Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(OCC)(=O)C.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.C1(C)C=CC=CC=1>[CH3:11][N:6]1[CH:5]=[C:4]2[C:8]([CH:9]=[CH:10][C:2]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[C:3]2[CH:12]2[CH2:14][CH:13]2[CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[N:7]1
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)NCC1CC1c1c(Br)ccc2nn(C)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)NCC1CC1c1c(-c2cccnc2)ccc2nn(C)cc12
Temperature: 80 °C
Yield: 94 %

Procedure:
N-{[2-(5-Bromo-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (200 mg, 0.621 mmol) obtained in Example 29, pyridin-3-ylboronic acid (191 mg, 1.552 mmol), 2 M aqueous sodium carbonate solution (6 mL) and tetrakis(triphenylphosphine)palladium(0) (71.8 mg, 0.062 mmol) were added to a mixed solution of ethanol (3 mL) and toluene (3 mL), and the mixture was stirred under nitrogen atmosphere with heating at 80° C. for 16 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was is purified by silica gel column chromatography (methanol/ethyl acetate=0/100→20/80) to give the title compound (187 mg, yield 94%)
Reaction SMILES: C1COCC1.C([O:8][C:9](=O)[C:10]([C:13]1[CH:14]=[N:15][C:16]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=3)=[O:24])=[C:17]([O:19][CH2:20][CH3:21])[CH:18]=1)([OH:12])[CH3:11])C.[BH4-].[Li+]>[Cl-].[Na+].O>[OH:12][C:10]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH3:21])[C:16]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=3)=[O:24])=[N:15][CH:14]=1)([CH3:11])[CH2:9][OH:8]
Reactant: CCOC(=O)C(C)(O)c1cnc(NC(=O)c2cc3cc(Cl)ccc3[nH]2)c(OCC)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(C)(O)CO)cnc1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a THF (2 mL) solution of 2-{6-[(5-chloro-1H-indole-2-carbonyl)-amino]-5-ethoxy-pyridin-3-yl}-2-hydroxy-propionic acid ethyl ester (90 mg) was added lithium borohydride (2M in THF), and the reaction was stirred for 1 hr. The reaction mixture was diluted with brine and extracted with EtOAc. The extracts were dried over magnesium sulfate, filtered, and evaporated to yield a colorless syrup. Further purification on a silica gel prep plate (10% methanol/methylene chloride) afforded 21 mg of the pure title compound as an off-white solid. LC/MS+=390.
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[C:32]1([CH:38]2[CH2:42][CH2:41][NH:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[C:32]1([CH:38]2[CH2:42][CH2:41][N:40]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(CCOC(=O)N2CCC(c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.8 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 2.10 g, 6.79 mmol) was dissolved in DMF (30 mL). DIPEA (2.37 mL, 13.59 mmol) and 3-phenylpyrrolidine (1.00 g, 6.79 mmol) were added and the reaction mixture was stirred at room temperature for 4 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (300 mL) and washed with 1M aq Na2CO3 solution (6×200 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (2.0 g) was added, the reaction mixture shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (60 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo, to give 2-(4-methylpiperazin-1-yl)ethyl 3-phenylpyrrolidine-1-carboxylate (1.03 g, 48.0%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([S:16][CH3:17])[CH:15]=2)=[CH:6][C:5]([N:18]=[CH:19][N:20](C)C)=[C:4]([C:23]#[N:24])[CH:3]=1.[CH:25](N)([CH3:27])[CH3:26].ClCCl.CO>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([S:16][CH3:17])[CH:15]=1)[N:18]=[CH:19][N:20]=[C:23]2[NH:24][CH:25]([CH3:27])[CH3:26]
Reactant: CSc1cncc(COc2cc(N=CN(C)C)c(C#N)cc2Br)c1
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CO
Product: CSc1cncc(COc2cc3ncnc(NC(C)C)c3cc2Br)c1
Yield: 77 %

Procedure:
According to GWP 5, the reaction of N′-(4-bromo-2-cyano-5-{[5-(methylsulphanyl)-pyridin-3-yl]methoxy}phenyl)-N,N-dimethylformimidamide (540 mg, 1.33 mmol) with isopropylamine (0.14 mL, 1.6 mmol) and chromatography (silica gel, dichloro-methane/methanol: 0→30% methanol) gives the desired product in 77% yield (430 mg)
Reaction SMILES: CS[S:3][CH3:4].N(OC(C)(C)C)=O.N[C:13]1[C:17]([Cl:18])=[C:16]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:15]([CH3:31])[N:14]=1.O>C(Cl)Cl>[Cl:18][C:17]1[C:13]([S:3][CH3:4])=[N:14][N:15]([CH3:31])[C:16]=1[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:28])([F:27])[F:29])=[CH:21][C:20]=1[Cl:30]
Reactant: Cn1nc(N)c(Cl)c1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: O
Product: CSc1nn(C)c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethyl disulfide (0.14 ml) and 0.2 ml of tert-butyl nitrite were added dropwise to a solution of 0.2 g of 3-amino-4-chloro-5-(2,6-dichloro-4-trifluoromethylphenyl)-1-methylpyrazole (18) in 5 ml of dry methylene chloride with ice cooling. The mixture was stirred at 0° C. for 30 minutes and thereafter poured into water, followed by extraction with chloroform. The organic layer was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography on silica gel, giving 0.2 g of the desired compound in the form of a light brown oil (quantitative yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11].[H][H]>CCO.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][P:6](=[O:12])([O:5][CH2:4][CH2:3][O:2][CH3:1])[O:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:19][CH:18]=1
Reactant: COCCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCCOC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCOP(=O)(Cc1ccc(N)cc1)OCCOC
Yield: 97.1 %

Procedure:
A mixture of bis(2-methoxyethyl)(4-nitrobenzyl)phosphonate (Compound 185B, 6.0 g, 18 mmol) and 5% Pd/C (0.8 g) in EtOH (150 mL) was hydrogenated under 40 psi hydrogen pressure at 40° C. for 6 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (5.3 g, 97%). 1H NMR (CDCl3, 400 MHz): δ=3.04 (d, J=21.2 Hz, 2 H), 3.28 (s, 6 H), 3.42-3.46 (m, 4 H), 3.97-4.03 (m, 4 H), 6.55 (d, J=8.4 Hz, 2 H), 6.99-7.02 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])(=[O:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][Cl:46]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:45][Cl:46])=[O:35])(=[O:25])=[O:24]
Reactant: ClCBr
Reactant: O=C(O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: O=C(CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)OCCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoic acid (0.060 mole) is dispersed with stirring in a methanol-water mixture (100 mL), and an aqueous solution of cesium carbonate (2 molar) is added dropwise until the solution pH is 6.6. The volatiles are removed by spin evaporation in vacuo. The resulting cesium salt is dried by addition of toluene and removal of the volatiles under reduced pressure. This is repeated several times. The dry cesium salt is dissolved in dimethylformamide (100 mL), and bromochloromethane (Aldrich) (0.060 mole) is slowly added to the solution. The reaction is stirred at ambient temperature in the dark for 12 hours. The mixture is filtered to remove cesium bromide, and the volatiles are removed by spin evaporation in vacuo. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give chloromethyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]I>C(#N)C.[Ag]=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH3:17])[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1nc(CO)cs1
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COCc1csc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
0.412 g of 2-(tert-butoxycarbonylamino)methyl-4-hydroxymethylthiazole was dissolved in 8 ml of acetonitrile. To this solution were added 0.98 g of silver oxide and 0.5 ml of methyl iodide, and the mixture was stirred at room temperature for 6 hours. The reaction solution was filtered, and then concentrated to dryness to give 0.385 g (yield 89%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:14])(=[O:24])=[O:23]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CNCCN1S(C)(=O)=O
Reaction time: 8 h
Yield: 38.8 %

Procedure:
First step: To a stirred solution of commercially available (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.38 g, 12 mmol) in CH2Cl2 (25 mL) at 0° C. were added pyridine (1.91 mL, 24 mmol) and methanesulfonyl chloride (0.92 mL, 12 mmol). Stirring was continued at RT overnight, the reaction was poured onto water and extracted with CH2Cl2. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The crude product was dissolved in CH2Cl2 (20 mL) and TFA (4 mL) was added. After 2 hours at RT, the volatiles were removed under vacuo, the crude was dissolved in CH2Cl2 and washed with aq. NaHCO3 (until pH=8). The organic phase was dried on Na2SO4 and concentrated under vacuo to yield 0.83 g (39%) of (s)-1-methanesulfonyl-2-methyl-piperazine as a light yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:29])=[N:11][N:10]=1>CN(C=O)C>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[CH2:21][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:10][N:11]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3cncn3)c2c1
Yield: 77.5 %

Procedure:
Operating substantially as described in example 50 starting from 1,2,4-triazole (0.19 g, 2.8 mmoles) in dry DMF (10 ml), NaH (0.084 g, 2.1 mmoles; 60% in oil) and 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.4 mmoles), prepared as described in example 45, 0.42 g of the title compound were obtained (yield: 77%). m.p.: 207-208° C.
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]([NH2:20])=O)[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O=P(Cl)(Cl)Cl>[CH2:1]([C:13]1[CH:14]=[C:15]([C:18]#[N:20])[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1csc(C(N)=O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1csc(C#N)c1
Yield: 53.1 %

Procedure:
4-Dodecyl-thiophene-2-carboxylic acid amide 2 (5.0 g, 16.9 mmol) was mixed with 50 mL of POCl3 and the mixture was heated at reflux temperature for 2 hours before POCl3 was removed by a rotary evaporator. Dichloromethane (100 mL) was added followed by drop-wise addition of ice water (100 mL). The organic layer was washed with 30 mL of water twice before the solvent was removed. The brown oil obtained was purified with a column of silica gel with hexane/dichloromethane (v/v: 1/1) as the eluent. After removal of the solvent, the product was obtained as a yellow oil (2.49 g, 53% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16]2.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH:19]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(-c3ccccc3[N+](=O)[O-])ccc2c1
Temperature: 110 °C
Reaction time: 7 h
Yield: 42.8 %

Procedure:
To a suspension of 2-iodo-1-nitrobenzene (2.5 g), (6-methoxynaphthalen-2-yl)boronic acid (2.9 g) and tetrakis(triphenylphosphine)palladium(0) (600 mg) in toluene (50 ml) was added an aqueous solution of 2N sodium carbonate (15 ml) under a nitrogen atmosphere, and the solution was stirred for 7 hours at 110° C. Ethyl acetate was added thereto, the solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:20])[CH2:15][C:16]([CH2:18]Cl)=O)[CH3:12].O>CCO>[CH2:11]([O:13][C:14](=[O:20])[CH2:15][C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:18]=1)[CH3:12]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1csc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Dissolve 4-chlorothiobenzamide (74.0 g, 431.1 mmol) in EtOH (470 mL) and treat with ethyl-4-chloroacetoacetate (58.0 mL, 70.1 g, 426.0 mmol). Stir the resulting solution mechanically at reflux for 2 h. Cool to room temperature, add water (1000 mL), and extract with Et2O (2000 mL, then 2×500 mL). Combine the organic solutions and wash with brine (950 mL). Concentrate in vacuo to give an oil that solidifies upon standing (121.8 g). Recrystallize the crude material from isopropanol/water to give the title compound (107.3 g, 89% yield). ES/MS m/z (35Cl) 282.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16]2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(C[C@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C1CC1)N1CC[C@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 65 %

Procedure:
In a round bottom flask equipped with reflux condenser, N-(4-bromophenyl)-2-{[(3R)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (1.896 mmol) in water (75 mL) was treated with potassium carbonate (9.48 mmol). The resulting slurry was stirred at reflux overnight (15 h). The heating was turned off and the reaction was allowed to cool to room temperature. The pH was adjusted to ˜4 using 6N aq HCl. The aqueous solution was concentrated in vacuo to ˜50 mL, which was then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% methanol/dichloromethane). The fractions were concentrated in vacuo to provide the title compound as an off-white amorphous solid (65%). MS(ES)+ m/e 391.1, 393.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:20])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:7]([CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([O:27][CH3:28])=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[C:13]([CH3:20])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:23][CH2:22][CH2:21][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3C)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
To a solution of methyl 4-chloro-1-(3-hydroxypropyl)-2-[(6-methoxy-2-methylpyridin-3-yl)amino]-1H-benzimidazole-7-carboxylate (Reference example 156, 6.40 g, 15.81 mmol) in tetrahydrofuran (42.0 mL) were added triethylamine (4.42 mL, 31.62 mmol) and methanesulfonyl chloride (1.84 mL, 23.71 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1.5 hrs. The mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting mesylate was dissolved into N,N-dimethylformamide (67.0 mL) and to the solution was added potassium carbonate (4.27 g, 31.62 mmol). The mixture was stirred at 70° C. for 4 hrs. After cooling, the mixture was diluted with water. The generated precipitate was collected by filtration and washed with diisopropyl ether to give the title compound as a colorless solid (5.50 g, 14.22 mmol, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)=[CH:16][CH:15]=3.[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C)c21
Reactant: COCC(=O)Cl
Product: COCC(=O)n1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 70 above, with the compound from Example 39 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and methoxyacetyl chloride.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14].C(=O)([O-])O.[Na+]>O.CC(C)=O>[CH2:16]([O:15][C:13]([O:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:14])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC(=O)Cl
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C#N)=NOC(=O)OCC(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of sodium salt of ethyl 2-hydroxyimino-2-cyanoacetate (16.4 g) in water (100 ml), isobutyl chloroformate (13.7 g) and acetone (10 ml) are added, and the resulting mixture is stirred at a temperature lower than 20°C. After adjusting pH to 7 with the addition of an aqueous solution of sodium hydrogencarbonate, stirring is continued for 3 hours. The reaction mixture is extracted with ethyl acetate, and the organic layer is washed with water, dried and concentrated. The residue is crystallized with the addition of petroleum ether and collected by filtration. Recrystallization from petroleum ether containing a small amount of ethyl acetate affords ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate (14.1 g) as scales. M.P. 60 to 62°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]#[C:10][CH2:11][OH:12]>C1(C)C=CC=CC=1>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][C:9]#[C:10][CH2:11][OH:12])[CH2:2][CH2:3]1
Reactant: OCC#CCCl
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: OCC#CCN1CCOCC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a mixture of morpholine (4.36 g) in toluene (15 mL) was added 4-chlorobut-2-yn-1-ol (2.09 g) in toluene (5 mL). The mixture was stirred at 85° C. for three hours. After cooling, the solid was filtered off. The filtrate was subjected to vacuum distillation to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]1=[O:9]>C(OCC)(=O)C.[Pt]=O>[CH3:1][N:2]1[CH2:7][CH:6]([CH3:8])[NH:5][CH2:4][C:3]1=[O:9]
Reactant: Cc1cn(C)c(=O)cn1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC1CN(C)C(=O)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,5-dimethylpyrazin-2(1H)-one (5.7 g, 45.9 mmol) and platinum oxide (0.57 g) in ethyl acetate (100 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum to provide 1,5-dimethyl-piperazin-2-one.