Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][OH:24])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][O:24][S:38]([CH3:37])(=[O:40])=[O:39])[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)c1ccc(C(C)(COS(C)(=O)=O)C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
A solution of 1.2 g (3.0 mmol) of 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one in 20 ml of tetrahydrofuran was mixed with 1.3 ml of (9.3 mmol) of triethylamine at room temperature. Subsequently, 0.27 ml (3.5 mmol) of methanesulfonylchloride were dropped to the reaction mixture at 2-5° C. The formed precipitate was filtered after 2 hours at room temperature and the filtrate evaporated down. The raw product was further processed without purification.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][C:4]1([F:27])[F:26].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][C:4]1([F:27])[F:26]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2)CC1(F)F
Solvent: CC(=O)Cl
Solvent: CSC
Product: NC(=O)CC[C@H]1CN(c2ccc(N3CCC(=O)C(F)(F)C3)cc2)C(=O)O1
Temperature: 40 °C
Reaction time: 96 h
Yield: 71 %

Procedure:
The mixture of (S)-{3-[4-(4,4-dimethoxy-3,3-difluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), freshly fused zinc chloride (3.1 mmol), dimethyl sulphide (5.1 mmol), acetyl chloride (3.1 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. The reaction mixture was extracted with ethyl acetate water mixture and the organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel to give title compound in 71% yield.
Reaction SMILES: [C:1](CCSCCC#N)#[N:2].[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[N:25]=[N:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([N+:36]([O-:38])=[O:37])=[CH:29][C:28]=1Br)[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=[O:12])[CH3:11].[C-]#N.[Na+]>O>[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[N:25]=[N:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([N+:36]([O-:38])=[O:37])=[CH:29][C:28]=1[C:1]#[N:2])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=[O:12])[CH3:11]
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: N#CCCSCCC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 60 °C
Reaction time: 0.42 h

Procedure:
Into a reactor there are introduced 765 parts of bis-(β-cyanoethyl) sulfide, followed by 14.35 parts of cuprous bromide. On heating to 60° C. with continuous stirring, a brownish-yellow solution of the copper complex is obtained. 95.8 parts of 3-acetamido-4-(2'bromo-4',6'-dinitrophenylazo)N,N-diethylaniline are added, and the temperature is raised to 115° C. Raising the temperature to 115° C. causes the compound to completely dissolve. At ths temperature, a solution of 10.8 parts of sodium cyanide in 40 parts of water is introduced into the reactor during a period of 20 minutes, allowing the steam to escape. Stirring is continued for a further 20 to 30 minutes while verifying by thin layer chromatography that the starting organic bromo-derivative is absent. The reaction mass is cooled to 30-35° C., which causes crystallization of the dyestuff. The resultant product is filtered off, washed with water to displace the solvent contained in the paste, and dried. 80.2 parts of 3-acetamido-4 -(2'-cyano-4',6'-dinitro-phenylazo)-N,N-diethylaniline are obtained. The titre (purity) of this product is 98.5% and it contains a copper concentration of less than 3000 parts per million. The wash water is introduced into a decanter, and the organic solvent part is withdrawn and reunited with the fraction of solvent obtained during filtration. There are thus recovered 720 parts of bis-(β-cyanoethyl) sulfide which contain 4.35 parts of the cyanoazo dyestuff (giving an overall balance of the reaction of 98%) and 5.75 parts of copper (which corresponds to a recovery of 91% of the initial copper complex.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[N:3]=[CH:4][N:5]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Solvent: C1CCOC1
Product: CN1CCN(c2cc(Cl)ncn2)CC1
Reaction time: 18 h
Yield: 84.2 %

Procedure:
4,6-dichloropyrimidine, (2 g, 13.4 mmol), and N-methylpiperazine, (1.5 mL, 13.4 mmol), were dissolved in 20 mL THF along with TEA (1.9 mL, 13.4 mmol) and stirred for 18 h. The THF was evaporated and 10 mL water was added and then extracted with DCM. The DCM was dried with sodium sulfate, filtered and evaporated affording 2.4 g of 4-Chloro-6-(4-methyl-piperazin-1-yl)-pyrimidine as a yellow waxy solid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27](CC4C=CC=CC=4)[CH2:26]3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[N:22]1([CH:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:21][CH2:20][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:24][CH2:23]1
Reactant: [H][H]
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCCN(Cc5ccccc5)C4)CC3)nc3ccccc32)cc1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(Cn2c(NC3CCN(C4CCCNC4)CC3)nc3ccccc32)cc1
Yield: 91.5 %

Procedure:
A mixture of 11.3 parts of 1-[(4-fluorophenyl)methyl]-N-[1'-(phenylmethyl)-[1,3'-bipiperidin]-4-yl]-1H-benzimidazol-2-amine and 200 parts of methanol was hydrogentated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 8.5 parts (91.5%) of N-([1,3'-bipiperidin]-4-yl)-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine (intermediate 72).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1[NH:11][CH2:12][C:13]([NH2:15])=[O:14].[NH4+].[Cl-]>CC(O)C>[NH2:10][C:9]1[C:5]2[C:4](=[C:3]([Br:2])[CH:8]=[CH:7][CH:6]=2)[NH:11][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: N#Cc1cccc(Br)c1NCC(N)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CC(C)O
Product: NC(=O)c1[nH]c2c(Br)cccc2c1N
Temperature: 0 °C
Yield: 79.5 %

Procedure:
1.17 g (50.9 mmol) sodium was dissolved in 150 ml 2-propanol. Then, 10.82 g (42.6 mmol) 2-(2-bromo-6-cyano-phenylamino)acetamide was added and the solution was refluxed for 15 min. Thereafter, the reaction mixture was cooled to 0° C. and saturated NH4Cl solution was added. The solvent was concentrated, the resulting precipitate was sucked off and washed with water. 8.6 g (79%) 3-amino-7-bromo-1H-indole-2-carboxylic acid amide was obtained. ESI-MS [m/z]: 254, 256 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 2-(4-methoxyphenyl)ethaneamine (500 mg, 3.31 mmol), 4′-chloro[1,1′-biphenyl]-4-carboxylic acid (846 mg, 3.64 mmol) and 1-hydroxybenzotriazole (760 mg, 4.96 mmol) in dimethylformamide (10 ml) was added ethyldimethylaminopropylcarbodiimide hydrochloride (951 mg, 4.96 mmol) at 0° C., and the mixture was was stirred at room temperature for 16 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the title compound (1.03 g).
Reaction SMILES: [CH2:1]([N:3]([C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][N:32]=1)=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[N:32][CH:33]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cn1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C)cn1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 101.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(5-hydroxypyridine-2-carbonyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N,N-dimethylacetamide (12 mg) following the synthetic method of Example 404 described below and purified by LC-MS, the title compound (24 mg) was obtained. ESI-Mass; 476 [M++H]
Reaction SMILES: C([O:8][C:9](=[O:39])[C@@H:10]([NH:23][C:24](=[O:38])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[CH2:11][CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])C1C=CC=CC=1.[NH2:40][CH2:41][C@@H:42]([C:44]1[CH:45]=[CH:46][C:47]([OH:55])=[C:48]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:49]=1)[OH:43]>>[OH:43][C@H:42]([C:44]1[CH:45]=[CH:46][C:47]([OH:55])=[C:48]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:49]=1)[CH2:41][NH:40][CH:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([NH:23][C@@H:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:39])=[O:8])=[O:38])=[CH:26][CH:27]=2)[CH2:36][CH2:35]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from (2S)-2-[4-(4-oxo-piperidine-1-yl)-benzoylamino]-pentanedioic acid dibenzyl ester (which was obtained in Example 156) and N-[ 5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; mp >230° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.60 (m, 2H), 1.90-2.10 (m, 4H), 2.31 (t, J=7.5 Hz, 2H), 2.65-3.20 (m, 7H), 3.00 (s, 3H), 3.85-4.00 (m, 2H), 4.25-4.35 (m, 1H), 4.65-4.80 (m, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.7 Hz, 2H), 7.08 (dd, J=8.4, 1.2 Hz, 1H), 7.25 (d, J=1.8 Hz, 1H), 7.74 (d, J=8.7 Hz, 2H), 8.14 (d, J=7.2 Hz, 1H); MS (ES) m/z: 579.1 (MH+); HRMS Calcd. for C26H35N4O9S(MH+): 579.1973. Found: 579.1955.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21](C3C=CC(C(OC)=O)=CC=3)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7].Br[C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1>>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:19][CH2:20][N:21]([C:42]3[CH:41]=[CH:40][CH:49]=[CH:48][C:43]=3[C:44]([O:46][CH3:47])=[O:45])[CH2:22][CH2:23]2)[CH2:14]1)=[O:11])=[O:7]
Reactant: COC(=O)c1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Reactant: COC(=O)c1ccc(Br)cc1
Product: COC(=O)c1ccccc1N1CCC(N2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was synthesized in similar fashion to methyl 4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidin-1-yl)benzoate, substituting methyl 2-bromobenzoate for methyl 4-bromobenzoate, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.80-2.01 (m, 3H), 2.25-2.45 (m, 2H); 2.51-3.00 (m, 6H), 3.25-3.41 (m, 2H), 3.31-3.45 (m, 2H), 3.87 (s, 3H), 4.05-4.40 (m, 2H), 4.60-4.75 (m, 1H), 6.98-7.20 (m, 1H), 7.20-7.24 (m, 2H), 7.30-7.42 (m, 2H), 7.50-7.60 (m, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.98-8.10 (m, 1H), 8.16 (s, 1H), 8.18-8.30 (m, 1H). MS m/z: 533 (M+1).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH:23]2[N:28]([C:29](=[O:38])[NH:30][C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)[CH:16]=1>>[ClH:1].[ClH:1].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH:23]2[CH2:24][NH:25][CH2:26][CH2:27][N:28]2[C:29]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)=[O:38])[CH:16]=1
Reactant: Cc1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2CCc2cccnc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)N2CCNCC2CCc2cccnc2)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 3-(2-(pyridin-3-yl)ethyl)-4-(p-tolylcarbamoyl)piperazine-1-carboxylate TFA salt (133.9 mg, 0.248 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 89.3 mg (90%) of the desired product as a white solid. LC-MS: RT=3.16 min, [M+H]+=325.2.
Reaction SMILES: [CH2:1]=[O:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH:16]3[CH2:18][CH2:17]3)[C:12](=[O:15])[NH:13][N:14]=2)=[CH:6][CH:5]=1>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]([CH:16]3[CH2:18][CH2:17]3)[C:12](=[O:15])[N:13]([CH2:1][OH:2])[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: C=O
Solvent: O
Product: O=c1n(CO)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7 ml of a 37% strength solution of formaldehyde in water were added to 1000 mg (4.24 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A], and the mixture was stirred at RT for 20 h. The precipitated solid was filtered off with suction and washed with water. Drying under high vacuum gave 878 mg (62% of theory) of the target compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=O)[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:8]1[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[CH3:1])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[N:9]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1
Yield: 80 %

Procedure:
The solution of methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (5.9 g, 20.54 mmol,) in phosphorus oxychloride (100 mL) was stirred overnight at 120° C. in an oil bath. The reaction mixture was concentrated in vacuo and diluted with dichloromethane (500 mL) and ice-water (500 mL), adjusted to pH 7 with NaHCO3 solution. The solution was extracted with dichloromethane (3×200 mL) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 2-chloro-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate as a yellow solid (5 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)[CH:3]=1
Reactant: Cc1ccnc(OC2CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1ccnc(OC2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(4-methyl-pyridin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.Cl.[O:10]([C:17]1[C:18]([NH:33][C:34]2[S:35][CH:36]=[C:37]([CH2:39][CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:38]=2)=[N:19][CH:20]=[C:21]([S:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[CH:31][S:32][C:25]=23)[CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[O:10]([C:17]1[C:18]([NH:33][C:34]2[S:35][CH:36]=[C:37]([CH2:39][CH:40]3[CH2:45][CH2:44][N:43]([C:1](=[O:3])[CH3:2])[CH2:42][CH2:41]3)[N:38]=2)=[N:19][CH:20]=[C:21]([S:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[CH:31][S:32][C:25]=23)[CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)cs2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Cc2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Added acetic anhydride (0.0169 g, 0.165 mmol) to a mixture of 3-phenoxy-N-(4-(piperidin-4-ylmethyl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine dihydrochloride (0.100 g, 0.165 mmol), triethylamine (0.0837 g, 0.827 mmol), and THF (5 mL) at 0° C. Warmed to ambient temperature and stirred for 4 hours. Partitioned between ethyl acetate and 2N NaOH, washed with water, brine, dried, and concentrated. The residue was dissolved in dichloromethane (2 mL) and 1N HCl in ether was added. Diluted in hexanes, and concentrated, added hexanes again and concentrated to afford the title compound ((Mixture of rotamers; 0.092 g, 91.2% yield) as a light yellow powder: 1H NMR (d6-DMSO) δ 8.65 (d, 1H); 8.47 (d, 1H), 8.46 (s, 1H), 7.77 (d, 1H), 7.41 (s, 1H), 7.41 (d, 2H), 7.15-7.20 (m, 4H), 6.84 (s, 1H), 0.95-4.36 (m, 1H), 1.97 (s, 3H).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])[CH:21]=[CH:22][CH:23]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:25]3[N:26]=[C:27]([CH3:29])[O:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[O:31])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c(-c2cccc(Cl)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=1>CCO>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1cccc(Sc2ccc(C)cc2N)c1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3cccc(NC(C)=O)c3)ccnc2n1
Temperature: 80 °C
Yield: 74.7 %

Procedure:
The title compound was prepared from the product of Example 2g (750 mg, 3.63 mmol), and the product of Example 199c (988 mg, 3.63 mmol) combined in 10 mL of EtOH and heated to 80° C. for 40 hrs. After cooling to room temperature the solvent was removed under vacuum giving the title compound (1.2 g, 74%).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[C:30]3[C:29](=O)[CH2:28][CH2:27][CH2:26][C:25]=3[NH:24][C:23]=2[CH3:32])=[CH:17][CH:16]=1.Cl.[NH2:34][OH:35]>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[C:30]3[C:29](=[N:34][OH:35])[CH2:28][CH2:27][CH2:26][C:25]=3[NH:24][C:23]=2[CH3:32])=[CH:17][CH:16]=1
Reactant: NO
Reactant: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=O)CCC2
Agent: Cl
Solvent: CCO
Solvent: CCCCN(CCCC)CCCC
Product: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=NO)CCC2
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Tributylamine (6.6 mL 28 mmol) was added to a stirred suspension of 3-(4-chlorophenylsulfanyl)-2-methyl-4,5,6,7-tetrahydro-1H-indol-4-one (8.0 g, 27 mmol) and hydroxylamine hydrochloride (1.9 g, 27 mmol) in ethanol (40 mL). The mixture was heated to 65° C. and maintained at this temperature for 4 h then allowed to cool to r.t. and left overnight. Additional hydroxylamine hydrochloride (0.15 g, 2.2 mmol) and tributylamine (1.0 mL, 4.2 mmol) were added and the mixture was re-heated to 65° C. for a further 2 h. After cooling to r.t., the solid product was collected by filtration, washed with ethanol (2×10 mL) then dried in a vacuum oven at 40° C. to give the title compound as an off-white solid; 5.71 g (68%); purity: 96.3 area % by HPLC; m/z: 307/309 (MH+); 1H-NMR: 11.26 (1H, s), 10.20 (1H, s), 7.23 (2H, m), 6.92 (2H, m), 2.62-2.58 (2H, m), 2.56-2.52 (2H, m), 2.12 (3H, s), 2.83-1.76 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][CH2:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:41](I)[CH:42]=[CH2:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)[CH2:16][C@H:15]([CH2:43][CH:42]=[CH2:41])[C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:29][CH:30]=1
Reactant: O=C1CC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
A solution of (R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (67 mg, 0.155 mmol) in THF (1 mL) is cooled to 0° C., then LiHMDS (0.31 mL, 1.0 M in THF, 0.31 mmol) is added. After addition, the resulting solution is further stirred at 0° C. for 45 min. Then allyl iodide (52 mg, 0.31 mmol) is added at 0° C. The resulting mixture is stirred at 0° C. for 1 h and 45 min, then the reaction is quenched with saturated NH4Cl solution (0.2 mL). THF is removed by evaporation and then the residue is dissolved in CH2Cl2 (40 mL), washed with brine (10 mL) and dried over Na2SO4. After concentration, the residue is purified on silica gel (0-50% ethyl acetate in hexane) to give (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (58.5 mg, 80%) and its (3R)-diastereomer (6.5 mg, 9%) as a colorless oil. HPLC-MS calculated for C26H21ClF3NO2 (M+H+) 472.12, found 472.10.