Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[C:34]2=[O:45])[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[C:34]2=[O:45])[S:28][C:29]=1[C:30]([NH2:7])=[O:31]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(N)=O
Yield: 52 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)-imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 52% yield: 1H NMR (300 MHz, CDCl3) δ 5.58 (s, 2H), 4.17-4.11 (m, 2H), 3.64-3.59 (m, 2H), 3.44-3.39 (m, 2H), 2.61 (s, 3H), 2.22-2.08 (m, 2H), 1.92-1.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ164.3, 157.7, 155.6, 155.5, 153.8, 128.6, 124.9, 116.9, 42.9, 42.3, 42.0, 31.8, 31.4, 30.9, 30.6, 20.2, 20.1, 17.3; MS (ES+) m/z 336.8 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][S:28][Si](C(C)C)(C(C)C)C(C)C)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][SH:28])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CS[Si](C(C)C)(C(C)C)C(C)C)cc3)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CS)cc3)cc2)CC1
Reaction time: 0.08 h

Procedure:
The mixture from Step 1 was dissolved in THF and tetrabutylammonium fluoride (1.0 M in THF, 2.27 mL, 2.27 mmol) was added. The reaction stirred for 5 minutes and was then submitted to standard aqueous workup and purification via silica gel chromatography to yield the title compound.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.O=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH2:21][N:20]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCC=C3)cc1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC=Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2,3-dip-tolyl-5,6-dihydropyrido[2,3-b]pyrazine (Example 8.2 step 1) (3.88 g, 12.38 mmol) in DCE (70 ml) was added ethyl 7-oxoheptanoate (6.40 g, 37.1 mmol) followed by sodium triacetoxyborohydride (10.4 g, 49.1 mmol). The reaction mixture was stirred for 2 days at room temperature under an atmosphere of nitrogen. The reaction mixture was diluted with water (70 ml) and extracted with EtOAc (3×70 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc/iso-hexane, followed by further purification using reverse phase chromatography eluting with MeCN/water (0.1% TFA) to afford the title compound;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:5])[CH3:2]
Reactant: COCCN
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(NCCOC)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
To 2.4 g. (0.006 mole) of 5-chloro-7,8-dihydro-8-(2-methoxyethyl)-7-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in 100 ml. of ethanol was added 0.45 g. (0.006 mole) of 2-methoxyethylamine and 0.65 g. (0.006 mole) of Na2CO3. This mixture was refluxed 3 hours, then filtered and the filtrate chilled. A solid formed amd was filtered off and rinsed with petroleum ether--m.p. 160°-163° C. No further purification was necessary.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1>C(Cl)Cl.CO>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[N:22][CH:23]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cn1
Yield: 69 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 2-aminopyridine-5-boronic acid pinacol ester with the reaction time of 15 h. Chromatography (methylene chloride/methanol 97:3) gave 69% of the title compound as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13](O)=[O:14].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:18]([O:17][C:11](=[O:16])[CH2:12][C:13]([NH:10][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:9])=[O:14])[CH3:19]
Reactant: CCOC(=O)CC(=O)O
Reactant: C[C@@H](N)c1ccc(Br)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a magnetically stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.51 g, 2.55 mmol) in anhydrous CH2Cl2 under argon and cooled to 0° C., were added ethyl hydrogen malonate (0.4 g, 3.06 mmol) EDC.HCl (0.58 g, 3.06 mmol) and HOBt (0.41 g, 3.06 mmol). The resulting solution was stirred at 25° C. overnight. CH2Cl2 was evaporate and residue partitioned between EtOAC and 1 N HCl. The organic layer was washed with H2O, brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (40% EtOAc in hexanes) to provide the desired product (0.57 g, 71%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6]([C:9]1[N:13]=[CH:12][NH:11][N:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18](Cl)=[O:19])[CH:15]=[CH2:16].C(N(CC)CC)C>O1CCCC1>[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18]([N:11]1[CH:12]=[N:13][C:9]([S:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:8])=[O:7])=[N:10]1)=[O:19])[CH:15]=[CH2:16]
Reactant: CCOCCS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCOCC)n1

Procedure:
A solution of 4.1 g. 3-(2-ethoxyethylsulphonyl)-1,2,4-triazole, 3.5 g. diallylcarbamoyl chloride and 4 ml. triethylamine in 40 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 15 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The residue was triturated with petroleum ether (b.p. 40°-60° C.) to give a solid product. This product was collected and recrystallised from ether/petroleum ether b.p. 40°-60° C. to give 1-diallylcarbamoyl-3-(2-ethoxyethylsulphonyl)-1,2,4-triazole, m.p. 62°-63° C. Elemental analysis satisfactory.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CCCCO>[OH:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Oc1cccc(Cl)n1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(O)n2)CC1
Temperature: 140 °C
Yield: 71.2 %

Procedure:
To 2-chloro-6-hydroxypyridine (12.3 g, 94 mmol) in n-BuOH (50 mL) was added t-butyl piperazine-1-carboxylate (46.0 g, 235 mmol). The mixture was heated at 140° C. for 3 days. The reaction mixture was extracted with ethyl acetate (1.5 L) and washed with saturated NH4Cl solution and then brine. The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. The resulting solid was dissolved by CH3CN (100 mL) and precipitated by adding water (1 L). The precipitate was filtered, washed with water and ether. The organic layer of the filtrate was separated and concentrated under reduced pressure. The residue was purified by column chromatography (50%-100% EtOAc/hexanes). A total of 18.7 g (71%) of t-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate was obtained as a white solid. MS m/z 280.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.40 (1H, m), 6.04 (1H, d, J=8.8 Hz), 5.64 (1H, d, J=7.2 Hz), 3.62 (4H, m), 3.36 (4H, m), 1.51 (9H, s).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH2:9])=[O:8])[CH:2]=1.[Cl:11][C:12]([Cl:16])([CH3:15])[CH:13]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH2:13][C:12]([Cl:16])([Cl:11])[CH2:15][NH:9][C:7](=[O:8])[C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1cccc(C(N)=O)c1
Reactant: CC(Cl)(Cl)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cccc(C(=O)NCC(Cl)(Cl)Cn2nnc3ccccc32)c1

Procedure:
A suspension of m-toluamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]([NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:13])[CH2:7]2)(=O)[CH3:2]>C(O)C.Cl.[Pd]>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]([NH:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH2:7]2)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(C)(NC(=O)c1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCc1ccc2c(c1)CC(C)(NC(=O)c1ccccc1)C2

Procedure:
A solution of N-(5-acetyl-2-methyl-indan-2-yl)-benzamide (3.4 g) in ethanol (200 ml) and conc. HCl (2 ml) is stirred under hydrogen in the presence of 10% Pd/C at room temperature for 48 hours. The mixture is filtered through celite and the filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[SH:23]>>[N+:10]([C:3]1[CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[S:6][C:2]=1[S:23][C:14]1[CH:15]=[N:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1cnc2ccccc2n1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2cnc3ccccc3n2)s1

Procedure:
Prepared according to the procedure described for example 18 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (250 mg, 1.215 mmol) and quinoxaline-2-thiol (197 mg, 1.215 mmol). The title compound was obtained as a solid (200 mg, 50% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.26 (1H, s), 8.63 (1H, s), 8.01 (1H, m), 7.98 (1H, m), 2.61 (3H, s). MS m/z: 331.88 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 30 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-butyl chloroformate. Yield: 30% of theory, C31H35N7O5 (585.7) Rf value: 0.62 (silica gel; dichloromethane/methanol=9:1) ##EQU75##
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27]O)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27][Br:32])[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)Oc1cccc(C(=O)N2CCC(CCO)(c3ccc(C(F)(F)F)cc3)C2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)Oc1cccc(C(=O)N2CCC(CCBr)(c3ccc(C(F)(F)F)cc3)C2)c1
Reaction time: 1 h

Procedure:
Combine 2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethanol (10 mmol), carbon tetrabromide (12.5 mmol), and dichloromethane (15 mL). Cool in an ice bath. Add in portions, triphenylphosphine (15 mmol). After 1 h, concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[O:20][C:19]([CH2:21][N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[CH2:21][C:19]1[O:20][C:16]([CH2:15][O:14][CH2:13][CH2:12][CH2:11][NH:10][C:3]([S:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:17][CH:18]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(COCCCN)o1
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCCOCc1ccc(CN(C)C)o1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a stirred solution of 1,1-bis(methylthio)-2-nitroethene (3.96 g) in dry dioxan (25 ml) at 70° was added dropwise 5-[(3-aminopropoxy)methyl]-N,N-dimethyl-2-furanmethanamine (1.27 g). After 1 hr the reaction was allowed to cool and the solid which separated was filtered. The filtrate and washings were combined and evaporated to dryness, a solution of succinic acid (1 g) in water (25 ml) added to the residue and the suspension filtered. The filtrate was washed with ethyl acetate (2×40 ml) then evaporated to 10 ml. The solution was basified with sodium carbonate and the oily precipitate which separated was extracted into ethyl acetate (3×25 ml). The combined extracts were dried (anhyd. sodium carbonate), the suspension filtered and evaporated to dryness to yield the title compound (1.34 g) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([N:17]4[CH2:21][CH2:20][CH2:19][C:18]4=[O:22])[CH:14]=[CH:15][CH:16]=3)[C:5]2=[N:6][CH:7]=1.[C:23]([O:26][CH2:27][CH3:28])(=O)[CH3:24]>>[O:26]1[CH:27]=[CH:28][C:24]([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([C:11]4[CH:12]=[C:13]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])[CH:14]=[CH:15][CH:16]=4)[C:5]3=[N:6][CH:7]=2)=[CH:23]1
Reactant: O=C1CCCN1c1cccc(-n2cnc3cc(Br)cnc32)c1
Reactant: CCOC(C)=O
Product: O=C1CCCN1c1cccc(-n2cnc3cc(-c4ccoc4)cnc32)c1

Procedure:
The title compound was prepared from 1-[3-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]pyrrolidin-2-one as described in Example 1. Free base, yellow crystals, m.p. 208-210° C. (from ethyl acetate); δH (360 MHz, d6-DMSO) 2.11 (2H, quin, J 7), 2.54 (2H, t, J 8), 3.93 (2H, t, J 7), 7.16 (1H, s), 7.60 (1H, t, J 8), 7.68-7.71 (1H, m), 7.78-7.81 (2H, m), 8.28 (1H, t, J 2), 8.35 (1H, s), 8.48 (1H, s), 8.76 (1H, s), 8.90 (1H, s); m/z (ES+) 345 (M++H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:18][CH2:19]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1

Procedure:
A mixture of tert-butyl ({trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methyl)carbamate (0.32 g, 0.79 mmol) and 10% palladium on carbon (0.01 g) in methanol (3 mL) was hydrogenated under balloon pressure of hydrogen at room temperature for 2 h. The mixture was filtered and concentrated to give the desired product (0.3 g, 100%) to be used in the next step directly. LCMS calculated for C19H29N4O2S (M+H)+: m/z=377.2. Found: 377.1.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1.Cl.[OH-].[Na+]>O.CO.C(O)C>[NH2:28][C:24]1[N:25]=[C:26]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([CH2:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[CH:22][N:23]=1
Reactant: N#Cc1c[nH]c2nccc(Cc3ccc(N)cc3F)c12
Reactant: Nc1nccc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: N#Cc1c[nH]c2nccc(Cc3ccc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
120 mg (0.45 mmol) of 4-(4-amino-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 64 mg (0.50 mmol) of 4-chloropyrimidine-2-amine are suspended in 4 ml of water, 2 ml of ethanol and 0.23 ml of 4N hydrochloric acid. The reaction mixture is heated at reflux for 2 hours. After cooling, the mixture is made alkaline using dilute aqueous sodium hydroxide solution, a little methanol is added, the mixture is extracted with ethyl acetate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC. This gives crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]([NH:18][NH2:19])=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[C:22](=S)=[S:23].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[O:17][C:22]([SH:23])=[N:19][N:18]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
The compound from Example 156 (100 mg, 0.31 mmol) was suspended in ethanol (2 ml) and cooled to 0° C. Carbon disulfide (0.04 ml, 0.71 mmol) was added follow by potassium hydroxide (20 mg, 0.31 mmol). The reaction was stirred 1 hr and the cold bath removed. After 1 hr at ambient temperature, the reaction was refluxed for 3 hours then concentrated to a solid. The crude solid was triturated with chloroform (1×5 ml) and concentrated. The residue was dissolved in water (15 ml) and acidified with formic acid. The resulting precipitate was isolated by filtration, washed with water (2×15 ml), and dried in a desiccator to yield the title compound (106 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:38]=[N:39][CH:40]=[N:41][CH:42]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:37]4[CH:38]=[N:39][CH:40]=[N:41][CH:42]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Brc1cncnc1
Product: C[C@@H](c1ccc(-c2cncnc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromopyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.332, m/z=436.1; 1H NMR (CD3OD) 1.49 (d, 3H), 1.83 (m, 2H), 2.14-2.28 (m, 4H), 2.42 (m, 1H), 3.08 (m, 1H), 3.49 (m, 2H), 5.52 (m, 1H), 6.99 (t, 2H), 7.08 (d, 2H), 7.23 (m, 2H), 7.42 (d, 2H), 8.91 (s, 2H), 9.06 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=S)[C:11]=2[CH:26]=1)[C:3]([F:6])([F:5])[F:4].IC.[N:30]#[C:31][NH2:32].[H-].[Na+]>O1CCCC1>[C:31]([N:32]=[C:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:12]1[C:11]2[CH:26]=[C:7]([C:2]([F:27])([F:1])[C:3]([F:6])([F:5])[F:4])[CH:8]=[CH:9][C:10]=2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=1)#[N:30]
Reactant: FCC1(CF)C=C(N2CCCC2=S)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Reactant: N#CN
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: N#CN=C1CCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To a mixture of 0.05 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-thioxo-1-pyrrolidinyl)-2H-1-benzopyran, 0.20 g of iodomethane, 0.05 g of cyanamide and 3 ml of tetrahydrofuran was added 0.06 g of sodium hydride (60%) under ice-cooling with stirring. The mixture was stirred under ice-cooling for 30 minutes and then stirred at room temperature for 17 hours. After addition of ice water, the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 49 mg of 4-(2-cyanoimino-1-pyrrolidinyl)-6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran represented by the following formula having a melting point of 207°-210° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1)#[N:2].[CH3:21][C@@H:22]([NH2:25])[CH2:23][CH3:24]>>[C@H:22]([NH:25][C:16](=[O:18])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7]2[CH:6]=[N:5][CH:4]=[C:3]([C:1]#[N:2])[N:8]=2)=[CH:14][CH:13]=1)([CH3:20])[CH3:19])([CH2:23][CH3:24])[CH3:21]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Reactant: CC[C@@H](C)N
Product: CC[C@@H](C)NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)n2)cc1
Yield: 43 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid (example 20a) and (R)-butan-2-amine. Yield 43%.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]#[N:13].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>>[CH3:11][C:7]1[C:5]2[S:6][C:2]([NH:1][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])=[C:3]([C:12]#[N:13])[C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1cccc2c(C#N)c(N)sc12
Product: Cc1cccc2c(C#N)c(Nc3ccccc3[N+](=O)[O-])sc12

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-7-methylbenzo[b]thiophene-3-carbonitrile and 2-fluoronitrobenzene, 7-methyl-2-(2-nitroanilino)benzo[b]thiophene-3-carbonitrile is obtained.