Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3](=[O:23])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6]1.C(O)(=O)C>[Pd].C(O)C>[NH2:12][CH2:11][CH:8]1[CH2:7][CH2:6][N:5]([CH2:4][C:3](=[O:23])[C:2]([CH3:24])([CH3:1])[CH3:25])[CH2:10][CH2:9]1
Reactant: CC(C)(C)C(=O)CN1CCC(CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)C(=O)CN1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 45.9 %

Procedure:
A mixture of benzyl [1-(3,3-dimethyl-2-oxobutyl)piperidin-4-yl]methylcarbamate (Step 1, 9.6 g, 27.7 mmol), 5% palladium on carbon (1.2 g) and acetic acid (4 mL) in ethanol (70 mL) was stirred at room temperature for 23 h under hydrogen atmosphere. Palladium on carbon was removed by filtration through a pad of Celite and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with aqueous ammonia and extracted with ethyl acetate (5×50 mL). After dried over magnesium sulfate, removal of solvent gave the title compound (2.7 g, 46%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([CH3:36])=[CH:31][C:30]=1[S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[N:10][N:11]=1)[S:37]([C:30]1[CH:31]=[C:32]([CH3:36])[C:33]([F:35])=[CH:34][C:29]=1[F:28])(=[O:39])=[O:38]
Reactant: Cc1cc(S(=O)(=O)Cl)c(F)cc1F
Reactant: COc1ccc(CNc2nncs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(C)c(F)cc2F)c(OC)c1
Yield: 66 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 86a by using N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (WO 2010/079443; 1.00 g, 3.98 mmol), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 4.78 mL, 4.78 mmol), 2,4-difluoro-5-methylbenzenesulfonyl chloride (WO 2010/079443; 0.989 g, 4.36 mmol) and THF (20 mL), to yield the title compound (1.16 g, 66%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:16])=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:16])=[O:4]
Reactant: CNC(=O)c1c(C)[nH]c2cc(OC)ccc12
Agent: BrB(Br)Br
Product: CNC(=O)c1c(C)[nH]c2cc(O)ccc12

Procedure:
This material was prepared from 6-methoxy-2-methyl-1H-indol-3-carboxylic acid methylamide 24a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (300 MHz, CD3OD) δ7.52 (1H, d, J=8.7 Hz), 6.72 (1H, d, J=2.3 Hz), 6.65 (1H, dd, J=2.3, 8.7 Hz), 2.93 (3H, s), 2.55 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 205, found 205.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([OH:20])=[O:19])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:24]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([O-:20])=[O:19])=[O:9])=[CH:21][CH:22]=1.[Na+:24]
Reactant: Cc1ccc(CCC(=O)Nc2ccccc2CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(CCC(=O)Nc2ccccc2CC(=O)[O-])cc1

Procedure:
297 Milligrams of 2-(4'-methylhydrocinnamoylamino)phenylacetic acid were dissolved in an alcohol and an equivalent amount of sodium hydroxide was added to the solution. The solution was warmed for 30 minutes and then concentrated under reduced pressure. Ether was added to the residual liquid to precipitate crystals which were then collected by filtration to obtain sodium 2-(4'-methylhydrocinnamoylamino)phenylacetate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21].Cl>C1C=CC=CC=1.C(OCC)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]([OH:11])[C:2]([NH:1][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1c(O)cc(Br)cc1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1c(O)cc(Br)cc1C(=O)O
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 98.4 %

Procedure:
2-Amino-5-bromo-3-hydroxybenzoic acid (I-219) (11.92 g, 51.37 mmol) was dissolved in benzene (360 ml), and pyridine (12.5 m, 154.12 mmol) and pivaloyl chloride (19.0 ml, 154.12 mmol) were added at room temperature. After stirred at 85° C. under nitrogen atmosphere for 3.5 hours, this was cooled to room temperature. The solution was fractionated with ethyl acetate and aqueous 1 M hydrochloric acid solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was subjected to column chromatography with silica gel, and the fraction with hexane:ethyl acetate=95:5 gave the entitled compound (15.98 g, 98.4%) as a brown solid.
Reaction SMILES: B.C1COCC1.[CH2:7]([O:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]([OH:17])=O)=[O:11])[CH3:8].[C:18]([Si:22](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)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>C1COCC1.O.CO>[Si:22]([O:17][CH2:15][C@@H:13]1[CH2:14][C@H:12]1[C:10]([O:9][CH2:7][CH3:8])=[O:11])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: B
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)[C@@H]1C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
1M Borane-THF complex THF solution (85 mL, 84.98 mmol) was added to a solution of trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (11.2 g, 70.82 mmol) in THF (100 mL) at 0° C., and the mixture was stirred overnight at room temperature. MeOH was added thereto, and then the gas was not generated. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (50 mL), tert-butylchlorodiphenylsilane (20.10 mL, 84.98 mmol) and imidazole (5.79 g, 84.98 mmol) were added thereto, and the mixture was stirred for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent gradient; 2→35% ethyl acetate/hexane) to give ethyl trans-2-((tert-butyldiphenylsilyloxy)methyl)cyclopropanecarboxylate (21.40 g, 55.9 mmol, 79%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][N:4]=[N:3]1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cn1nncc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nncc1Nc1cc(Br)cn(C)c1=O
Temperature: 25 °C
Yield: 15.2 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (20 mL), 154a (500 mg, 5.10 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1362 mg, 5.10 mmol), and cesium carbonate (3.325 g, 10.2 mmol). After bubbling nitrogen through the suspension for 20 minutes, Xantphos (0.59 g, 1.02 mmol) and tris(dibenzylideneacetone)dipalladium(0) (467 mg, 0.51 mmol) were added. The system was subjected to three cycles of vacuum/nitrogen flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 154b (220 mg, 15%) as a brown solid. LCMS: [M+H]+ 284.1
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:15]=O)=[C:4]([CH3:14])[C:5]([CH3:13])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7]2.O.[OH-].[Na+].Cl.[CH3:21][C:22]([CH3:24])=[O:23]>>[Cl:1][C:2]1[C:3]([CH:15]=[CH:21][C:22](=[O:23])[CH3:24])=[C:4]([CH3:14])[C:5]([CH3:13])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7]2
Reactant: Cc1c(C)c2c(c(Cl)c1C=O)CC(C)(C)C2
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c(C)c2c(c1Cl)CC(C)(C)C2
Yield: 35 %

Procedure:
To a solution of 14.7 g of the 7-chloro-2,2,4,5-tetramethylindan-6-carboxaldehyde in 48 ml of absolute acetone was added 23 ml of water and 25 g of 2% NaOH. After refluxing for 20 hours the solution was acidified with 2N HCl extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 5.35 g of the title compound as yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([C@@H:14]1[C@H:19]([CH3:20])[CH2:18][CH2:17][NH:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][CH:12]=[N:13][C:6]=12.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O>[N:13]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:3])[C@@H:14]2[C@H:19]([CH3:20])[CH2:18][CH2:17][N:16]([C:24](=[O:25])[CH2:23][C:21]#[N:22])[CH2:15]2)[NH:11][CH:12]=1
Reactant: N#CCC(=O)O
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ccnc2[nH]cnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ccnc2[nH]cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of N-methyl-N-[(3R,4R)-4-methyl-3-piperidinyl]-3H-imidazo[4,5-b]pyridin-7-amine dihydrochloride (40 mg) in N,N-dimethylformamide (0.6 mL) were added cyanoacetic acid (16 mg), 1-hydroxybenzotriazole (25.5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.033 mL). The mixture was stirred at ambient temperature overnight, then extracted with EtOAc and washed with brine. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 3-{(3R,4R)-3-[3H-imidazo[4,5-b]pyridin-7-yl(methyl)amino]-4-methyl-1-piperidinyl}-3-oxopropanenitrile (25 mg) as a white powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)=[N:2]1
Reactant: NCCCNc1nsc2ccccc12
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(-c2ccc(CNCCCNc3nsc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
N1-(Benzo[d]isothiazol-3-yl)propane-1,3-diamine (600 mg, 2.8 mmol) and 4′-methoxy-biphenyl-4-carboxaldehyde (614 mg, 2.8 mmol) were combined in 1,2-dichloroethane (20 mL) and treated with sodium triacetoxyborohydride (1.2 g, 5.7 mmol) and acetic acid (160 μL, 5.6 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution. The crude product was extracted with ethyl acetate (2×50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography, on silica gel, eluting with 98:2 methylene chloride: methanol to yield N1-(benzo[d]isothiazol-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (330 mg) as a light yellow foam. 1H NMR (CDCl3): 7.80 (d, 1H), 7.75 (d, 1H), 7.25-7.45 (m, 8H), 6.90 (d, 2H), 3.95 (s, 2H), 3.85 (s, 3H), 3.70 (t, 2H), 3.00 (t, 2H), 2.30-2.40 ppm (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1.[OH-].[Na+].C(O)(=O)C.O>C(O)C>[CH3:1][CH:2]1[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CC(C)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC1CNC(=O)c2cc3ccc(C(=O)O)cc3n2C1
Temperature: 80 °C
Yield: 59.3 %

Procedure:
To a solution ethyl 4-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (1.4 g, 4.9 mmol) in ethanol (50 mL) is added 1M NaOH (12.5 mL, 12.5 mmol) and the mixture is heated at 80° C. for 2 h. Acetic acid (10 mL) and water (650 mL) are added and the resulting solid is filtered and rinsed with water to afford the title compound (751 mg, 58%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:8]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:41][CH2:40]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[F:45])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Cl)c(C(=O)O)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1cc(Cl)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n1
Yield: 80.2 %

Procedure:
In the same manner as in Example 259 and using 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (130 mg, 0.79 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (230 mg, 80%) was obtained as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([O:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH:10]=[CH:9][C:8]=1[CH:19]=[O:20])(=O)=O.[Cl-].[Li+].[CH2:25]([Sn](CCCC)(CCCC)C=C)[CH2:26]CC.[F-].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:16][N:15]([CH3:17])[C:14](=[O:18])[O:13][C:11]1[CH:10]=[CH:9][C:8]([CH:19]=[O:20])=[C:7]([CH:25]=[CH2:26])[CH:12]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C)C(=O)Oc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Cl-]
Solvent: C1COCCO1
Product: C=Cc1cc(OC(=O)N(C)C)ccc1C=O
Yield: 79.5 %

Procedure:
To a solution of 5-dimethylcarbamoyloxy-2-formyl-phenyl trifluoromethanesulfonate (4.13 g, 12.1 mmol) obtained in step (b) of Example 192 in 1,4-dioxane (15 ml) were added tetrakis(triphenylphosphine)palladium (693 mg, 0.600 mmol), 2,6-di-t-butylphenol (5 mg), lithium chloride (1.54 g, 36.4 mmol) and tributyl(vinyl)tin (4.23 ml, 14.5 mmol) with stirring, and the resulting mixture was stirred for 3 hours at 100° C. under a nitrogen atmosphere. Subsequently, saturated aqueous potassium fluoride solution (5 ml) was added to the reaction mixture, and the resulting mixture was stirred for 2 hours at room temperature, filtered, and evaporated in vacuo. To the residue was added water (40 ml), and the resulting mixture was extracted with ethyl acetate (50 ml×2). The organic layer was washed successively with 1N hydrochloric acid (40 ml×1) and saturated aqueous sodium chloride solution (40 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (10:1-1:1) as the eluent to afford the title compound (2.11 g, yield: 79%) as a colorless oil.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([S:25][C:26]2[N:30]4[CH:31]=[C:32]([C:35]([O:37]CC)=[CH2:36])[CH:33]=[CH:34][C:29]4=[N:28][N:27]=2)=[CH:20][CH:19]=3)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Cl>C1COCC1>[OH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([S:25][C:26]2[N:30]4[CH:31]=[C:32]([C:35](=[O:37])[CH3:36])[CH:33]=[CH:34][C:29]4=[N:28][N:27]=2)=[CH:20][CH:19]=3)[CH2:13][CH2:14]1
Reactant: C=C(OCC)c1ccc2nnc(Sc3ccc4ncc(N5CCC(O[Si](C)(C)C(C)(C)C)CC5)cc4c3)n2c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CCC(O)CC5)cc4c3)n2c1
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
To the solution of (76.2) (90 mg, 0.160 mmol) in THF (2 ml) was added about 2 N HCl (1 mL) at rt and the mixture was continue stirred for 30 mins, Checked the reaction by LCMS and TLC. The reaction solution was neutralized with sat.NaHCO3 aqueous until the pH to 8˜9 and extracted with DCM for three times, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give crude product which was purified by flash chromatography and eluented with DCM/MeOH (40:1˜20:1) to obtained pure desired product (76.3) as yellow solid (42 mg, yield 62.5%). 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.95 (s, 1H), 8.72 (s, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.75 (s, 1H), 7.39-7.43 (m, 2H), 3.78-3.84 (m, 1H), 3.68-3.74 (m, 2H), 3.02-3.08 (m, 2H), 2.57 (s, 3H), 1.98-2.01 (m, 2H), 1.62-1.71 (m, 2H). LCMS (method A): [M+H]+=420.1, tR=2.013 min.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)([C:13]#[N:14])[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:21][Mg+].[Br-].CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCCCC)CCC>[CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][C:10]([CH:13]([NH2:14])[CH3:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9][CH2:8]1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: C[Mg+]
Reactant: CCCS(=O)(=O)N1CCC(C#N)(c2ccccn2)CC1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCOCCCC
Product: CCCS(=O)(=O)N1CCC(c2ccccn2)(C(C)N)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 1-(propylsulfonyl)-4-pyridin-2-ylpiperidine-4-carbonitrile (5.0 g, 17 mmol) in toluene (130 mL) at room temperature was treated with MeMgBr (48.9 mL of a 1.0 M solution in dibutyl ether, 28.9 mmol). After 18 h, the reaction was cooled to 0° C. and treated with MeOH (29 mL). After 10 min, the reaction was treated with NaBH4 (1.0 g, 26.4 mmol), warmed to room temperature, and stirred an additional 10 min after which the reaction mixture was cooled to 0° C. and quenched with the dropwise addition of saturated aqueous NH4Cl (15 mL). The reaction was diluted with H2O (300 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and dissolved in pH 7 phosphate buffer (300 mL). The buffered solution was washed with EtOAc (200 mL) and the organic layer was extracted with fresh pH 7 buffer (2×150 mL). The combined buffer solutions were made basic with concentrated NH4OH and extracted with CH2Cl2 (3×200 mL), and these extracts were dried (Na2SO4) and concentrated under reduced pressure to afford {1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}amine. This material was fully resolved into 1R and 1S isomers (>99% ee) using a ChiralPak AD column. NOE analysis of Mosher's amides and single X-ray crystal analysis of a derivative confirmed the absolute stereochemistry of each isomer.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][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.CCN(C(C)C)C(C)C.O=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO.O>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[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: CCOC(=O)CCCCCC=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3-Dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate E) (10 g, 31.7 mmol) in DCE (300 ml) was added DIPEA (6.09 ml, 34.9 mmol) followed by ethyl 7-oxoheptanoate (10.92 g, 63.4 mmol). The mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (16.80 g, 79 mmol) was added portionwise. The reaction mixture was heated at 40° C. overnight and then added slowly to water (500 ml) and stirred at RT for 10 minutes. The organic layer was separated and the aqueous layer extracted with dichloromethane (2×200 ml). The combined organics were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give a pale yellow oil. Isolute Separtis SCX-2 (capture/release super cation exchange resin) (222 g, 127 mmol) was added to a column and the product was loaded with MeOH (50 ml). The column was flushed with MeOH (750 L) followed by 2 N NH3/MeOH (1000 ml, prepared from 280 ml 7 N+720 ml MeOH) to afford the title compound. No further purification was carried out; HPLC (Agilent 1200) Rt 6.38 min, Method B
Reaction SMILES: C(O)=O.[CH:4]([NH2:6])=O.[NH2:7][C:8]1[NH:9][C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[CH:11][C:12]=1[C:13](OCC)=[O:14]>CN(C)C=O>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]2[NH:9][C:8]3[N:7]=[CH:4][N:6]=[C:13]([OH:14])[C:12]=3[CH:11]=2)=[CH:19][CH:20]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)[nH]c1N
Solvent: O=CO
Solvent: CN(C)C=O
Product: Oc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Temperature: 140 °C
Reaction time: 48 h

Procedure:
After adding 84 ml of formic acid, 338 ml of formamide and 169 ml of dimethylformamide to 56.7 g of the ethyl 2-amino-5-(4-benzyloxyphenyl)-1H-pyrrole-3-carboxylate synthesized in Production Example 153-1, the mixture was stirred at 140° C. for 48 hours and then allowed to stand at room temperature for 24 hours. The precipitated solid was filtered out and dried under reduced pressure to obtain 41 g of the title compound.