Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[F:31])[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[C:28]([F:31])[CH:27]=[CH:26][CH:25]=3)[CH2:30][CH:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC1Cc2c(F)cccc2N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Agent: [Na+]
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 49.1 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 133 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 8a and 75 mg of (+)-2-methyl-4-fluoro-2,3-dihydro-1H-indole (reference example 5a). After silica column purification: eluent 98/02 dichloromethane/methanol, 90 mg of 5-fluoro-2-[2-((−)-4-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3-methyl-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[CH:9]=[C:8]([C:12]([O:14]C)=[O:13])[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:3]12.[Li+].[OH-].C1COCC1.O>CO>[O:1]=[C:2]1[NH:11][C:10]2[CH:9]=[C:8]([C:12]([OH:14])=[O:13])[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:3]12
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C1CCCCN21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)NC(=O)C1CCCCN21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1008.2 %

Procedure:
Methyl 6,6a,7,8,9,10-hexahydro-6-oxo-5H-pyrido[1,2-a]quinoxaline-3-carboxylate (0.762 g, 0.29 mmole) and LiOH (0.25 g) were suspended in MeOH (5 mL), THF (5 ml) and Water (2 mL). The mixture was stirred at room temperature overnight. The reaction was evaporated to near dryness, and 2N HCl was added to adjust the PH about 2. The solid was filtered and dried to provide 6,6a,7,8,9,10-hexahydro-6-oxo-5H-pyrido[1,2-a]quinoxaline-3-carboxylic acid as white solid (0.72 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@@H:14]([CH2:19][CH:20]=[CH2:21])[C:15]([O:17][CH3:18])=[O:16])(=[O:12])=[O:11])([O-:3])=[O:2].[CH2:22]=[C:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:22]=[C:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][N:13]([C@@H:14]([CH2:19][CH:20]=[CH2:21])[C:15]([O:17][CH3:18])=[O:16])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: C=CC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC
Reactant: C=C(CCC)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)OC)N(CCC(=C)CCC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
Tetrahydrofuran (30.2 ml) was added to 2.27 g (7.22 mmol) of the title compound produced in step (i) of Example 47 and 1.07 g (9.39 mmol) of the title compound produced in step (ii) of Example 47. The mixture was cooled to 0° C., 2.84 g (10.8 mmol) of triphenylphosphine was added thereto, and the mixture was stirred for 10 min. Diisopropyl azodicarboxylate (2.1 ml, 10.8 mmol) was added thereto. The temperature of the mixture was raised over a period of 2 hr before it was stirred for 19 hr. The solvent was removed under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1) to give 2.42 g (yield 82%) of the title compound.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH2:4][CH3:5])[CH3:2].[Cl:12][SiH:13]([Cl:15])[Cl:14].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH2:4]([CH:3]([CH:6]([Si:13]([Cl:15])([Cl:14])[Cl:12])[CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH2:1][CH3:2])[CH3:5]
Reactant: Cl[SiH](Cl)Cl
Reactant: CCC(=CC(CC)CC)CC
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CCC(CC)C(C(CC)CC)[Si](Cl)(Cl)Cl
Yield: 56 %

Procedure:
A one-liter autoclave equipped with a stirrer was charged in a nitrogen atmosphere with 77 grams (0.50 mol) of 3,5-diethyl-3-heptene, 134 grams (1.0 mol) of trichlorosilane and 24 grams (0.1mol) of 1,1'-azobis(cyclohexane-1-carbonitrile) and the mixture was reacted at a temperature of 130° C. for 5 days. The resulting reaction mixture was purified by distillation thereby obtaining 80 grams (0.28 mol) of 3,5-diethyl-4-trichlorosilylheptane. The structure of the resulting product was identified by 1H-NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@@H:9]([N:12]3C(=O)C4=CC=CC=C4C3=O)[CH2:8]2)[CH:2]=1>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]2)[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CC[C@@H](c2cccnc2)C1
Solvent: CCO
Product: N[C@@H]1CC[C@@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of (1R,3R)-N-[3-(3-pyridyl)cyclopentyl]phthalimide (3.00 g, 10.3 mmol) and hydrazinemonohydorate (1.00 mL, 20.5 mmol) in EtOH (40 mL) was stirred at room temperature for 1 h. The reaction mixture was filtered followed by the removal of solvent. The crude product was purified by column chromatography (NH, CHCl3/MeOH=50/1) to yield (1R,3R)-3-(3-pyridyl)cyclopentylamine (1.63 g, 97%) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:38]([OH:40])=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:46](=[O:53])([O:50][CH2:51]I)[S:47][CH2:48][CH3:49]>O.C(Cl)Cl>[C:46](=[O:53])([S:47][CH2:48][CH3:49])[O:50][CH2:51][O:39][C:38](=[O:40])[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:24][C:22](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CCSC(=O)OCI
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCSC(=O)OCOC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a mixture of dipeptide 51 (969 mg, 1.69 mmol) in H2O (3.25 mL) and CH2Cl2 (3.25 mL) was added NaHCO3 (294 mg, 3.50 mmol) and TBAHSO4 (572 mg, 1.69 mmol). After stirring for 15 min, S-ethyl O-iodomethyl carbonothioate (322 mg, 1.30 mmol) in CH2Cl2 (1 mL) was added. The biphasic reaction was stirred vigorously for 2.5 h and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on silica gel, using a gradient of 0-50% EtOAc in CH2Cl2 as eluent to provide compound 52 (818 mg, 91%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 1.30-1.53 (m, 8H), 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 27H), 1.60-1.75 (m, 2H), 1.82-1.90 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 3.06-3.14 (m, 4H), 4.04-4.10 (m, 1H), 4.58-4.64 (m, 1H), 4.70 (bs, 2H), 5.18-5.21 (m, 1H), 5.78 (d, J=5.6 Hz, 1H), 5.90 (d, J=5.6 Hz, 1H) 6.67 (bd, J=6.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:22]([C:21]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1OC

Procedure:
Prepared from 2-benzyl-benzo[b]thiophene and 3,4-dimethoxybenzoyl chloride according to the procedure in Example 8. White solid: MS (EI): [M+], 388.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[OH:14][CH2:15][C:16]1([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[CH:24]2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>O1CCCC1.CN(C)C=O>[OH:14][CH2:15][C:16]1([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[CH:24]2)[CH2:21][CH2:20][C:19](=[CH:3][C:1]#[N:2])[CH2:18][CH2:17]1
Reactant: O=C1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC=C1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (38.6 mg, 0.218 mmol) in tetrahydrofuran (0.5 mL) stirring at about 0° C. was added sodium hydride (10.5 mg, 0.262 mmol). To this was added a solution of 4-(hydroxymethyl)-4-(1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexanone (56 mg, 0.18 mmol) in N,N-dimethylformamide (0.45 mL). The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, causing formation of solids. The solids were filtered to give 18 mg of pure desired product. The filtrate was diluted with EtOAc, washed with water, and concentrated to give an additional 39 mg of the crude product. LCMS calculated for C17H17N4OS (M+H)+: m/z=325.1. Found: 325.0. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 8.15 (s, 1H), 7.47 (d, J=5.6 Hz, 1H), 7.18 (d, J=5.6 Hz, 1H), 5.20 (s, 1H), 4.34 (s, 2H), 2.80 (d, J=4.0 Hz, 3H), 2.59-2.29 (m, 4H), 1.26 (d, J=15.3 Hz, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
2-Methylphenol (12.53 g, 115.9 mmol) was dissolved in DMF (60 mL), and stirred at 0° C. To the solution was added K2CO3 (24.03 g, 173.9 mmol) and 4-trifluoromethylbenzyl bromide (23.08 g, 96.6 mmol), and the reaction was stirred at room temperature for 2 h. Water was added to the reaction, and the product was extracted with EtOAc twice. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo to give a crude residue. The crude residue was purified using silica gel column chromatography (hexane/EtOAc=30/1) to give 4.1 (25.1 g). 1H NMR (400 MHz) (CDCl3) δ 7.64 (2H, d, J=8.2 Hz); 7.56 (2H, d, J=8.2 Hz); 7.18-7.08 (2H, m); 6.90 (1H, t, J=7.2 Hz); 6.84 (1H, d, J=8.1 Hz); 5.14 (2H, s); 2.30 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>CO.O.C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][CH2:15][NH:16][CH:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1=NCCn2c1ccc2-c1ccc(Cl)c(Cl)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CC1NCCn2c(-c3ccc(Cl)c(Cl)c3)ccc21
Yield: 92 %

Procedure:
6-(3,4-Dichlorophenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine (1.8 g) was dissolved in a mixture of 100 ml of methanol and 10 ml of water under argon. The solution was treated portionwise with 0.7 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 150 ml of methylene chloride and washed with 65 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 70 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.8 g of brown oil, was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 2.0 g (92%) of 6-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (2:1); m.pt.: 224°-226° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].CN(C1C=CC=CN=1)C.[C:22]([O:25]C(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:25][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([CH3:11])=[CH:4][N:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)c[n+]([O-])c(C)c1C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1c(C)cnc(COC(C)=O)c1C
Reaction time: 0.17 h

Procedure:
A solution of 30.06 g (0.18 mole) of 2,3,5-trimethyl-4-methoxypyridine N-oxide in 100 ml of methylene chloride was added slowly (over approximately one hour) over a solution of 0.38 g of dimethylaminopyridine in 53.4 ml (0.565 mole) of acetic anhydride, heated to 90°-95° C., with the temperature being held within the abovementioned range and the methylene chloride being removed by distillation. At the end of the addition, the distillation was continued for a further 10 minutes, the mixture was cooled to below 90° C. and 7.5 ml of water were added slowly, holding the temperature below 90° C. Crude 2-acetoxymethyl-3,5-dimethyl-4-methoxypyridine was obtained by distillation at reduced pressure and was used directly as starting product for the hydrolysis (Example 2).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][C@@H:20]([C:29](=[O:49])[N:30]([CH:46]4[CH2:48][CH2:47]4)[CH2:31][C:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:50](Cl)(=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52]>CC#N>[CH:46]1([N:30]([CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=2)[C:29]([C@@H:20]2[CH2:21][C@H:22]([N:24]([C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][NH:18][CH2:19]2)=[O:49])[CH2:48][CH2:47]1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCC(C)C)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(CC(C)C)C(=O)C(C)(C)C)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example ??? using (3R,5S)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-isobutylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester and pivaloylchloride. MS: 525 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.29 min.
Reaction SMILES: [NH:1]1[C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[CH3:20][CH2:21][O:22][C:23]([CH:25]([N:34]1C(=O)O[C:36](=[O:37])[CH:35]1[CH3:41])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24].Cl>ClCCl.O>[CH3:20][CH2:21][O:22][C:23]([C@@H:25]([NH:34][C@H:35]([C:36]([N:1]1[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C@@H:4]2[C@@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:37])[CH3:41])[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24]
Reactant: O=C(O)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Reactant: CCOC(=O)C(CCc1ccccc1)N1C(=O)OC(=O)C1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
(2S,3aR,7aS) octahydro-1H-indole-2-carboxylic acid (65 gms 0.384 moles) was stirred in dichloromethane (200 ml), triethyl amine (30 ml) was added under stirring at ambient temperature for 30 mins. N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine N-carboxy anhydride (110 gms; 0.378 moles) (residue from Step A) dissolved in dichloromethane (50 ml) was added dropwise to the reaction mass at ambient temperature and further stirred for 3 hrs. Water (500 ml) was added and the reaction mass was cooled to 15° C., pH of the reaction mass was adjusted to 4.2 using 2N HCl. The organic layer was separated and aqueous layer reextracted with dichloromethane. The combined organic layer was dried with sodium sulphate and concentrated to residue. The residue was dissolved in ethylacetate at reflux temperature. The reaction mass was cooled to ambient temperature. The resulting solid was filtered and dried under vacuum to get 50 gms of Trandolapril (HPLC purity 99.5%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:26][O:27][NH2:28].N1C=CC=CC=1.O>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:28][O:27][CH3:26])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
To a solution of 200 mg of the N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide prepared in Step 1 in Synthetic Example 15 and 133 mg of methoxyamine hydrochloride in 2.7 ml of ethanol, 168 mg of pyridine was added, and the mixture was stirred at 80° C. for 6 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (10 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 191 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:28]=1[N:42]1[N:51]=[CH:50][C:49]2[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=2)[C:43]1=[O:57])(=[O:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O>[C:52]([C:47]1[CH:48]=[C:49]2[C:44](=[C:45]([F:56])[CH:46]=1)[C:43](=[O:57])[N:42]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:27]=1[CH2:26][O:25][C:22](=[O:24])[CH3:23])[N:51]=[CH:50]2)([CH3:53])([CH3:54])[CH3:55]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: CCS(=O)(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)nn(C)c2=O)nc1
Temperature: 85 °C

Procedure:
In a 250 mL round-bottomed flask, 6-chloro-4-(5-(ethylsulfonyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (79 mg, 240 μmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (154 mg, 312 μmol) and Cs2CO3 (235 mg, 721 μmol) were combined with dioxane (10 ml) and water (1 ml) to give a light yellow suspension. The mixture was evacuated and filled with argon. PdCl2(DPPF) (9.81 mg, 12.0 μmol) was added, the reaction mixture was purged with argon and heated to 85° C. for 60 h. The reaction mixture was diluted with DCM and filtered through celite. The filter cake was washed with DCM until clear. The filtrate was dried over Na2SO4 and concentrated in vacuo to give a dark brown oil. The brown oil was used crude in the subsequent reaction. (M−H)+=659 m/e.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([CH2:34][C:35]3[CH:36]=[C:37]4[C:42](=[CH:43][C:44]=3[F:45])[N:41]=[CH:40][CH:39]=[CH:38]4)=[CH:32][N:33]=2)[N:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:45][C:44]1[CH:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[N:41]2)=[CH:36][C:35]=1[CH2:34][C:31]1[N:29]2[N:30]=[C:25]([C:13]3[CH:12]=[N:11][N:10]([CH2:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:14]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12

Procedure:
A solution of [2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 77 mg, 0.240 mmol), 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 55 mg, 0.160 mmol), PdCl2(PPh3)2 (5.6 mg) and 2 M K2CO3 (0.216 mL) in DME (0.5 mL was stirred at 90° C. for 2 h under argon atmosphere. The RM was then diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, evaporated to dryness and the residue was purified (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/DCM/MeOH 9:1=100:0->0:100) to afford the title compound (tR 3.97 min (conditions 3), MH+=473.1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C([Li])CCC.[CH3:19][S:20]SC.[OH-].[Na+]>O1CCCC1>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:20][CH3:19])[CH:3]=2)[CH:8]=1
Reactant: CSSC
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2cc(SC)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A solution of 2-bromo-6-methoxynaphthalene (22.2 g, 93.6 mmol) in tetrahydrofuran (500 ml) was cooled to -78° C. and n-butyllithium (75 ml 1.6 M in THF, 121.7 mmol) was added dropwise over 15 minutes. After 0.5 h, dimethyl disulfide (13 ml, 140 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 16 h, 1N sodium hydroxide (100 ml) was added and the reaction mixture was stirred for 1 h. The organic layer was separated and washed with 1N sodium hydroxide, 5% aqueous sodium sulfite, and brine, and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was recrystallized form ethyl acetate and hexane to give 11.1 g of 2-methoxy-6-methylthio-naphthalene as a solid (58% yield).