Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]2=[C:10]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:49])[NH:37][C:38]4[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=4[F:48])=[C:31]([F:50])[CH:30]=3)[C:11]([CH2:26][O:27][CH3:28])=[C:12]([C:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=3)[N:8]2[N:7]=[CH:6][N:5]=1>[Pt]=O.C(O)(=O)C>[NH2:3][C:4]1[C:9]2=[C:10]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:49])[NH:37][C:38]4[CH:43]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:41]=[CH:40][C:39]=4[F:48])=[C:31]([F:50])[CH:30]=3)[C:11]([CH2:26][O:27][CH3:28])=[C:12]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]3)[N:8]2[N:7]=[CH:6][N:5]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]
Agent: N#N
Solvent: CC(=O)O
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 17 h
Yield: 75.3 %

Procedure:
To a flask charged with N2 was added tert-butyl 4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-6-(methoxymethyl)-pyrrolo-[2,1-f][1,2,4]triazin-7-yl}-3,6-dihydropyridine-1(2H)-carboxylate (424 mg, 0.629 mmol, 1.0 eq) followed by glacial acetic acid (40 mL). To this solution was added platinum oxide (42 mg, 10% w/w). The reaction solution was evacuated via vacuum and replaced with nitrogen (5×). The reaction mixture was then evacuated again via vacuum and placed under 1 atm of hydrogen and was allowed to stir for 17 hours. The solution was filtered through a pad of celite, washed with acetic acid and concentrated. The crude concentrate was dissolved in EtOAc and washed with saturated sodium bicarbonate. The organic layer was dried (Na2SO4), filtered, condensed, and purified via flash chromatography (1:1 tetrahydrofuran/hexanes). The purified fractions were collected, evaporated, and left under vacuum overnight to yield the title compound (320 mg, 75.3% yield). 1H-NMR (DMSO-d6) MS [M+H]+=676; LCMS RT=3.52 min.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN1C(=O)CCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=3)[N:3]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Fc1ccccc1-c1nc(Cl)nc2ccc(Cl)cc12
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3F)c3cc(Cl)ccc3n2)CC1
Yield: 66 %

Procedure:
A mixture of 2,6-dichloro-4-(2-fluoro-phenyl)-quinazoline (0.92 g, 3.14 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 4.08 mmol, 1.3 equiv; commercially available) in anhydrous NMP (8 mL) was heated by microwave irradiation to 180° C. for 40 min. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified by column chromatography on silica eluting with a gradient of heptane/ethyl acetate (6:1 h 1:1) providing 0.66 g (66%) of the title compound. MS (ISP): 457.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:20])[C:4](=[O:19])[C:5]2[C:6](=[N:8][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:7]=1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24].O>CN1C(=O)CCC1>[OH:24][CH2:23][C:22]([NH:21][C:2]1[N:3]([CH3:20])[C:4](=[O:19])[C:5]2[C:6](=[N:8][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:7]=1)([CH3:26])[CH3:25]
Reactant: Cn1c(Cl)nc2nn(Cc3ccc(Br)cc3)cc2c1=O
Reactant: CC(C)(N)CO
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1c(NC(C)(C)CO)nc2nn(Cc3ccc(Br)cc3)cc2c1=O
Temperature: 122.5 °C
Yield: 74.3 %

Procedure:
A mixture of 6-chloro-5-methyl-2-(4-bromobenzyl)-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (157 g, 444 mmol) and 2-amino-2-methylpropan-1-ol (236 g, 2.65 mol) in NMP (1.3 L) is heated at 120-125° C. for 2 h, and then poured into cold water. After filtration, the filter cake is washed with water twice, and then dried under vacuum to give 134 g of product (yield: 74%). MS (ESI) m/z 406.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].C(N(CC)CC)C.[Cl:21][CH2:22][CH2:23][C:24](Cl)=[O:25].Cl>C(Cl)Cl>[Cl:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12])=[O:25]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Reaction time: 2 h
Yield: 78.9 %

Procedure:
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (250 mg, 1.28 mmol) and triethylamine (0.18 mL, 1.28 mmol) were stirred in DCM (5 mL). 3-chloropropionylchloride (162 mg, 1.28 mmol) was added dropwise under a nitrogen atmosphere. Stirring was continued for 2 h. 2 M HCl (20 mL) was added and the reaction mixture extracted into DCM (3×50 mL). The combined DCM layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to give the desired product as a yellow solid (290 mg, 1.01 mmol, 79%).
Reaction SMILES: [CH2:1]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([CH3:13])[C:8]([CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[CH3:17])[CH2:2][C:3]#[CH:4].C([Li])CCC.Cl[C:24]([O:26][CH3:27])=[O:25].[Cl-].[NH4+]>C1COCC1>[CH3:12][O:11][C:10]1[C:9]([CH3:13])=[C:8]([CH3:14])[C:7]([O:15][CH3:16])=[C:6]([CH3:17])[C:5]=1[CH2:1][CH2:2][C:3]#[C:4][C:24]([O:26][CH3:27])=[O:25]
Reactant: C#CCCc1c(C)c(OC)c(C)c(C)c1OC
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CCCc1c(C)c(OC)c(C)c(C)c1OC
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 5 g (21.5 mmol) of 1-(3-butynyl)-3,6-dimethoxy-2,4,5-trimethylbenzene in 80 ml of THF was cooled to -78° C. and treated firstly with 13.4 ml of a 1.6M n-butyllithium solution and then with 2.2 g (23.3 mmol) of methyl chloroformate. The mixture was left at -78° C. for 1 hour, then warmed to -20° C., held at this temperature for 2 hours and finally poured into saturated ammonium chloride solution. Extraction with ethyl acetate yielded, after washing the extracts with water and drying over sodium sulphate, a yellow oil which was purified on silica gel (eluent: hexane/ethyl acetate 95:5→90:10). There were obtained 3.6 g of spontaneously crystallizing methyl 5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-pentynoate. M.P. 71°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[O:23][CH3:24])(=[O:13])=[O:12])[C:6](=[O:25])[C:5]2([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[NH:26][CH3:27].CO>[Ni].C1COCC1>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)([NH:26][CH3:27])[C:6]2=[O:25])(=[O:12])=[O:13])=[C:15]([O:23][CH3:24])[CH:16]=1
Reactant: CNC1(CC2CCCCC2)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2OC)c2ccc(Cl)cc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CNC1(CC2CCCCC2)C(=O)N(S(=O)(=O)c2ccc(N)cc2OC)c2ccc(Cl)cc21
Reaction time: 0.67 h
Yield: 53.1 %

Procedure:
A mixture of 1.2 g of the compound obtained in EXAMPLE 102, 3 g of Raney® nickel, 30 ml of MeOH and 40 ml of THF is hydrogenated at atmospheric pressure and at RT. After 40 minutes, the catalyst is filtered off on C elite® and the filtrate is evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (75/25; v/v) as the eluent to give 0.6 g of the expected product, which is used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Temperature: 50 °C
Reaction time: 144 h
Yield: 54.9 %

Procedure:
A mixture of 2-amino-5-morpholin-4-yl-benzamide (820.0 mg, 3.71 mmol, Heterocyclic Comm. 2001, 7, 473-480), 2,4,5-trichloropyrimidine (679.8 mg, 3.71 mmol) and potassium carbonate (614.6 mg, 4.45 mol) in THF (10 mL) was stirred at 50° C. for 20 h and at RT for 6 days. The reaction was diluted with water (10 mL) and extracted into EtOAc. The organic layer was washed with NaHCO3, brine and dried by passing through a funnel filled with MgSO4. The filtrate was evaporated and the residue triturated with ether (5×3 mL) to afford 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-benzamide as a yellow solid (0.75 g) that was used without further purification in the subsequent step.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([NH:16][CH2:17][CH2:18][OH:19])(=[O:15])=[O:14].[H-].[Na+].[Na].[C:25]1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([N:16]([CH2:17][CH2:18][OH:19])[CH3:25])(=[O:15])=[O:14]
Reactant: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)N(C)CCO
Reaction time: 20 h

Procedure:
A solution of N,N-Dimethyl-2-(N-(2-hydroxyethyl) aminosulfonyl]-6-nitrobenzamide (3.97 g, 12.5 mmol) in dry DMF (40 ml) was added slowly to a stirred suspension of 50% NaH (0.60 g, 12.5 mmol) in dry DMF (10 ml) under N2 at 20°-25°. After formation of the sodium salt was complete, a solution of methyl p-toluenesulfonate (2.40 g, 12.9 mmol) in DMF (4 ml) was added and the reaction mixture stirred at 20°-25° for 20 hours and then at 60° for 23 hours. The orange solution was mixed with EtOAc (400 ml) and the white solid which formed was filtered off. This precipitate was washed with EtOAc (100 ml). The combined EtOAc solutions were washed with a saturated aqueous NaCl solution, dried (Na2SO4), filtered and concentrated under reduced pressure. Pure product, mp 107°-08°, 2.5 g (60%) was obtained by flash chromatography over silica gel and elution with a 65% n-butylchloride-35% acetonitrile solvent mixture.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1.[C-]#N.[Na+]>CN(C)C=O.O>[CH:1]1([O:6][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: Brc1ccsc1
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(OC2CCCC2)cs1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a solution of cyclopentanol (8.75 ml, 95.8 mmol) in N,N-dimethylformamide (250 mL) was added sodium hydride (60% dispersion in mineral oil, 3.84 g, 95.8 mmol) at 0–5° C. under nitrogen. After 10 minutes, the mixture was allowed to reach room temperature and stirred for 40 minutes. 3-Bromothiophene (3.59 mL, 38.3 mmol) was added followed by cuprous iodide (14.63 g, 76.8 mmol). The mixture was heated at 120° C. for 22 hours. After cooling to about 10° C., a solution of sodium cyanide (12.1 g, 0.25 mol) in water (200 mL) was added under vigorous stirring. The mixture was stirred for additional 10 minutes then filtered. The filtrate was extracted with hexane. The extract was washed with water, dried (Na2SO4) and concentrated to dryness. Distillation (100° C., 8 mm Hg) gave 3-cyclopentyloxythiopene (4.52 g, 70%) as a slightly pale yellow oil; 1H NMR (300 Mz, CDCl3) δ 7.15 (dd, J=5.2, 3.1 Hz, 1H), 6.72 (dd, J=5.2, 15 Hz, 1H) 6.19 (dd, J=3.1, 1.5 Hz, 1H), 4.65 (quintet, J=4.2 Hz, 1H), 1.55–1.95 (m, 8H). MS m/e (%): 168 (M+; 17).
Reaction SMILES: [OH-].[K+].[C:3]([CH:5]([C:10]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C(OC)=O)#[N:4].O>C(O)CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2([CH2:5][C:3]#[N:4])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(C#N)C1(c2ccc(F)cc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: N#CCC1(c2ccc(F)cc2)CCOCC1
Temperature: 120 °C

Procedure:
To a pre-dissolved solution of KOH (441 mg, 7.87 mmol) in ethylene glycol (20 ml) was added methyl 2-cyano-2-[4-(4-fluorophenyl)oxan-4-yl]acetate (1.09 g, 3.93 mmol). The mixture was heated to 120° C. for 3 h, and then cooled. H2O was added (50 ml), the product extracted with Et2O (3×50 ml), washed with H2O (50 ml), dried over NA2SO4, filtered and concentrated. Purified by normal phase SiO2 chromatography (5 to 40% EtOAc/hexanes) to give 2-[4-(4-fluorophenyl)oxan-4-yl]acetonitrile as a colorless oil (450 mg, 78%, m/z: 219.1 [M+H]+ observed).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]3[N:29]=[C:28]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH:27]=[CH:26][N:25]=3)[CH:17]=2)=[O:14])=[CH:11][CH:10]=1>C(O)C.O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:37][CH:36]=2)=[CH:17][C:18]=1[NH:23][C:24]1[N:29]=[C:28]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: C1CNCCN1
Solvent: CCO
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
25.8 g (300 mmol) of piperazine are suspended in a mixture of 25 ml of ethanol and 25 ml of water. After almost a clear solution has formed, 12.9 g (30 mmol) of 4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide are added step by step. The yellow solution is boiled under reflux for 14 hours, cooled to room, temperature and filtered over Celite. 100 ml of water is added to the solution, the ethanol is evaporated under vacuum and 30 ml of 1N NaOH is added, leading to crystallization of the product. Drying at 50 mbar and 60° C. yields N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide; Rf=0.15 (methylene chloride:ethyl acetate:methanol:conc. aqueous ammonium hydroxide solution=60:10:30:2); tR (HPLC)2) 14.6 min.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([C:13]2[N:18]=[C:17]3[N:19]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:20](=[O:23])[CH2:21][NH:22][C:16]3=[N:15][CH:14]=2)[CH:8]=[C:9]([CH3:12])[C:10]=1[NH2:11]>CN(C)C=O.CO>[NH2:1][C:2]1[NH:4][C:5]2[CH:6]=[C:7]([C:13]3[N:18]=[C:17]4[N:19]([CH2:24][CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:20](=[O:23])[CH2:21][NH:22][C:16]4=[N:15][CH:14]=3)[CH:8]=[C:9]([CH3:12])[C:10]=2[N:11]=1
Reactant: Cc1cc(-c2cnc3c(n2)N(CC2CCOCC2)C(=O)CN3)cc(N)c1N
Reactant: N#CBr
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(-c2cnc3c(n2)N(CC2CCOCC2)C(=O)CN3)cc2[nH]c(N)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
Cyanogen bromide (0.059 g, 0.556 mmol) in N,N-dimethylformamide (0.5 mL) was added to a stirred solution of 7-(3,4-diamino-5-methylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.195 g, 0.529 mmol) in N,N-dimethylformamide (3 mL) at 0° C. The resulting dark brown mixture was capped and stirred at room temperature for 16 h. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparatory HPLC (5-50% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. The residue was loaded onto a Strata X-C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol eluent and was concentrated under reduced pressure and dried under high vacuum at 50° C. to give the desired product (0.130 g, 0.331 mmol, 62% yield) as an orange solid. 1H NMR (400 MHz, D2O and DMSO-d6) δ (ppm) 8.13 (s, 1H), 7.56 (s, 1H), 7.36 (s, 1H), 4.18 (s, 2H), 4.03 (d, J=6.64 Hz, 2H), 3.84-3.90 (m, 2H), 3.24 (t, J=11.32 Hz, 2H), 2.40 (s, 3H), 2.04-2.19 (m, 1H), 1.59 (d, J=12.10 Hz, 2H), 1.25-1.41 (m, 2H); MS (ESI) m/z 394.2 [M+1]+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[N+:16]([O-])=O)(O)=[O:2].[H][H].O>C(O)(=O)C.[C].[Pd]>[O:2]=[C:1]1[CH2:4][C:5]2[C:6](=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=2)[NH:16]1
Reactant: CCOC(=O)c1ccc(CC(=O)O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)C2

Procedure:
4 g (15.8 mmol) of the thus obtained ethyl 4-(carboxymethyl)-3-nitrobenzoate and 0.45 g of 10% palladium-carbon were suspended in 15 mL of acetic acid, and the resulting mixture was stirred at room temperature in a hydrogen gas atmosphere for 23 hours. After completion of the reaction, water was added to the reaction mixture and the mixture was filtered to remove insoluble matter, and the filtrate was subjected to extraction with chloroform. The obtained chloroform layer was evaporated to dryness under reduced pressure, and water was added to the residue. Precipitated ethyl 2-oxoindoline-6-carboxylate was then obtained by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=4[CH3:28])[C:21]([O:23]C)=O)[CH:14]=3)[C:9]2=[O:29])=[CH:5][CH:4]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.C([Mg]Cl)(C)C>O1CCCC1>[CH:32]1([NH:35][C:21](=[O:23])[C:20]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[C:9](=[O:29])[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[CH:17]=[CH:16]4)[CH:19]=2)[CH2:34][CH2:33]1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(OC)cc4)ccc3c2)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(Cn2ccc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-4-methyl-benzoic acid, methyl ester (product of step v)) (1.0 g) and cyclopropylamine (0.71 g) in tetrahydrofuran (3 mL) was treated with isopropylmagnesium chloride (2M in THF, 0.77 mL) and stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride and extracted into ethyl acetate. The organic phase was dried, filtered and evaporated to yield the title compound as a solid (850 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:34])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=O)[CH:24]([NH:26][C:27]([O:29]CC)=O)[CH3:25])=[CH:19][C:18]=2[Cl:33])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:36][NH2:37]>C(O)CCC>[Cl:33][C:18]1[CH:19]=[C:20]([C:23]2[CH:24]([CH3:25])[NH:26][C:27](=[O:29])[NH:36][N:37]=2)[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:34]
Reactant: NN
Reactant: CCOC(=O)NC(C)C(=O)c1ccc(OCC(=O)NCCc2ccc(OC)c(OC)c2)c(Cl)c1
Solvent: O
Solvent: CCCCO
Product: COc1ccc(CCNC(=O)COc2ccc(C3=NNC(=O)NC3C)cc2Cl)cc1OC
Yield: 21.5 %

Procedure:
A mixture of 556 mg of N-[2-(3,4-dimethoxyphenyl)-ethyl]-α-{2-chloro-4-[2-(ethoxycarbonylamino)propionyl]phenoxy}acetamide [prepared as described in step (c) above] and 723 mg of hydrazine hydrate in 7 ml of butanol was heated under reflux for 67 hours. At the end of this time, the mixture was cooled, and the butanol used as the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 10:1 by volume mixture of chloroform and methanol, to give 112 mg of the title compound as a white powder melting at 167°-169° C. (with decomposition).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[N:25][C:26](Cl)=[CH:27][C:28]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[C:18]([C:36]#[N:37])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=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>[C:36]([C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[N:25][C:26]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=2)=[CH:27][C:28]=1[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)#[N:37]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2cnc(Cl)cc2-c2cccnc2)c(C#N)c1
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: O
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cccnc1
Reaction time: 0.08 h
Yield: 31.5 %

Procedure:
10 mg (0.03 mmol) of tert-butyl((4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-3-cyanophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.6 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.