
Temperature: 140 °C
Yield: 74.8 %

Procedure:
Paraformaldehyde (4.05 g, 0.135 mole) and 5-nitro-1,2,4-trimethylimidazole (4.2 g, 0.027 mole) were combined in 25 ml of DMSO and heated at 140° C. for 48 hours (24 hours are found to be optimum), in a 300 ml glass-lined bomb. The reaction mixture was then evaporated in vacuo at 80° C. to give a dark brown oil. This was dissolved in about 60 ml of water, 5 ml of concentrated ammonium hydroxide are added, and the mixture was extracted six times with 70 ml of ethyl acetate. The ethyl acetate layers were dried over sodium sulfate and evaporated to give 3.74 g of residue. The crude product was dissolved in 3% methanol/chloroform to give a final volume of 8 ml. This is chromatographed preparatively on a partisil M20/50 column, eluting with 3% methanol/chloroform at 10 ml/min., with 4×2 ml injections. The product eluting at 46-55 minutes was collected. Combining the cuts from the four injections and evaporation of solvent gave 600 mg. This major product was a yellow oil which crystallized only with difficulty. The material was rechromatographed preparatively on a Whatman ODS-3 column eluting with 25% Methanol/water at 10 ml/min. The major peak was collected, and the solvent was evaporated to give 390 mg of pale yellow oil which readily crystallized on cooling. This product was 1,4-dimethyl-2-(2-hydroxyethyl)-5-nitroimidazole.
Reaction SMILES: CO[CH2:3][N:4]([CH2:12][Si](C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C:31](=[CH2:36])[C:32]([O:34][CH3:35])=[O:33])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:21][CH2:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C:31]3([C:32]([O:34][CH3:35])=[O:33])[CH2:36][CH2:3][N:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:12]3)[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=C(C(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(OC)c(OC3CCCC3)c2)CCN(Cc2ccccc2)C1
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a solution of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (1.42 g, 6.0 mmol) and methyl 2-(3-cyclopentoxy-4-methoxyphenyl)prop-2-enoate (1.38 g, 5.0 mmol) in 10 mL of CH2Cl2 cooled to 0° C. was added a 0.7 mL of a 1M solution of trifluoroacetic acid. Stirring was continued for 12 hr, and the solution was partitioned between ether and sat. NaHCO3. The layers were separated and the aqueous layer was extracted ethyl acetate (2×). The combined organic layers were dried (K2CO3), filtered, and concentrated under reduced pressure to a pale yellow oil. Chromatography on silica gel (3:1, hexanes:ethyl acetate) provided 3-(3-cyclopentoxy-4-methoxyphenyl)-3-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (2.0 g, 99%) as a colorless oil. 1H-NMR (300 MHz): δ 2.75 (d, 1, J=9), 3.54 (d, 1, J=9), 3.67 (s, 3), 3.69 (s, 2), 3.81 (s, 3). Anal. Calcd for C25H31NO4 : C, 73.32; H, 7.63; N, 3.42. Found: C, 73.25; H, 7.65; N, 3.40.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[NH2:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:37]([C:34]1([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=3)=[CH:10][CH:11]=2)[CH2:36][CH2:35]1)#[N:38]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CC1(NC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)CC1
Reaction time: 1 h
Yield: 20.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 60 mg, 0.139 mmol), 1-aminocyclopropanecarbonitrile-HCl (24.74 mg, 0.21 mmol), HATU (68.8 mg, 0.181 mmol), and 4-methylmorpholine (56.3 mg, 0.556 mmol) were dissolved in DMF (1 mL). After stirring 1 h, this was purified by prep HPLC (PHENOMENEX® 21.0×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.8 min) to provide single enantiomer N-(1-cyanocyclopropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.028 mmol, 20.46% yield): LCMS=496.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.28 (2 H, m), 7.52-7.79 (7 H, m), 5.16 (1 H, s), 1.42-1.61 (2 H, m), 1.12-1.34 (2 H, m); HPLC peak RT=9.9 min (Method A).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:23]=[CH:22][C:18]2=[N:19][O:20][N:21]=[C:17]2[CH:16]=1.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][NH:37][C:36]2=[O:40])[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[N:19]1[O:20][N:21]=[C:17]2[CH:16]=[C:15]([CH2:14][N:37]3[CH2:38][CH2:39][N:35]([C:27]4[S:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:25]([CH3:24])[N:26]=4)[C:36]3=[O:40])[CH:23]=[CH:22][C:18]=12
Reactant: BrCc1ccc2nonc2c1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc4nonc4c3)C2=O)nc1C
Yield: 92 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 5-(bromomethyl)benzo[c]-[1,2,5]oxadiazole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 92% yield: MS (ES+) m/z 388.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]>[N:17]1([C:2]2[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]3[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CC1Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1Oc2cc([N+](=O)[O-])c(-n3ccnc3)cc2NC1=O

Procedure:
485 mg of 6-chloro-7-nitro-2-methyl-1,4-benzoxazin-3-one is stirred with 136 mg of imidazole and 332 mg of potassium carbonate in 15 ml of DMF with the addition of copper powder for 6 hours at 180° C. It is diluted with ethyl acetate, extracted with brine, and the organic phase is dried. The crude product is purified by column chromatography with ethyl acetate with the addition of ethanol. 88 mg results.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:39]([O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54]Br)=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53][CH2:54][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:51][CH:52]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: BrCCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(OCc2ccccc2)cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
To a solution of 1.11 g di-tert-butyl (5S)-2-(benzyloxycarbonyl)-5-[(tert-butoxycarbonyl)-amino]hexanedioate (2.19 mmol; see example 12f) in N,N-dimethyl formamide (30 mL) was added under argon atmosphere 96 mg of sodium hydride (60% in oil, 2.40 mmol), and the mixture was stirred for 30 min at room temperature. Subsequently, a solution of 700 mg of 1-(benzyloxy)-4-(2-bromoethyl)benzene (2.40 mmol) in N,N-dimethyl formamide (15 mL) was added, an the mixture was stirred at 60° C. for 3 hours. The mixture was concentrated in vacuo, partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by preparative HPLC (Method A) to give 413 mg of the target compound in approx. 90% purity (26% purity adjusted yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][C:11]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:10]1=2.O.NN>CO.[Ni]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][C:11]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:10]1=2
Reactant: CN1CCCC1CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN1CCCC1CCN1CCSc2cc(N)ccc21
Reaction time: 3 h

Procedure:
A solution of 4-(2-(1-methylpyrrolidin-2-yl)ethyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.82 g, 2.67 mmol) in methanol (10 mL) under an argon atmosphere was treated with hydrazine hydrate (1.29 mL, 26.7 mmol) and a small amount of Raney Nickel (˜0.15 g, 2.67 mmol). The reaction was transferred to a pre-heated oil bath at 65° C. After 3 hours, the reaction was poured over a pad of Celite, rinsing with methanol. The filtrate was concentrated, and the residue was poured over a pad of silica gel. The silica gel pad was rinsed with 1:9 (2M NH3 in methanol):dichloromethane (200 mL). The filtrate was concentrated, dried under reduced pressure, and carried on to the next step. 1H-NMR (DMSO-d6) δ 6.48 (brd, J=9.3 Hz, 1H), 6.27-6.24 (m, 2H), 4.42 (brs, 2H), 3.33-3.29 (m, 2H), 3.13-3.06 (m, 2H), 2.99-2.96 (m, 2H), 2.96-2.90 (m, 1H), 2.19 (s, 3H), 2.06-1.97 (m, 2H), 1.96-1.78 (m, 2H), 1.63-1.60 (m, 2H), 1.56-1.40 (m, 2H); ESI-MS (m/z, %): 278 (MH+, 100).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:21]3[CH:20]=[C:19]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:24]=[CH:23][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(-c3ccccc3)c2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(-c4ccccc4)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-biphenyl-3-yl-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.16 min; [M+H]+=466.33.
Reaction SMILES: [S:1](=[O:15])(=[O:14])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][CH3:13])[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([O:17][CH3:16])[N:19]=[C:20]([NH:26][C:27](=[O:28])[NH:2][S:1]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH2:11][CH2:12][CH3:13])(=[O:14])=[O:15])[N:21]=1
Reactant: CCCOc1ccccc1OS(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
1.74 g (0.008 mol) of 2-propoxyphenyl sulfamate are added at room temperature to 2.32 g (0.0084 mol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate, dissolved in 100 ml of acetonitrile. After 1.33 g (0.0088 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been added, the reaction mixture is stirred at room temperature for 18 hours, concentrated, diluted with H2O and acidified using 2N hydrochloric acid to give a pH of 3-4. After the solids have been filtered off with suction and dried, 2.85 g (86% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)- 1-(2-propoxyphenoxysulfonyl)urea of melting point 108°-109° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:12])[S:5][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1>[CH2:37]([NH:44][C:7]([C:6]1[S:5][C:4]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:3][C:2]=1[CH3:1])=[O:9])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a mixture of 4-methyl-2-[(pyridine-4-carbonyl)amino]thiazole-5-carboxylic acid (0.40 g, 1.50 mmol) and 4-methylmorpholine (0.25 mL, 2.20 mmol) in tetrahydrofuran (50 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.32 g, 1.80 mmol). The resulting mixture was stirred at ambient temperature for 4 h, and then benzylamine (0.2 mL, 1.80 mmol) was added. The reaction mixture was stirred at room temperature for 47 h and then concentrated. Purification of the residue by column chromatography afforded the title compound in 45% yield (0.24 g); m.p. 171-172° C.; 1H NMR (DMSO-d6, 300 MHz) δ 13.15 (s, 1H), 8.78-8.63 (m, 3H), 7.94 (dd, J=1.5, 4.5 Hz, 2H), 7.32-7.17 (m, 5H), 4.38 (d, J=6.0 Hz, 2H), 2.51 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 162.0, 150.9, 140.0, 139.5, 128.7, 127.7, 127.2, 122.2, 114.3, 43.1, 17.1; MS (ES+) m/z 353.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.I[CH2:17][CH3:18]>CN(C)C=O>[CH2:17]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:18]
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)ccc2n1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
(washed beforehand with petroleum ether) and of 15 g (72.4 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in 100 ml of dimethylformamide is stirred for 2 h at room temperature. 7.5 ml (93.7 mmol) of iodoethane, in solution in 20 ml of dimethylformamide, are subsequently added. After stirring for 10 h at room temperature, the reaction mixture is poured onto ice-cold water. It is extracted with diethyl ether. The organic phase is washed several times with water, dried over magnesium sulphate and concentrated under reduced pressure. 17 g (72 mmol) of a yellow oil are obtained, which oil is used as is in the following stage.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[NH2:10][C:11]1[N:12]([CH2:25][CH3:26])[C:13]2[C:18]([C:19](=[O:23])[C:20]=1[C:21]#[N:22])=[CH:17][CH:16]=[C:15]([I:24])[CH:14]=2>COCCOC.Cl[Cu]>[NH2:10][C:11]1[N:12]([CH2:25][CH3:26])[C:13]2[C:18]([C:19](=[O:23])[C:20]=1[C:21]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[NH:22])=[CH:17][CH:16]=[C:15]([I:24])[CH:14]=2
Reactant: CCn1c(N)c(C#N)c(=O)c2ccc(I)cc21
Reactant: CCOC(CN)OCC
Agent: Cl[Cu]
Solvent: COCCOC
Product: CCOC(CNC(=N)c1c(N)n(CC)c2cc(I)ccc2c1=O)OCC

Procedure:
0.38 g (2.86 mmol) of aminoacetaldehyde diethylacetal and 0.155 g (1.57 mmol) of CuCl were added to 0.48 .g (1.43 mmol) of 2-amino-1-ethyl-7-iodo-4-oxo-1,4-dihydro-quinoline-3-carbonitrile dissolved in 20 ml of DME. The solution was stirred and irradiated with microwaves for 0.5 hour at 100° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8](CC)=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].Br[C:31]1[C:36]2[S:37][CH:38]=[CH:39][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:31]2[C:36]3[S:37][CH:38]=[CH:39][C:35]=3[CH:34]=[CH:33][CH:32]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Reactant: Brc1cccc2ccsc12
Product: CCOC(=O)c1c(-c2ccc(-c3cccc4ccsc34)cc2)c(C#N)cn1C

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-222 using 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-97a or 97b) and 7-bromo-benzo(b)thiophene. Purify the material by silica gel chromatography (Chromatotron™ eluting with methylene chloride/ethyl acetate 4:1 to provide the title compound a white solid. Mass spectrum (m/e): 413.2 (M*−1).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]Br)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.[I-].[K+]>[CH3:8][O:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: Sc1ccccc1
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)OC)c1ccccc1CSc1ccccc1
Yield: 52.8 %

Procedure:
1.5 g (0.014 mole) of thiophenol and 4 g (0.014 mole) of methyl 2-(bromomethyl)-phenylglyoxylate O-methyloxime (Method 3) are dissolved in 100 ml of acetone. 2.2 g of potassium carbonate and 0.1 g of potassium iodide are added. The stirred mixture is refluxed for 17 hours and then cooled, after which 100 ml of water are added. The aqueous phase is extracted with methylene chloride and the extract is dried over sodium sulfate and evaporated down. The crude product is crystallized by trituration with n-pentane. 2.33 g (55%) of the abovementioned compound are obtained as a colorless solid (mp.=60°-65° C.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[O:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:19])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C

Procedure:
A solution of (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (1 g, 4.3 mmol) in a 1:1 mixture of methanol and toluene (60 ml) was made. Trimethylsilyl diazomethane (6.5 ml of a 2M solution in hexanes, 13 mmol) was then added dropwise to the stirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue filtered through a pad of silica gel, eluting with ethyl acetate. Removal of solvent from the filtrate gave a yellow oil (1.05 g, near quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13](F)[CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH2:16].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29](O)=[O:30])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29]([NH:16][CH:5]3[C:4]4[C:12](=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=4)[O:11][C:7]4([CH2:10][CH2:9][CH2:8]4)[CH2:6]3)=[O:30])=[CH:26][C:21]=2[O:20][CH:19]=[CH:18]1
Reactant: NC1CC2(CCC2)Oc2c(F)cc(F)cc21
Reactant: O=C(O)CCc1ccc2c(c1)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccc2c(c1)OC=CO2)NC1CC2(CCC2)Oc2ccc(F)cc21

Procedure:
The title compound was prepared from Intermediate 6 (200 mg, 0.963 mmol) and 3-(2,3-dihydro-1,4-benzodioxin-6-yl)propanoic acid (187 mg, 0.963 mmol) in presence of EDCI.HCl (276 mg, 1.441 mmol), HOBt (221 mg, 1.441 mmol) and triethylamine (403 μl, 2.891 mmol) in dichloromethane (10 ml) as described in Example 1 to give 16 mg of the product as a white solid; IR (KBr) 3307, 2951, 1869, 1643, 1508, 1257, 1071, 817 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 1.13-1.23 (m, 1H), 1.66-1.78 (m, 3H), 2.04-2.13 (m, 3H), 2.18-2.27 (m, 2H), 2.42-2.49 (m, 1H), 2.72-2.79 (m, 2H), 4.17 (s, 4H), 5.01 (br s, 1H), 6.54 (d, J=11.1 Hz, 1H), 6.38-6.74 (m, 4H), 6.93 (t, J=8.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H); ESI-MS (m/z) 396.66 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[CH3:18])([O-])=O.CO.[H][H]>[Pt].ClCCl>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[CH3:18]
Reactant: [H][H]
Reactant: Cc1cc(Br)ccc1Nc1ccccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Br)ccc1Nc1ccccc1N

Procedure:
A suspension of 5.34 g (17.4 mmol) of N-(2-nitrophenyl)-4-bromo-2-methyl-aniline and 1.7 g of platinum on charcoal is stirred in 100 ml of dichloromethane and 100 ml of methanol at a hydrogen pressure of 3 bar for 1 hour. Then the catalyst is filtered off and the filtrate is evaporated down.