Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:34][O:35][C:36]([C:38]1([NH2:46])[CH2:43][CH2:42][N:41]([O:44][CH3:45])[CH2:40][CH2:39]1)=[O:37]>O1CCCC1>[CH3:34][O:35][C:36]([C:38]1([NH:46][C:9](=[O:11])[CH2:8][C:6]2[CH:7]=[C:2]([Br:1])[C:3]([F:13])=[CH:4][C:5]=2[CH3:12])[CH2:43][CH2:42][N:41]([O:44][CH3:45])[CH2:40][CH2:39]1)=[O:37]
Reactant: Cc1cc(F)c(Br)cc1CC(=O)O
Reactant: COC(=O)C1(N)CCN(OC)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2cc(Br)c(F)cc2C)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid (preparation example P5.3) (8.0 g) and 1,1′-carbonyldiimidazole (5.8 g) in tetrahydrofuran (150 ml) was heated at reflux for 30 minutes. Upon cooling to room temperature, triethylamine (9.0 ml) and 4-amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride salt (preparation example P1, step P1.3) (13.8 g) were added and warming at reflux was continued for 3 hours. The cold reaction mixture was poured on water/ethyl acetate, the layers separated, the organic phase washed with brine, dried over sodium sulfate and concentrated. The residue was solubilised in ethyl acetate/cyclohexane 3:1 and purified by filtration on alumina. Yield: 6.83 g of 4-[2-(5-bromo-4-fluoro-2-methyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester as a solid, mp: 192-193° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(Cl)cc1Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2,4-dichlorophenyl)-5-(pent-1-enyl)pyridine (Example 147) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.80 (t, J=7.0 Hz, 3 H), 1.12-1.48 (m, 18 H), 2.12 (m, 1 H), 2.35 (m, 1 H), 3.26 (m, 1 H) 3.45 (m, 1 H), 4.31 (AB, J=12.0 Hz, 2 H), 7.16 (d, J=8.0 Hz, 1 H), 7.36 (dd, J=8.0, 2.0 Hz, 1 H), 7.54 (d, J=2.0, 1 H). Rf0.38 (10% ethyl acetate/n-hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:23][CH2:22][C:15]3([O:19][C:18](=O)[O:17][C:16]3=[CH2:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][C:15]3([O:19][C:18](=[O:17])[N:35]([CH2:31][CH2:32][CH2:33][CH3:34])[C:16]3=[CH2:21])[CH2:22][CH2:23]2)=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: C=C1OC(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: C=C1N(CCCC)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A mixture containing 8.2 g of 8-[4,4-bis(4-fluorophenyl)-3-butenyl]-4-methylene-2-oxo-1,3-dioxa-8-azaspiro[4,5]decane, 25 ml of xylene and 2.0 ml of butylamine is stirred at room temperature for 18 hours, then 0.8 g of p-toluenesulfonic acid monohydrate and 70 ml of xylene are added and the reaction mixture is boiled while azeotropically distilling off the water formed in the reaction. After termination of the reaction which is observed by thin layer chromatography (TLC), the mixture is cooled down and made alkaline to a pH of 9 to 10 by adding 5% by weight aqueous sodium hydroxide solution. After washing the organic phase with water to neutral and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The crude product obtained as evaporation residue is recrystallized from ethanol under clarifying by activated carbon to give the title product in 72.5% yield, m.p.: 92°-93° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:27])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:33][CH2:32][N:31]=[C:30]1SC.CCN(CC)CC>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]3[N:29]([CH3:28])[CH2:33][CH2:32][N:31]=3)=[CH:8][CH:7]=2)=[O:10])=[O:27])=[N:21][CH:22]=1
Reactant: CSC1=NCCN1C
Reactant: NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1CCN=C1NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (74 mg, 0.195 mmol), 1-methyl-2-methylthio-2-imidazoline (25 mg, 0.195 mmol), NEt3 (2 mL) and pyridine (5 mL) was stirred at 80° C. overnight, concentrated and HPLC (C18 reversed phase)eluting with 0.1% TFA in H2O/CH3CN gave N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-{[(1-methyl(2-imidazolin-2-yl))amino]methyl}phenyl)carboxamide (52 mg, 65%). MS found for C24H23ClN6O2 (M+H)+: 463.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:26])[C:13]([NH:15][N:16]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]1[C:22]([O:24]C)=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[N:32][CH:33]=1>>[Br:21][C:18]1[CH:19]=[CH:20][N:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:26])[C:17]=1[C:22](=[O:24])[NH:34][C:30]1[CH:31]=[N:32][CH:33]=[C:28]([F:27])[CH:29]=1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Nc1cncc(F)c1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cncc(F)c1
Yield: 69.6 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(benzyloxycarbonylamino)propanamido)-3-bromo-1H-pyrrole-2-carboxylate (2.00 g, 4.7 mmol) and 5-fluoropyridin-3-amine (4.23 g, 37.6 mmol) following the experimental procedure described in Preparation 44a. 1.65 g (69% yield) of the desired compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.Cl.[NH2:24][CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:24][CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2ncc(C(F)(F)F)cc2Cl)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester, 2-aminomethyl-3-chloro-5-(trifluoromethyl)pyridine hydrochloride and DBU in DME. ES-MS m/e (%): 396 (M{37Cl}+H+, 40), 394 (M{35C}+H+, 100).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[O:29]1[C:33]2[CH:34]=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][C:32]=2[O:31][CH2:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:8]3[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@H:2]4[CH3:1])=[N:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=4)[N:9]=3)=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@H]3C)nc2c1
Reactant: CC1(C)OB(c2ccc3c(c2)OCO3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCO4)c(N3CCC[C@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (5 mL) was added 2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 1.51 mmol), K3PO4 (380 mg, 1.79 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated under vacuum to give a residue, which was purified via silica gel chromatography (1%-5% ethyl acetate in petroleum ether) to afford (R)-methyl 2-(benzo[d][1,3]dioxol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (120 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:13][CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:4]2[CH2:5][N:6](CC2C=CC=CC=2)[CH2:7]1>O1CCCC1.[Pd]>[NH2:1][CH2:2][C:3]12[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13]1)[CH:8]1[CH:4]2[CH2:5][NH:6][CH2:7]1
Reactant: NCC12C=CC(CC1)C1CN(Cc3ccccc3)CC12
Agent: [Pd]
Solvent: C1CCOC1
Product: NCC12CCC(CC1)C1CNCC12

Procedure:
7.4 g (27.5 mmol) of 1-aminomethyl-4-benzyl-4-azatricyclo[5.2.2.02,6 ]undec-8-ene are hydrogenated in 100 ml of tetrahydrofuran using 1.5 g of palladium/active charcoal at 100° C./100 bar. The catalyst is filtered off with suction and the residue is distilled.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: OCCNCCO
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: OCCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 5, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and diethanolamine were converted to yield 2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-hydroxy-ethyl)-amino]-ethanol as white semisolid, MS: 465 (MH+, 1Br).
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:32][C:33]#[N:34])[CH2:26][N:25]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.[OH-].[Na+]>CO.O1CCCC1>[N:14]1[C:13]2[NH:9][CH:10]=[CH:11][C:12]=2[C:17]([C:18]2[CH:19]=[N:20][N:21]([C:23]3([CH2:32][C:33]#[N:34])[CH2:24][N:25]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])[CH2:26]3)[CH:22]=2)=[N:16][CH:15]=1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COC(=O)C(C)(C)C)cn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
A suspension of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 1.0 g, 2.06 mmol) in methanol (MeOH, 5 mL) and tetrahydrofuran (THF, 20 mL) was treated with a 1 M aqueous sodium hydroxide solution (NaOH, 2.3 mL, 2.3 mmol, 1. 12 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2-3 h. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and a 1 N aqueous HCl solution (0.2 mL) to adjust pH to 7-7.5 at room temperature. The resulting mixture was stirred at room temperature for 30 min before the solids were collected by filtration. The solids were washed with a mixture of acetonitrile and water (2/3 by volume, 2×4 mL) and dried in vacuum at 40-45° for 24 h to afford crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14, 658 mg, 765 mg theoretical, 86% yield) as off-white solids, which was found to be identical to the material prepared by Method A. For crude 14: 1H NMR (DMSO-d6, 300 MHz) δ 12.15 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.63 (d, 1H), 7.09 (d, 1H), 4.62 (d, 2H), 4.25 (d, 2H), 3.71 (s, 2H), 3.24 (q, 2H), 1.26 (t, 3H) ppm; C16H17N7O2S (MW, 371.42), LCMS (EI) m/e 372 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.C(NC(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: Cc1cccc(N)c1
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cnc(Cl)nc1Nc1cccc(C)c1

Procedure:
2,4-Dichloropyrimidine-5-carboxylic ethyl ester and m-toluidine were allowed to undergo the reaction in acetonitrile in the presence of diisopropylamine to obtain 2-chloro-4-[(3-methylphenyl)amino]pyrimidine-5-carboxylic ethyl ester. Said ester compound was hydrolyzed in THF with 1 M sodium hydroxide aqueous solution, and the resulting carboxylic acid compound was allowed to react with oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF and then treated with a mixture of aqueous ammonia and ice to obtain 2-chloro-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide. F: 263.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][O:12][CH:13]([O:17][CH3:18])[C:14](=O)[CH3:15].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH:14]([NH:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:15]
Reactant: COC(OC)C(C)=O
Reactant: COc1cccc(CN)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(CNC(C)C(OC)OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.7 %

Procedure:
(3-Methoxyphenyl) methanamine (100 g, 730 mmol, 1 equiv.) and 1,1-dimethoxypropan-2-one (172.2 g, 1.46 mol, 2 equiv.) were dissolved in acetic acid (1.8 L). Anhydrous sodium sulfate (207 g, 1.46 mol, 2 equiv.) was added. The mixture was stirred for 1.5 hour at room temperature. Sodium triacetoxyborohydride (463 g, 2.19 mmol, 3 equiv.) was added in portions over 40 minutes. The mixture was stirred for an additional 2 hours. Most of the acetic acid was removed under reduced pressure. The resulting black oil was dissolved in ethyl acetate (2 L) and saturated aqueous sodium bicarbonate (1 L) was added slowly followed by solid potassium carbonate to adjust the pH to 7. The organic layer was separated, dried over sodium sulfate and filtered. The filtrate was concentrated under reduce pressure to give a black oil which was purified by silica gel chromatography to give the title compound (120 g, ˜85% purity by LC/MS, 68% yield).
Reaction SMILES: C([N:3](C([O-])=O)[N:4]=[C:5]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)C.O=[S:21](Cl)Cl>>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:5]1[N:4]=[N:3][S:21][C:6]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCN(N=C(Cc1cccs1)c1cccs1)C(=O)[O-]
Reactant: O=S(Cl)Cl
Product: c1csc(-c2nnsc2-c2cccs2)c1
Temperature: 25 °C
Yield: 66 %

Procedure:
Acylhydrazine 31 (14.13 g, 14.04 mmol) was added to SOCl2 (60 ml) at 0° C. The reaction was allowed to warm to room temperature. The reaction was complete (by TLC) after 2 hours. SOCl2 was removed under reduced pressure. The dark residue was chromatographed on SiO2 (300 g), eluting with CH2Cl2. The isolated oil was bulb to bulb distilled at 0.2 mm (Hg) at 150° C. to yield 29 (2.3 g, 66.0%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([O:13]C2C=CC=CC=2)=O)[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:42]=2)=[O:13])[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Oc2ncnc3cc(OC)c(OC)cc23)c1
Yield: 66 %

Procedure:
In the manner described in Example 159B, ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate from the previous step (0.138 g, 0.4 mmol) was reacted with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 7 hours, to afford ethyl 2-(3-tert-butyl-5-{3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]ureido}-1H-pyrazol-1-yl)acetate as solid (0.145 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.59 (s, 1H), 8.56 (s, 1H), 7.59 (m, 1H), 7.56 (s, 1H), 7.39 (m, 2H), 7.22 (d, 1H), 6.94 (d, 1H), 6.11 (s, 1H), 4.85 (s, 2H), 4.16 (q, 2H), 3.99 (s, 6H), 1.19 (t and s, 12H); LC-MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[Cl:13].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:17]([O-:19])=[O:18])[C:6]([C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:5][C:4]=1[Cl:13]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(C(C)(C)C)cc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 2740.6 %

Procedure:
4-tert-Butyl-2-chlorophenyl methyl carbonate (36.0 g, 0.15 mol) was dissolved in conc. H2SO4 (100 mL) at 0° C. KNO3 (0.53 g, 5.2 mmol) was added in portions over 25 min. The reaction was stirred for 1.5 h and poured into ice (200 g). The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with aq. NaHCO3, dried over Na2SO4 and concentrated under vacuum to give 4-tert-butyl-2-chloro-5-nitrophenyl methyl carbonate (41.0 g), which was used without further purification.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:39])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of Boc-Phe(4-Cl)-OH (354 mg, 1.18 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 0.908 mmol) and CMPI (301 mg, 1.18 mmol) in THF (8 ml), TEA (0.38 ml, 2.72 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=40:1:0.05) to give Boc-Phe(4-Cl)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.45 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH3:24])[CH:9]=2)=[O:4].[Cu](C#N)[C:27]#[N:28].ClCCl>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:27]#[N:28])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH3:24])[CH:9]=2)=[O:4]
Reactant: CCc1ccccc1Oc1ccc2c(O)c(C(=O)OC)nc(I)c2c1
Reactant: N#C[Cu]C#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccccc1Oc1ccc2c(O)c(C(=O)OC)nc(C#N)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.5 %

Procedure:
A mixture of 7-(2-Ethyl-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid methyl ester (1.5 g, 3.34 mmole) and copper cyanide (598 ml, 6.68 mmole) in anhydrous dimethylformamide (13 ml) was refluxed for 5 minutes before it was cooled to room temperature and dichloromethane was added and stirred for 5 minutes. The suspension was filtered. The filtrate was washed with 0.1 N HCl, twice with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized with acetonitrile. The crystal was filtered and dried to give the title compound as a white solid (902 mg): MS: (+) m/z 349.08 (M+1), (−) m/z 347.10 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12]O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][Br:33])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methyl 3-bromo-5-(hydroxymethyl)benzoate (2.0 g, 8.2 mmol) and triphenylphosphine (4.28 g, 16.3 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. N-Bromosuccinimide (3.05 g, 17.1 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethylacete/hexanes) gave 2.1 g (83%) as a light brown oil. 1H-NMR (CDCl3, 300 MHz) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 4.42 (s, 2H), 3.90 (s, 3H). Mass spec.: 308.93 (MH)+.