Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].[CH3:28][CH2:29][O-].[Na+].C(Br)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:28][CH3:29])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[N:8]=[C:7]1[NH2:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCBr
Product: CCOC(=O)C1=C(C)N=C(N)C(CC)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A solution of 37.4 g of 2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol is brought to the boil and treated with 10.9 g of ethyl bromide. After boiling for a further 60 minutes under reflux, the mixture is concentrated by distillation and the residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water. Concentration of the organic phase and recrystallization from ethanol gave 2-amino-3-ethyl-6-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 122°-3°C (16.5 g, 41% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C@H:18]1[O:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:19][C@H:18]([CH3:17])[O:23][C@H:22]([CH3:24])[CH2:21]2)=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(Br)cc2F)C[C@H](C)O1
Yield: 6.8 %

Procedure:
To a suspension of 4-bromo-2-fluorobenzyl bromide (1.0 g, 3.7 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in THF (37 mL) was added cis-2,6-dimethylmorpholine (0.43 g, 3.7 mmol). The reaction mixture was heated under reflux for 6 h and then cooled, the solid removed by filtration and the filtrate was evaporated. The resultant residue was loaded onto a 10 g SCX-2 cartridge which was washed with methanol then 2N ammonia in methanol. Concentration of the combined basic fractions in vacuo afforded the title compound (76 mg, 7%). 1H NMR (CDCl3, 300 MHz): 7.28-7.19 (m, 3H), 3.73-3.59 (m, 2H), 3.49 (d, J=1.5 Hz, 2H), 2.71-2.64 (m, 2H), 1.86-1.73 (m, 2H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method G): RT=2.84 min, M+H+=302.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH:14]4[CH2:16][CH2:15]4)[NH:11][N:10]=3)[C:5]([Cl:17])=[CH:4][N:3]=2)[CH3:26])=[N:23][CH:24]=1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: C[C@H](N)c1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(Br)cn1
Temperature: 180 °C
Yield: 68.6 %

Procedure:
A mixture of 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 7; 0.15 g, 0.553 mmol), (S)-1-(5-bromopyridin-2-yl)ethanamine (Method 26; 0.245 g, 0.611 mmol), and DIEA (0.145 ml, 0.833 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 180° C. in a microwave for 1 hour. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a white solid (0.165 g, 68%). 1H NMR (400 MHz) δ 12.48, 12.38 and 12.07 (s, 1H), 9.66 (br s, 1H), 8.62 (s, 1H), 8.33 and 7.57 (br s, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.92 (br s, 1H), 7.32 (br s, 1H), 5.81 (bs, 1H), 4.99 (br s, 1H), 1.84 (br s, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.94 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 435. Found: [M+11]+ 436.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[OH:11].[Br:12]Br>S(=O)(=O)(O)O.C(Cl)(Cl)(Cl)Cl.S([O-])([O-])(=O)=O.[Ag+2]>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[C:2]([OH:11])[CH:3]=[N:4]2
Reactant: BrBr
Reactant: Oc1cnc2ccccc2n1
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
2-Quinoxalinol (2.9 g, 20 mmol) and silver sulfate (3.1 g, 10 mmol, 0.5 eq.) in sulfuric acid (20 mL) were treated with bromine (1.03 mL, 20 mmol, 1.0 eq.). After stirring at ambient temperature for 18 h, the reaction mixture was diluted with carbon tetrachloride (50 mL), heated to 50° C., and filtered. The filtrate was poured onto ice and the solids collected by filtration and recrystallized from HOAc, giving 6-bromo-2-quinoxalinol (1.8 g, 40%).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:11]=[C:9]1[CH2:10][C:4]2[CH:3]=[C:2](/[CH:16]=[CH:15]/[C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: C=CC(=O)OCC
Reactant: O=C1CCCc2ccc(Br)cc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)CC(=O)CCC2
Temperature: 100 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
A mixture of 3-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (2.00 g), ethyl acrylate (1.26 g), palladium acetate (94 mg), tris(2-methylphenyl)phosphine (764 mg), triethylamine (1.69 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 20 hours under nitrogen atmosphere. After cooling, ice water (20 ml) was added to the mixture. The resulting precipitates were collected by filtration and the powder was dissolved in ethyl acetate (20 ml). The solution was washed with water (20 ml) three times, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform as an eluent to give ethyl (E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)acrylate (1.34 g).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C>CCCCCC>[CH:9]1[C:10]([F:13])=[CH:11][C:12]2[CH:4]=[CH:5][O:6][C:7]=2[CH:8]=1
Reactant: CCOC(COc1ccc(F)cc1)OCC
Solvent: CCCCCC
Product: Fc1ccc2occc2c1
Yield: 50.3 %

Procedure:
To a solution of 16.0 g of 1-(2,2-diethoxyethoxy)-4-fluorobenzene in 50 ml n-hexane was added 3.2 g of amberlyst 15 at room temperature. After the mixture was treated in a sealed tube at 200° C. for 11 hours, the amberlyst 15 was filtered off. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (n-hexane), to give 4.8 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([CH:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:5]([O:7]CC)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.O>[CH:1]1([CH:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Oc1cccc2ccccc12)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Oc1cccc2ccccc12)C1CC1
Temperature: 80 °C
Yield: 61 %

Procedure:
To a solution of 1-naphthol (170 mg, 1.18 mmol) in anhydrous DMF (10 mL) was added K2CO3 (510 mg, 3.53 mmol) and ethyl α-bromocyclopropaneacetate (295 mg, 1.41 mmol). The mixture was stirred at room temperature for 2 h and then diluted with water (50 mL) and then extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography using a mixture of ethyl acetate and n-hexane (1:9) to furnish ethyl 2-cyclopropyl-2-(1-naphthalenyloxy)acetate (8, R=c-Pr, 296 mg, 93%) as a white solid. The ester (250 mg, 0.92 mmol) was dissolved in 20 mL THF: H2O (2:1) and then 3M NaOH (111 mg, 2.77 mmol) was added. The reaction was heated at 80° C. for 6 h. After cooling, the reaction mixture was quenched with 1N HCL to a pH ˜7 and then extracted with chloroform. The organic extract was dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography eluting with a mixture of ethyl acetate/n-hexane (a gradient of 2:1) to furnish 2-cyclopropyl-2-(1-naphthalenyloxy)acetic acid (41, R=c-Pr) (136 mg, 61%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 8 h

Procedure:
Trans-4-aminocyclohexanol (2.6 g, 22.6 mmol) was suspended in 60 mL DCM, then 4 mL (28.7 mmol) triethylamine was added. The mixture was cooled in ice bath, and trityl chloride (6.3 g, 22.6 mmol) was added. The mixture was stirred overnight, allowing it to slowly warm up. Saturated NaHCO3 was added to quench the chloride, and product was extracted with EtOAc three times. The combined organic layer was washed with brine, and dried over Na2SO4. Column chromatography with 20-40% EtOAc in hexanes provided 5.3 g (66%) white solid.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:4]=1SC)#[N:2].[CH3:27][NH2:28]>C(O)C>[C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:4]=1[NH:28][CH3:27])#[N:2]
Reactant: CN
Reactant: CSc1ccc(-n2c(-c3ccc(F)cc3)nc(SC)c(C#N)c2=O)cc1
Solvent: CCO
Product: CNc1nc(-c2ccc(F)cc2)n(-c2ccc(SC)cc2)c(=O)c1C#N
Yield: 42 %

Procedure:
The title compound was prepared from 5-cyano-2-(4-fluorophenyl)-1-[4-(methylthio)phenyl)-4-(methylthio)-6-oxo-1,6-dihydropyrimidine (1 g, 2.6 mmol, prepared according to the procedure disclosed in example 2) in ethanol (10 ml) with methylamine (0.16 g, 5 mmol) was refluxed for 2 hr. Then the reaction mass poured on to ice and the resulted solid filtered, washed thoroughly with water. The solid thus obtained was purified by column chromatography using ethyl acetate and hexane mixture as eluent to yield title compound (0.4 g, yield 42%, mp 219-222° C. purity 95.3% by HPLC). 1H-NMR (CDCl3):δ 2.45 (s, 3H), 3.17-3.18 (d, 3H), 6.0 (s, 1H, NH, D2O exchangeable), 6.91-6.99 (m, 4H), 7.14-7.16 (d, 2H), 7.31-7.34 (m, 2H). IR (KBr) cm−1: 3279, 2981, 2931, 2208, 1736, 1651, 1604 (—C═O). MS m/z: 367.1 (M+).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:57]1[CH2:62][CH2:61][CH:60]([CH2:63][NH2:64])[CH2:59][CH2:58]1.O>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]([NH:64][CH2:63][CH:60]3[CH2:61][CH2:62][O:57][CH2:58][CH2:59]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(C(Cc3ccccc3)C(=O)O)cs2)c1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(-c2nc(C(Cc3ccccc3)C(=O)NCC3CCOCC3)cs2)c1-c1ccc(F)cc1
Yield: 17.4 %

Procedure:
A solution of the compound (11 mg, 0.02 mmol) obtained in step 2, HATU (76 mg, 0.20 mmol), DEIA (5.13 μL, 0.03 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (3.04 μL, 0.03 mmol) in DMF (2 mL) was stirred at room temperature for 1 day. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed to with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 0→50% ethyl acetate/hexane) to give the title compound (1.9 mg, 3.48 μmol, 14.2%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[N:16]([O-])=[O:17].[Na+]>O>[C:1]([O:5][C:6](=[O:11])[C:7](=[N:16][OH:17])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a mixture of 158 g of acetoacetic acid-tert. butylester and 1000 ml of glacial acetic acid is added dropwise, while maintaining the temperature at 5°, a solution of 86.4 g of NaNO2 in 500 ml of water. After 4 hours stirring at 5°, the mixture is extracted 5 times with ether, the purified ether extracts are washed 5 times with water and twice with saturated sodium chloride and evaporated to dryness to obtain the heading compound, m.p. 55°-63°.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]([NH2:21])=[S:20].[OH-].[Na+].C>>[SH:20][C:19]1[N:21]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)[CH:4]=[CH:3][N:18]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cccc(-c2ccnc(S)n2)c1

Procedure:
A mixture of 12.2 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone and 15.2 g. of thiourea is heated at 180°-190° C. for 2 hours. The cooled crude reaction mixture is dissolved in 200 ml. of 1 N sodium hydroxide solution and is treated with activated charcoal and filtered. The filtered solution is acidified with 1 N hydrochloric acid and the desired compound is collected by filtration, m.p. 200°-205° C.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]I)=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:11]([O:10][C:2]([CH:3]([CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCc1ccc(CCI)cc1
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(C(=O)OCC)C(=O)OCC)cc1
Temperature: 40 °C
Reaction time: 0.05 h
Yield: 65.9 %

Procedure:
Sodium (2.67 g) was dissolved in absolute ethanol (100 ml) and diethyl malonate (18.6 g) was dropwise added thereto at 27°-30° C. for 3 minutes. The mixture was stirred at 40° C. for 40 minutes and 2-(4-octylphenyl)ethyl iodide (40 g) was dropwise added to the reaction mixture at 44°-45° C. over 10 minutes. The mixture was refluxed at 50° C. for 1 hour and stirred under heating for 1.5 hours. The reaction mixture was cooled and the solvent was distilled away under reduced pressure. Water was added thereto and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was subjected to silica gel column chromatography to give the subject compound (28.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:16][C:4]1[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
Iron powder (293 mg, 5.2 mmol) was added to a solution of tert-butyl 5-bromo-3-nitropyridin-2-ylcarbamate (167 mg, 0.52 mmol) in acetic acid (2.5 mL). The mixture was stirred at 60° C. for 1 h 20 min before cooling to rt. The mixture was then diluted with ethyl acetate, and solids were removed by filtration through celite. The filtrate was washed with water followed by saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide tert-butyl 3-amino-5-bromopyridin-2-ylcarbamate (96.3 mg, 0.33 mmol, 64% yield) as a gray solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, 1H), 7.20 (d, 1H), 6.95 (br s, 1H), 4.42 (br s, 2H), 1.51 (s, 9H); MS (EI) for C10H14BrN3O2: 232, 234 (Br isotopes, MH+-t-butyl).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH2:15])[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH:15][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)N1CCc2c(sc(N)c2C#N)C1
Product: CCOC(=O)N1CCc2c(sc(NC(=O)c3ccccc3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from 2-amino-3-cyano-4,7-dihydro-thieno[2,3-c]pyridine-6(5H)-carboxylic acid ethyl ester (compound A1) and benzoyl chloride.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:42])[C:21]=1[NH:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:43]([O:47][C:48]([NH:50][CH2:51][C:52](ON1C(=O)CCC1=O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(Cl)(Cl)Cl>O1CCCC1>[C:43]([O:47][C:48]([NH:50][CH2:51][C:52]([NH:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:42])[C:21]=1[NH:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl (4S)-4-amino-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (1.71 g) in tetrahydrofuran (30 ml) was added N-[2-(tert-butoxycarbonylamino)acetoxy]-succinimide (820 mg). The mixture was stirred at room temperature for 6 hours. To the reaction mixture was added chloroform (50 ml). The mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl (4S)-4-{[2-(tert-butoxycarbonylamino)acetyl]amino}-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (2.1 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH2:30][CH2:31][N:27]([CH3:26])[C:28]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2)CC1
Yield: 9.5 %

Procedure:
Using (4-bromophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) described in Preparation Example 185 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (24 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1C(=O)O[C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[CH3:14][NH2:15]>C1COCC1>[CH3:14][NH:15][C:5](=[O:6])[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[NH:2][CH3:1]
Reactant: CN
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1NC
Reaction time: 18 h

Procedure:
A solution of N-methylisatoic anhydride (5 g, 28 mmol) in THF (100 mL) was treated with methylamine (THF solution, 2.0 M, 60 mL). The mixture was stirred for 18 h and the solvent was evaporated. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was washed once with brine (30 ml), dried over sodium sulfate, and concentrated to give N-methyl-2-methylamino-benzamide (5 g, 30 mmol): 1H NMR (300 MHz, CDCl3): δ 7.3 (m, 2H), 6.67 (d, 1H), 6.58 (t, 1H), 2.96 (d, 3H), 2.86 (d, 3H); MS (m/e) 165 (M+1).
Reaction SMILES: S(O)(O)(=O)=O.[C:6](=[NH:10])([O:8][CH3:9])[NH2:7].C[O-].[Na+].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([C:34](=O)[CH2:35][CH2:36][CH2:37][CH3:38])[C:30](OC)=[O:31])=[CH:24][CH:23]=1)#[N:15]>CO>[CH2:35]([C:34]1[N:10]=[C:6]([O:8][CH3:9])[NH:7][C:30](=[O:31])[C:29]=1[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:17]2[C:16]([C:14]#[N:15])=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:27][CH:26]=1)[CH2:36][CH2:37][CH3:38]
Reactant: COC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(OC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 37.2 %

Procedure:
A solution of methyl imidocarbamate sulfate (10 g), 28% sodium methoxide (29 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (9.8 g) in methanol (100 mL) was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure, and water and acetic acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (3.9 g, 37%) as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[CH3:25][NH:26][CH3:27]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17](=[O:19])[N:26]([CH3:27])[CH3:25])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid (570 mg, 2.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and the solution was mixed with 1,1-carbonyldiimidazole (320 mg, 2.0 mmol) and stirred at room temperature for 1 hour. The reaction solution was mixed with dimethylamine tetrahydrofuran solution (2.0 M, 4.0 ml, 2.0 mmol) and the stirring was continued for 15 hours. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the residue was mixed with ethyl acetate and washed with water, hydrochloric acid (1 N), sodium hydroxide aqueous solution (1 N) and saturated brine. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation under a reduced pressure to obtain 470 mg (1.5 mmol, 77% in yield) of the title compound.