Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]=1[C:5](OC)=[O:6].Cl.[NH2:17][OH:18].[OH-].[K+]>CO>[OH:18][NH:17][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: NO
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1C(=O)NO
Yield: 101.7 %

Procedure:
Methyl 2-methoxy-5-nitrobenzoate (10 g, 47.39 mmol) and hydroxylamine hydrochloride (13.17 g, 189.56 mmol) were taken up in MeOH (100 ml) and a solution of KOH (13.27 g, 236.95 mmol) in MeOH (55 ml) was added carefully. Note—an exothermic reaction was observed; solids initially dissolved, then a solid precipitated out of solution. TLC (run in EtOAc) of an acid washed aliquot showed a trace of the starting benzoate and a new product. H2O (100 ml) was added and any undissolved solid collected by filtration off, washed with isopropyl alcohol (IPA) and dried in vacuo to give 10.23 g (>100%) of N-hydroxy-2-methoxy-5-nitrobenzamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:9]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cncc(Br)c1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromopyridin-3-ol (1.0 eq.), benzyl bromide (1.2 eq.), and silver carbonate (1.3 eq.) in toluene (0.1 M) was heated to 50° C. and stirred for 18 hours. After cooling to room temperature, the reaction mixture was filtered, eluting with ethyl acetate. The filtrate was concentrated en vacuo into a residue that was purified by a COMBIFLASH® system (ISCO) using 20% ethyl acetate in hexane to give 3-(benzyloxy)-5-bromopyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1=O.C1CNC(=O)C1.[Br:35][Br-]Br>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:35])=[CH:11][C:10]=1[CH2:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CS(C)(=O)=O)c1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1cc(C(=O)CBr)ccc1OCc1ccccc1

Procedure:
To a stirred solution of 7.7 g. of 4'-benzyloxy-3'-methylsulfonylmethylacetophenone and 2.15 g. of 2-pyrrolidinone in 300 ml. of tetrahydrofuran is added 12.5 g. of pyrrolidinone hydrotribromide (PHT) and the stirring is continued for 56 hours at room temperature. The mixture is filtered and the filtrate concentrated in vacuo to give an oil which crystallizes upon standing. The crystals are redissolved in chloroform. The chloroform solution is washed with water, dried and concentrated to yield a solid which is recrystallized from acetonitrile to give 4'-benzyloxy-2-bromo-3'-methylsulfonylmethylacetophenone, m.p. 143°-144° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:34])[CH:15]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:14]2[C:21]([CH3:33])=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:23]([CH3:26])=[C:24]([CH3:25])[C:13]=2[O:12]1.[ClH:35]>C(OCC)(=O)C>[ClH:7].[ClH:35].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:30]2[CH2:31][CH2:32][N:27]([C:22]3[C:23]([CH3:26])=[C:24]([CH3:25])[C:13]4[O:12][C:11]([CH3:34])([CH3:10])[CH:15]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[C:14]=4[C:21]=3[CH3:33])[CH2:28][CH2:29]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Reactant: Fc1ccc(CCl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(Cc3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Yield: 25 %

Procedure:
Using 4-fluorobenzyl chloride and (2,2,4,6,7-pentamethyl-3-pyrrolidinyl-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 134, the free base was obtained in the same manner as in Example 2. The free base was treated with 4N hydrogenchloride in ethyl acetate (10 mL) to obtain the title compound. Yield 25% mp. 227–232° C. (decomposition) (ethanol-ethyl acetate).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CN1C(=O)CCC1>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(O)cc2s1
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CSc1nc2ccc(Oc3ccnc4ccccc34)cc2s1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 79.7 %

Procedure:
To the reaction mixture of 2-(methylthio)benzo[d]thiazol-6-ol (750 mg, 3.79 mmol) in 10 ml of NMP was added Cesium Carbonate (3.2 g, 9.5 mmol) and stirred at RT for 3 minutes. To this mixture was added 4-chloroquinoline (682 mg, 4.17 mmol). The reaction mixture was stirred at 110° C. for 24 hours. The reaction was worked up by adding 250 ml ethyl acetate and washed with 75 ml of saturated NaHCO3, 2×60 ml water, 1×50 ml saturated NaCl, dried with sodium sulfate, filtered and concentrated in vacuo. The resulting solid residue was purified by silica gel column chromatography, eluted with (40% EtOAc:60% Hexanes) and concentrated in vaccuo to give 2-(methylthio)-6-(quinolin-4-yloxy)benzo[d]thiazole as solid (980 mg). ES/MS m/z 325.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]([OH:17])=[O:16]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][C:15]([O:17][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:16])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C(O)CBr
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21

Procedure:
Prepared according to the method of Example 15a) from 5-nitroindole (0.207 g) and 2-bromoaceticacid, 1,1 -diemthylethyl ester (0.23 ml) to leave sub-title compound as a yellow oily solid (0.29 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[C:16]([CH3:22])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][C:16]([CH3:22])=[C:17]([CH3:21])[CH:18]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(N2CCNCC2)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (10 g), 1-Boc-piperazine (8.6 g) and potassium carbonate (13 g) was added 2-butanone (140 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g). To a mixture of 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g), palladium (II) acetate (516 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.9 g), potassium fluoride (24 g) and methylboronic acid (12 g) was added tetrahydrofuran (140 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g). 4-(3,5,6-Trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in chloroform (28 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (11 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:6]([CH2:14][C:15]([N:17]([O:19][CH3:20])[CH3:18])=[O:16])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=[CH2:5].S(OC)(O[CH3:25])(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:20][O:19][N:17]([CH3:18])[C:15](=[O:16])[CH2:14][N:6]([C@@H:3]([CH:4]=[CH2:5])[CH2:2][O:1][CH3:25])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: COS(=O)(=O)OC
Reactant: C=C[C@@H](CO)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C[C@@H](COC)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of (S)-tert-butyl 1-hydroxybut-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 250, 7 g, 24.28 mmol) in THF (75 mL) at 0° C. was added dimethyl sulfate (2.436 mL, 25.49 mmol) followed by LiHMDS (26.7 mL, 26.70 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for two hours. The reaction mixture was then partitioned between ethyl acetate and water. The layers were separated and the organics were washed with saturated sodium bicarbonate, water and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (5%-30% ethyl acetate/hexanes) afforded the title compound as a clear oil (6.89 g, 91%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]
Reactant: O=C(O)c1cnccn1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2cnccn2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-pyrazinecarboxylic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 12.34 (s, 1H), 9.50 (d, J=1.2, 1H), 8.91 (d, J=9.0, 1H), 8.84 (d, J=2.4, 1H), 8.72-8.70 (m, 1H), 7.75 (d, J=3.0, 1H), 7.33-7.28 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC3CC3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC5CC5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-4-(4-cyclopropylmethyl-piperazin-1-yl)-3-nitro-pyridin-2-ylamine (0.043 g, 0.12 mmol) and EtOH (3 ml) was added 4-methoxybenzaldehyde (0.027 g, 0.18 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was stirred at 70° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 4%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.012 g, 23%). 1H-NMR (500 MHz, DMSO-d6) 0.12 (m, 2H) and 0.50 (m, 2H) (cyclopropyl CH2), 0.90 (m, 1H, cyclopropyl CH), 2.27 (d, J=6.4 Hz, 2H, N—CH2cyclopropyl), 2.67 (br s, 4H, piperazine N(CH2)2), 3.66 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.8 Hz, 2H) and 8.14 (d, J=8.8 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)C1C=CC=CC=1.O1CCCC1>C(Cl)(Cl)Cl.[OH-].[Pd+2].[OH-].[C]>[F:16][C:13]([F:14])([F:15])[C:11]1[NH:10][C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([CH3:35])([CH3:36])[C:32]([OH:34])=[O:33])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[N:8][CH:12]=1
Reactant: CC(C)(COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3Cc3ccccc3)cc2)cc1)C(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cc2)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 6 h
Yield: 93.6 %

Procedure:
The mixture of 3-({4′-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]biphenyl-4-yl}oxy)-2,2-dimethylpropanoic acid (830 mg), 20% palladium hydroxide-carbon (850 mg) and tetrahydrofuran (20 mL) was stirred at 60° C. under hydrogen atmosphere for 6 hours. Nitrogen gas was passed through the reaction mixture, and the mixture was diluted with chloroform. The mixture was filtered by using a membrane filter, and the filtrate was washed with tetrahydrofuran, methanol and chloroform. The filtrates were combined, and n-hexane and propanol were added to the residue obtained by concentrating the same under the reduced pressure. The precipitated solid was collected by filtration to obtain 3-({4′-[5-(trifluoromethyl)-1H-imidazol-2-yl]biphenyl-4-yl}oxy)-2,2-dimethylpropanoic acid (635 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:20])[NH:15][CH2:16][C@H:17](O)[CH3:18])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[C:9]([O:13][C:14](=[O:20])[NH:15][CH2:16][C@@H:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:18])([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(Br)cc1
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](CNC(=O)OC(C)(C)C)Oc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Bromophenol (0.33 g, 1.88 mmol), ((R)-2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.33 g, 1.88 mmol) and triphenylphosphine (0.74 g, 2.82 mmol) were dissolved in anhydrous toluene. A solution of di-tert-butyl azodicarboxylate (0.65 g, 2.82 mmol) in toluene (5 ml) was added slowly ensuring that the temperature did not exceed 35° C. The reaction mixture was heated to 80° C. and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and subsequently washed with 1M HCl, water, then brine and dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield: 0.62 g, 100. LCMS method: 2, RT: 6.18 min; MI: 330-332 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[C:13]([C:14](O)=[O:15])[C:12]([OH:18])=[C:11]([I:19])[CH:10]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.CC([N:35]=C=NC(C)C)C.C(=O)(O)[O-].[NH4+]>C(#N)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[C:13]([C:14]([NH2:35])=[O:15])[C:12]([OH:18])=[C:11]([I:19])[CH:10]=1
Reactant: CC(C)N=C=NC(C)C
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Agent: O=C([O-])O
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1cc(-c2ccc(F)cc2F)cc(I)c1O

Procedure:
1 g (2.66 mmol) of 5-(2,4-difluorophenyl)-3-iodo-salicylic acid was mixed with 0.738 g (4.01 mmol) of pentafluorophenol in 20 ml of acetonitrile. 10 ml of N,N-diisopropylcarbodiimide was added at 0° C. and it was stirred continuously. 0.634 g of ammonium bicarbonate was dissolved in water. Consumption of the starting product was confirmed by HPLC and the crude was diluted with water and extracted with dichloromethane. The organic phase was dried over magnesium sulphate and purified on a silica gel column, using chloroform and methanol as eluents, in increasing polarity beginning with a proportion (v/v) of (40:1) up to (10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.C(OC(N1C[C@@H](S)C[C@H]1CN[C:32]([C:34]1[S:35][C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:38]=1)=[O:33])=O)C=C>C(#N)C>[CH2:42]([O:41][C:39]([C:36]1[S:35][C:34]([C:32](=[O:33])[NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:38][CH:37]=1)=[O:40])[CH3:43]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNC(=O)c1ccc(C(=O)OCC)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 90 %

Procedure:
Starting material (12(e)) was prepared as follows. To a stirring solution of 3,4-dichlorobenzylamine (0.53 mL; 4.0 mmole) in acetonitrile (10 mL) was added triethylamine (1.67 mL; 12.0 mmole) and a solution of (11(a)) (0.87 g; 4.0 mmole. see Example 11) in acetonitrile (20 mL). The solution was stirred at ambient temperature, under argon, for 22 hours. The solvent and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and brine, dried over magnesium sulphate and vacuumed to dryness to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid ethyl ester (12(a)) as a cream solid (90%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].C1N2CN3CN(C2)C[N:22]1C3>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:22]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C

Procedure:
To 1350 ml. of ethanol there was added 90 gm. of 2-chloroacetamido-5-chlorobenzophenone and 92.5 gm. of hexamethylenetetramine. Ammonia was bubbled through the resultant medium under a pressure. The resultant medium was heated to reflux. The resultant reaction medium was evaporated in vacuum to dryness. It was triturated then with 250 ml. of hot water twice on a steam bath. The aqueous phase was removed by decantation. The crystalline residue was heated for 30 minutes in 250 ml. of toluene on a steam bath and then cooled to room temperature. The crystals which formed were filtered, washed twice with 25 ml. of toluene and 25 ml. of petroleum ether and dried to constant weight yielding 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one melting point 213°-215° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[C:12]=[O:13])[C:10]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=[C:4]1[C:5]([OH:7])=O.[NH2:25][C:26]1[C:34]2[N:33]=[C:32]([CH3:35])[N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1.OS1C2C=CC=CC=2N=C1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH:3]1[C:11](=[C:12]=[O:13])[C:10]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=[C:4]1[C:5]([NH:25][C:26]1[C:34]2[N:33]=[C:32]([CH3:35])[N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:7]
Reactant: COC1C(=C=O)C(N2CCCCc3ccccc32)=CC=C1C(=O)O
Reactant: Cc1nc2c(N)cccc2n1C(=O)OC(C)(C)C
Agent: O[SH]1C=Nc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1C(=C=O)C(N2CCCCc3ccccc32)=CC=C1C(=O)Nc1cccc2c1nc(C)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
A mixture of 2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-carbonylbenzoic acid (200 mg), 4-amino-1-tert-butoxycarbonyl-2-methyl-1H-benzimidazole (152 mg), WSCD·HCl [water soluble carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 141 mg] and 1-hydroxybenzotiazole (100 mg) in N,N-dimethylformamide (5 ml) was stirred at room temperature overnight, and the mixture was diluted with ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogencarbonate solution, water, and brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography using chloroform as an eluent to give 2-methoxy-N-[2-methyl-1-(tert-butoxycarbonyl)-1H-benzimidazol-4-yl]-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-carbonylbenzamide (185 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([NH2:20])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([NH:20][C:42](=[O:44])[CH3:43])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(N)nc2CCN1C(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(NC(C)=O)nc2CCN1C(=O)OCc1ccccc1

Procedure:
To an-ice cooled solution of (±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (50 mg, 100 μmol, 1 eq.) and NEt3 (69 μL, 500 μmol, 5 eq.) in DCM (1 mL), acetyl chloride (14 μL, 200 μmol, 2 eq.)
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:7]2=[O:14].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:32])([F:20])[F:33])=[CH:27][CH:26]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:14])[N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[CH:5]=[CH:4]2
Reactant: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1N
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-amino-6-methoxy-1-oxoisoquinolin-2(1H)-yl)propanamide (98.34 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at room temperature overnight. the solvent was removed under reduced pressure and the residue purified by reverse phase preparative HPLC to afford the product as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[C:16]1([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:25]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:23][NH:24][C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)NCC(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 2,2-diphenylethylamine (11.8 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.0 mg). Calcd for C25H22N2O2: 382.1681, found 382.1682.