Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.N12CCCN=C1CCCCC2.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH2:39][C@H:40](O)[CH2:41][O:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:34]([CH:37]=1)[C:35]#[N:36].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH2:39][C@@H:40]([F:1])[CH2:41][O:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:34]([CH:37]=1)[C:35]#[N:36]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N#Cc1cc(Cl)ccc1OC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cc(Cl)ccc1OC[C@@H](F)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 35 °C
Yield: 81 %

Procedure:
Perfluorobutanesulfonyl fluoride (594 g, 2.0 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (282 g, 1.85 mol) were added to an ice-cooled toluene (14.5 L) solution of 5-chloro-2-[[(2S)-2-hydroxy-3-(trityloxy)propyl]oxy]benzonitrile (580 g, 1.23 mol) at the same temperature in a nitrogen atmosphere, followed by stirring the reaction mixture at 35° C. Toluene (2.0 L) and a 1N sodium hydroxide aqueous solution (1.7 L) were added to the reaction mixture to separate an organic layer which was then washed 3 times each sequentially with the 1N sodium hydroxide aqueous solution (1.7 L) and water (1.1 L), followed by vacuum concentration. Methanol (3.3 L) was added to the resultant crude crystal, followed by heating the reaction mixture to 44° C. before cooling to room temperature. The precipitated crystal was filtered and then washed with methanol (0.75 L), followed by drying at 50° C. for 18 hours to obtain 470 g of the title compound (yield: 81%).
Reaction SMILES: [CH3:1][CH2:2]CC[O-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:10][C:9]=1[CH:27]=[C:28]([Cl:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl.O>C(O)CCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:10][C:9]=1[CH:27]=[C:28]([Cl:34])[C:29]([O:31][CH2:32][CH2:33][CH2:1][CH3:2])=[O:30]
Reactant: CCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reactant: CCCC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 5 h

Procedure:
50 ml of a sodium n-butylate solution in n-butanol (prepared from 0.3 g of 80% strength sodium hydride and 50 ml of n-butanol) were added to a solution of 4.4 g of 3-[4-chloro-3-(2-chloro-2-ethoxycarbonylethen-1-yl)-phenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 50 ml of n-butanol, and stirring was carried out for 5 hours at room temperature. Thereafter, the mixture was neutralized with 10% strength hydrochloric acid at 0-5° C. and the resulting solution was stirred into 100 ml of water at 0-5° C. The aqueous phase was extracted with 100 ml of toluene, and the combined organic phases were washed with three times 50 ml of water, dried over sodium sulfate and evaporated down. The oil obtained was chromatographed over silica gel (dichloromethane), and the oil obtained therefrom was stirred with petroleum ether. The resulting solid was filtered off, washed with petroleum ether and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[O:13]1[CH:17]=[CH:16][C:15]([Li])=[CH:14]1>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([C:15]1[CH:16]=[CH:17][O:13][CH:14]=1)([C:15]1[CH:16]=[CH:17][O:13][CH:14]=1)[OH:6]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: [Li]c1ccoc1
Product: Nc1ccc(Br)cc1C(O)(c1ccoc1)c1ccoc1

Procedure:
Prepared from methyl 2-amino-5-bromobenzoate and 3-furyllithium following the procedure described in example 24. 1H NMR (DMSO-d6): δ 7.6 (t, J=1.73 Hz, 2H), 7.25 (q, J=1.51, 0.81 Hz, 2H), 7.10 (q, J=8.46, 2.43 Hz, 1H), 6.79 (d, J=2.43 Hz, 1H), 6.56 (d, J=8.46 Hz, 1H), 6.46 (d, J=8.46 Hz, 1H), 6.39 (q, J=1.73, 0.81 Hz, 2H), 5.35 (s, 2H); MS (ESI) m/z 332/334 ([M−H]−).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([C:35](O)=[O:36])[C:29]=2[CH:28]=[CH:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:29]=4[CH:28]=[CH:27][NH:26]5)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5[nH]ccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-4-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7][CH:8]([S:11][CH3:12])[S:9][CH3:10].[Si:13]([N:20]1[C@H:23]([CH2:24]I)[CH2:22][C:21]1=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Si:13]([N:20]1[C@H:23]([CH2:24][C:8]([S:11][CH3:12])([S:9][CH3:10])[S:7][CH3:6])[CH2:22][C:21]1=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CSC(SC)SC
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1CI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSC(C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
n-Butyllithium (19.4 ml of 2.5 M hexane solution, 48.5 mmol) is added slowly by syringe to a solution of tri(methylthio)methane (7.47 g, 48.5 mmol) in 150 ml of freshly distilled THF at -78° C. The resulting solution is stirred at -78° C. for 30 min. prior to the addition of a solution of (4S)-1-(tert-butyldimethylsilyl)-4-iodomethylazetidin-2-one (15.0 g, 46.15 mmol) in 50 ml of THF. This solution is stirred at -78° C. for 30 min., then quenched by addition of saturated aqueous ammonium chloride solution. The reaction mixture is allowed to warm to room temperature, then poured into ether (250 ml), washed with water (2×100 ml) brine (100 ml) and dried over magnesium sulfate. Removal of solvents in vacuo gives an oil which is crystallized from petroleum ether to give 13.3 g (82%) of (4S)-1-(t-butyldimethylsilyl)-4-(2,2,2-tri(methylthio)ethyl)azetidin-2-one as colorless prisms. m.p. 61°-62° C. IR(CHCl3, CM-1) 2918, 2850, 1730; n.m.r. (CDCl3) δ 4.0(m,l), δ 3.35(dd,l,J=5.5,16), δ 2,83 (dd,l,J=3,16) δ 2,5(ABq,2) δ 2,15(s, 9), δ 0.98(s,9), δ0.25(s,6).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(-c3ccccc3)n2)c1
Temperature: 80 °C

Procedure:
{3-[(6-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (77) (198 mg, 0.54 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. for 25 min. The crude product was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:12])[CH3:11])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH3:27]>[Cu]Br>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH3:27])[C:10](=[O:12])[CH3:11])[CH3:2]
Reactant: CCc1ccccc1NC(C)=O
Reactant: CCc1ccccc1Br
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccccc1N(C(C)=O)c1ccccc1CC
Temperature: 200 °C
Yield: 67 %

Procedure:
The mixture of the N-(2-ethylphenyl)acetamide (7.35 g, 45.03 mmol), anhydrous K2CO3 (6.22 g, 45.03 mmol), copper(I) bromide (452.2 mg, 3.15 mmol) in 1-bromo-2-ethylbenzene was stirred and heated to 200° C. under argon for 48 h. After cooling the reaction mixture was poured into ice-H2O and extracted with ethyl acetate (2×500 mL), the combined organics were washed with brine, dried over anhydrous (K2CO3), filtered and concentrated to dryness. The crude product was purified using an ISCO machine using a ethyl acetate-hexane gradient to afford the product, N,N-bis(2-ethylphenyl)acetamide (8.1 g, 67%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH:9]([F:27])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].N.CO>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[C@@H:9]([F:27])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(F)C2NC(=O)Nc1cccc2[nH]ncc12
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C[C@H](F)[C@@H]2NC(=O)Nc1cccc2[nH]ncc12

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound N-(5-tert-butyl-2-fluoro-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea (Ex. 39) using a chiral column ChiralCel OD. 1H NMR (300 MHz, d6-DMSO) 13.01 (broad s, 1H), 8.87 (s, 1H), 8.08 (s, 1H), 7.71 (d, 1H), 7.33 (s, 1H), 7.30 (d, 1H), 7.21 (m, 2H), 7.09 (d, 1H), 6.87 (d, 1H), 5.33-5.46 (m, 2H), 3.05-3.27 (m, 2H), 1.27 (s, 9H). MS (DCI/NH3) m/e 367 (M+H)+. [α]D−32.75° (c=0.800, 1:1 MeOH:CH2Cl2). Structure is cis by ROESY NMR, absolute stereochemistry assigned arbitrarily.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[CH:15]=2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)=[N:21][CH:22]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:12][C:9]3[CH:10]=[CH:11][C:6]4[N:7]([CH:15]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)=[O:30])=[CH:25][CH:24]=2)=[N:21][CH:22]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cn2)cc1
Reactant: O=[N+]([O-])c1ccc2nc(C3CC3)cn2c1
Product: O=C(Nc1ccc2nc(C3CC3)cn2c1)c1ccc(-c2ccc(Cl)cn2)cc1

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-6-nitroimidazo[1,2-a]pyridine and 4-(5-chloro-2-pyridyl)benzenecarboxylic acid, to provide 4-(5-chloro-2-pyridyl)-N-(2-cyclopropylimidazo[1,2-a]pyridine-6-yl)benzamide as white solid. Further treating the resulting compound in the manner similar to Example 36, the title compound was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[N:7]=[N:6]1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:12])[N:7]=[N:6]1
Reactant: O=C(O)c1cn(Cc2ccccc2Cl)nn1
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C(c1cn(Cc2ccccc2Cl)nn1)N1CCCCC1

Procedure:
In a manner analogous to that described in Example 14, starting from 11.8 g (50 mmol) of 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid, converting this into the acid chloride and treating the latter with piperidine (50 mmol), there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid piperidide having a melting point of 141°-142° (from ethanol) and, by treating the acid chloride with dimethylamine (50 mmol), there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid N,N-dimethylamide having a melting point of 120°-121° (from ethanol).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:15][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:12])=[O:13])=[CH:7][C:5]=2[N:6]=1
Reactant: NS(=O)(=O)c1ccc2oc(S)nc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2cc(S(N)(=O)=O)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To a solution of 2-mercapto-benzooxazole-5-sulfonic acid amide (17.0 g, 73.8 mmol, 1.0 equiv) in anhydrous DMF (200 mL) was added anhydrous K2CO3 (51.0 g, 369.1 mmol, 5.0 equiv) and methyl iodide (16.1 mL, 36.7 g, 258.4 mmol, 3.5 equiv). After stirring for 3 h at rt, the K2CO3 was removed by filtration and the reaction mixture concentrated by evaporation under reduced pressure. The residue was washed with ethyl acetate (50 mL) give 17.4 g (97%) of the title compound. 1H NMR (300 MHz, DMSO): δ 2.80 (s, 3H), 7.47 (br s, 2H), 7.83 (s, 2H), 8.07 (s, 1H). 13C NMR (75 MHz, DMSO): δ 4.28, 110.47, 115.71, 122.04, 140.99, 141.37, 152.92, 167.84. MS (ISP): 244.9 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1.P(CCCC)(CCCC)CCCC>C1COCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(CCC(=O)OCC)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Yield: 37.3 %

Procedure:
To a stirred solution of the 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (50 mg, 0.16 mmol) and ethyl 3-(4-hydroxyphenyl)propanoate (31 mg, 0.16 mmol) in anhydrous THF (3.2 mL) under nitrogen at 0° C. (ice/water bath) was added ADDM (83 mg, 0.32 mmol). After a few minutes, nBu3P (81 μL, 0.32 mmol) was added (drop-wise) and the solution was stirred at 0° C. warming to rt overnight. After 17.5 hours the solvent was concentrated under vacuum and the solid residue dissolved in DCM (5 mL) and washed with water (5 mL) using a hydrophobic frit. The aqueous layer was re-extracted with DCM (5 mL) and the combined organic layers concentrated under vacuum. The resulting solid residue was then purified by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 100:1 to 1:1) to afford the title compound (29 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]=[CH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[O:38]1[CH:17]2[CH:16]1[CH2:15][CH2:14][N:13]([C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])=[CH:25][CH:24]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=12
Reactant: O=C(Nc1ccc(C(=O)N2CCC=Cc3ccccc32)cc1)c1ccccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCC3OC3c3ccccc32)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
1-[4-(2-Chlorobenzoylamino)benzoyl]-2,3-dihydro-1H-benzazepine (4.7 g) is dissolved in dichloromethane (50 ml) and thereto is added 80% m-chloroperbenzoic acid (3 g). The mixture is stirred at room temperature overnight. The dichloromethane layer is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) to give 4,5-epoxy-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (4.26 g) as white powder.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([CH3:11])=[CH:9][C:8]([NH2:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1>C(O)CCC>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([NH:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1nc2cc(N)cc(C)c2o1
Solvent: CCCCO
Product: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2o1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
600 mg (1.90 mmol) 2,7-dimethyl-benzoxazol-5-ylamine, 400 mg (2.70 mmol) 4,6-dichloropyrimidine and 1.50 mL (11.0 mmol) TEA were combined in 8.0 mL 1-butanol and stirred for 2 h at 90° C. The reaction mixture was cooled to RT and purified by preparative HPLC. The product-containing fractions were combined, evaporated down and the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([O:5]C)=[O:4].[OH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][OH:15].[OH-].[Na+].Cl>C(O)CC.C(N(CC)CC)C>[OH:9][CH2:10][CH2:11][N:12]([C:2]([CH3:8])([CH3:7])[C:3]([OH:5])=[O:4])[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)C(C)(C)Br
Reactant: OCCNCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: CC(C)(C(=O)O)N(CCO)CCO

Procedure:
Methyl 2-bromo-2-methylpropanoate (181.04 grams, 1 mole) is dissolved in 1-propanol (500 ml.) and bis-(2-hydroxyethyl)amine (105.14 grams, 2 moles) and triethylamine (111.1 grams, 1.1 moles are added and the mixture stirred and heated at reflux for 3 hours. The mixture is treated with 10 normal sodium hydroxide (110 ml., 1.1 moles) and the solvents are removed by distillation in vacuo. The residue is filtered and the solid washed with 1-propanol. The combined filtrates are dissolved in ethanol (400 ml) and 10 normal sodium hydroxide (130 ml, 1.3 moles) is added. The mixture is stirred and heated at reflux for 3 hours. The mixture is acidified with 12 normal hydrochloric acid (108 ml., 1.3 moles). Upon cooling, 2-[N,N-bis-(2-hydroxyethyl)-amino]-2-methylpropanoic acid separates and is collected by filtration, and is washed with a 50% aqueous ethanol and dried.
Reaction SMILES: [CH3:1][C:2]1[C:15](=[O:16])[CH:14]=[C:13]2[C:4](=[N:5][C:6]3[C:11]([S:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.[CH2:24]([SH:28])[CH2:25][CH2:26][CH3:27].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClC(Cl)C>[CH2:24]([S:28][C:14]1[C:15](=[O:16])[C:2]([CH3:1])=[CH:3][C:4]2[C:13]=1[S:12][C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[N:5]=2)[CH2:25][CH2:26][CH3:27]
Reactant: Cc1cc2nc3ccccc3sc-2cc1=O
Reactant: CCCCS
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCSc1c2sc3ccccc3nc-2cc(C)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methyl-phenothiazin-3-one (0.23 g) in 12 ml dichloroethane was added triethylamine (0.8 ml) and n-butanethiol (0.7 ml). The mixture was stirred at room temperature for 72 hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.22 g) was added. The mixture was stirred at room temperature for 2 hours. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was chromatographed on neutral alumina (Act III) eluting with 15% EtOAc/hexane to give the title compound (120 mg), m.p. 97° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([CH:26]=O)=[CH:24][NH:23][N:22]=2)=[CH:17][CH:16]=1>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:26]/[C:25]1[C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[N:22][NH:23][CH:24]=1
Reactant: COc1ccc(-c2n[nH]cc2C=O)cc1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: COc1ccc(-c2n[nH]cc2/C=C2\C(=O)Nc3sc(C(N)=O)cc32)cc1
Temperature: 75 °C
Yield: 52.6 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (25 mg, 0.14 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). 3-(4-Methoxyphenyl)-1H-pyrazole-4-carboxaldehyde (0.15 mmol, 28 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (2 ml) and the precipitated solid was collected by filtration and washed with water to give 27 mg of (Z)-5,6-dihydro-5-oxo-4-[[3-(4-methoxyphenyl)-1H-pyrazol-4-yl]methylene]-4H-thieno [2,3-b]pyrrole-2-carboxamide as a brown solid. MS(ES): m/e 367 [M+H].
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:18][C:19](=O)[CH2:20][C:21]1[CH:26]=[C:25]([C:27]2[O:28][C:29]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:30][N:31]=2)[CH:24]=[CH:23][C:22]=1[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH:1]1([N:6]2[C:7]3[N:8]=[C:9]([S:15][CH3:16])[N:10]=[CH:11][C:12]=3[CH:13]=[C:20]([C:21]3[CH:26]=[C:25]([C:27]4[O:28][C:29]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:30][N:31]=4)[CH:24]=[CH:23][C:22]=3[CH3:36])[C:19]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: COC(=O)Cc1cc(-c2nnc(CC(C)C)o2)ccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CSc1ncc2cc(-c3cc(-c4nnc(CC(C)C)o4)ccc3C)c(=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Yield: 40 %

Procedure:
A mixture of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (0.05 g, 0.22 mmol, from Preparation 4), [5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl]-acetic acid methyl ester (0.06 g, 0.21 mmol) and cesium carbonate (0.14 g, 0.43 mmol) in N,N-dimethylacetamide (4 mL) was heated in a microwave reactor at 100° C. for 3.5 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The combined organic phase was washed with water and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl}-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (Yield: 0.04 g, 40%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)SC)#[N:2].[NH2:17][CH2:18][CH2:19]SCC1SC=CN=1.C(N)C>C(O)C>[C:1]([NH:3][C:4]([NH:17][CH2:18][CH3:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)#[N:2]
Reactant: NCCSCc1nccs1
Reactant: CSC(=NCCSCc1nccs1)NC#N
Agent: CCN
Solvent: CCO
Product: CCNC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of N-cyano-N'-[2-(2-thiazolylmethylthio)ethyl]-S-methylisothiourea, prepared by reacting 2-[(2-aminoethyl)thiomethyl]thiazole with dimethyl-N-cyanoimidothio carbonate in ethanol by the procedure of Example 97, with ethylamine in ethanol under reflux for 8 hours gives N-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylthio)ethyl]-guanidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)c(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a 0° C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g, 11.7 mL, 0.100 mol) and H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such a rate that the internal temperature was <7° C. The resulting mixture was stirred for 1 h at 0° C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH2Cl2 (400 mL). The organic layers were washed with brine (1×500 mL), dried over Na2SO4, filtered and evaporated to give the product as a yellow oil (23.5 g, 95% yield). 1H NMR (CDCl3) δ 8.39 (t, J=7.2 Hz, 1H), 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H).