Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[NH:17][C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:25]N(C)C=O>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]([CH3:22])[CH:18]([CH3:23])[N:17]([CH3:25])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C
Product: CC(C)OC(=O)c1cc(N2C(=O)C(C)C(C)N(C)C2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,5-dihydro-3,4,5-trimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 119°-120° C.,
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[CH2:12]1[O:15][C@H:13]1[CH3:14]>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([CH2:12][C@@H:13]([OH:15])[CH3:14])=[CH:5][CH:6]=1
Reactant: C[C@H]1CO1
Reactant: Clc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](O)Cc1ccc(Cl)s1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 2-chlorothiophene (8.17 g) in tetrahydrofuran (80 ml) is cooled to -30° C. and 1.6M n-butyllithium in hexanes (43.0 ml) is added dropwise. The mixture is stirred at -30° C. for about 1 hour, (S)-propylene oxide (4.00 g) is added, and the mixture is warmed to 0° C. and stirred at that temperature for about 3 hours. The reaction is quenched with saturated aqueous ammonium chloride solution, diluted with ether, and the layers separated. The organic layer is washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the desired product.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:21])=[O:20]
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2,5-dichlorobenzenesulfonyl chloride (2.46 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as apale yellow solid (1.65 g, 51%). 1H-NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.55 (s, 2H), 6.56 (s, 2H), 6.46 (s, 1H), 5.29 (s, 1H), 2.25 (s, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[CH:34][C:35](B4OC(C)(C)C(C)(C)O4)=[C:30]3[CH:29]=[CH:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:7][C:5]1[S:6][C:2]([C:35]2[CH:34]=[CH:33][N:32]=[C:31]3[N:27]([S:24]([C:21]4[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=4)(=[O:25])=[O:26])[CH:28]=[CH:29][C:30]=23)=[C:3]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c(Br)s1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4sc(C)nc4-c4ccc([N+](=O)[O-])cc4)ccnc32)cc1

Procedure:
Following the procedure described for Intermediate 6 with 5-bromo-2-methyl-4-(4-nitrophenyl)-1,3-thiazole and [(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine provided title compound. ESMS [M+H]+: 491.2
Reaction SMILES: C(O[C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:16]2[N:24]=[C:4]([OH:15])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:23]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)c1ccccc1
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1O
Yield: 64 %

Procedure:
The title compound was prepared by (a) reaction of diethylethoxymethylenemalonate (31 g, 144 mmol) with benzamidine (22 g, 144 mmol) under basic conditions to afford ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate in 64% yield in analogy to Example 15, (b) reaction of ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate (1.5 g, 6 mmol) and POCl3 (9.4 g, 62 mmol) to afford 81% of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate (12 g, 46 mmol) with hydrazine (4.4 g, 137 mmol) to afford 99% of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate (12 g, 46 mmol) with citraconic anhydride (10 g, 92 mmol) to afford 75% (12 g) of the title compound (m.p. 155-156° C.) in analogy to Example 21.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][CH:9]=1
Reactant: CC(=O)Nc1ncc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ncc(N)cn1
Reaction time: 2 h

Procedure:
To N-(5-nitropyrimidin-2-yl)acetamide (0.54 g, 3.0 mmol) suspended in EtOH (20 mL) under N2 was added palladium, 10 wt. % on activated carbon (0.32 g, 0.3 mmol). The reaction mixture was hydrogenated under 1 atm of H2 at RT for 2 h and then filtered through a pad of celite and washed with MeOH. The filtrate was concentrated to give N-(5-aminopyrimidin-2-yl)acetamide as a light-yellow solid. MS (ESI, pos. ion) m/z: 153 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([F:44])=[CH:31][N:30]=1>>[F:28][C:29]1[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:33][C:32]([F:44])=[CH:31][N:30]=1
Reactant: CC1(C)OB(c2cc(F)cnc2F)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc(F)cnc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a solid. UPLC-MS (Condition 3), tR=1.05 min, m/z=481.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.78 (br. s, 1H) 1.87 (br. s, 1H) 2.97 (br. s, 1H) 3.17-3.29 (m, 2H) 3.42 (dd, J=16.03, 7.04 Hz, 1H) 4.23 (br. s, 1H) 4.91 (br. s, 1H) 7.35 (m, J=8.60 Hz, 2H) 7.50 (br. s, 1H) 7.85 (m, J=8.99 Hz, 2H) 8.05-8.13 (m, 1H) 8.28-8.39 (m, 1H) 8.74-8.86 (m, 1H) 10.18 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][O:8][CH:9]=[CH:10][CH:11]=[CH2:12]>C(=O)([O-])O.[Na+]>[CH3:7][O:8][CH:9]1[CH:10]=[CH:11][CH2:12][CH:2]([C:1]([O:5][CH3:6])=[O:4])[O:3]1
Reactant: C=CC=COC
Reactant: COC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1CC=CC(OC)O1
Temperature: -70 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
The above-obtained solution was cooled to -70° C. in a dry ice-acetone bath. To this solution were successively added 88 mg (1 mmole) of methyl glyoxylate and 0.168 g (2 mmole) of 1-methoxy-1,3-butadiene. Reaction was then allowed to proceed at -30° C. for 3 hours, and 10 ml of a sodium hydrogencarbonate aqueous solution was added to the reaction mixture to terminate the reaction. This reaction mixture was filtered through Celite and then subjected to extraction once with a 20 ml of diethyl ether and twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (200 mesh; developing solvent: hexane/ethyl acetate=10/1), thereby obtaining 0.12 g of desired optically active 2-methoxy-6-methoxycarbonyl-5,6-dihydropyran (yield: 79%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[CH:18]=[CH:17][S:16][C:13]=2[NH:14][N:15]=1.[I:19]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[I:19][C:17]1[S:16][C:13]2[NH:14][N:15]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:12]=2[CH:18]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc2cc(-c3n[nH]c4sccc34)ccc2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1cc2c(-c3ccc4ccccc4c3)n[nH]c2s1
Temperature: 40 °C
Yield: 71.3 %

Procedure:
To a solution of 70 mg of 3-naphthalene-2-yl-1H-thieno[2,3-c]pyrazole obtained by Example 78 in 3.0 mL of N,N-dimethylformamide was added 63 mg of N-iodosuccinimide at room temperature, and stirred at 40° C. for a day. Then the solution was added with 1.0 mL of 10% sodium thiosulfate aqueous solution, and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to afford 75 mg of the title compound as colorless crystals.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2([CH3:17])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.C1COCC1.CCO.O[Li].O>O>[CH3:17][C:14]1([C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:13])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C1CCN(C(=O)C2(C)CC2)CC1
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred solution of 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (26.09 g, 0.109 mol) in 500 mL of a mixture of THF, EtOH and H2O) (1/1/1) was added LiOH.H2O) (6.86 g, 0.163 mol). After one hour at RT, the solvent were evaporated and the residue taken up in CH2Cl2 and the organic phase was washed with aqueous HCl 1M. The organic phases were dried over Na2SO4 and evaporated under vacuo to gave 19.8 g (86%) of the title compound as a white solid. ES-MS m/e: 212.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[N:6][C:5]=1[O:11][CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[C:5]([O:11][CH3:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(F)cnc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(F)cc1CO
Yield: 94.3 %

Procedure:
To 5-fluoro-2-methoxy-nicotinic acid methyl ester (35, 10 g, 54.0 mmol) in 200 mL of tetrahydrofuran, lithium aluminum hydride (81 mL, 1 M in tetrahydrofuran, 81 mmol) was added dropwise at −78° C. and stirred for several hours. The reaction was quenched with dropwise addition of 3 mL water, 3 mL of 15% aqueous sodium hydroxide, and 10 mL of water sequentially, then 200 mL of methyl t-butyl ether was added. Solids were filtered out and the filtrate concentrated under vacuum to provide the desired compound as a white solid (36, 8 g, 50.9 mmol, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([NH:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[CH:25]=1)#[N:2].Cl[C:27](OC1C=CC([N+]([O-])=O)=CC=1)=[O:28].N1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:10]1([CH3:13])[CH2:9][CH:8]([N:14]2[CH2:15][CH2:16][N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:27]2=[O:28])[C:7]2[CH:25]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: CC1(C)CC(NCCNCc2ccccc2)c2cc(C#N)ccc2O1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(N2CCN(Cc3ccccc3)C2=O)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-N'-benzylethylenediamine (0.91 g, 2.71 mmole, from Example 22, part A) and 4-nitrophenyl chloroformate (0.57 g, 2.85 mmole) in methylene chloride (22.5 ml) cooled to 0° C. was added pyridine (0.27 g, 3.39 mmole ). The reaction mixture was stirred at room temperature for 24 hours, diluted with methylene chloride and washed with 5% aqueous HCl solution, 2N NaOH solution and saturated NaCl solution. The extract was dried over MgSO4 and evaporated in vacuo to obtain 1.32 g of an orange gum. The crude product was chromatographed on silica eluting with hexane/ethyl acetate (3:2) to obtain 0.65 g (66%) of the title compound as a colorless amorphous solid, m.p.=45°-48° C. 1H NMR (CDCl3) δ7.51-7.39 (m, 7H), 6.9 3 (d, J=9.38 Hz, 1H), 5.43 (dd, J=7.03 and 11.14 Hz, 1H), 4.55 (m, 2H), 3.36-3.20 (m, 3H), 3.05 (m, 1H), 1.99 (m, 2H), 1.59 (s, 3H), 1.45 (s, 3H); 13C (CDCl3) δ160.77, 158.29, 136.70, 132.49, 1 31.66, 128.60, 128.03, 127.48, 121.38, 119.16, 1 18.61, 103.29, 76.94, 48.17, 45.15, 41.90, 37.26, 34. 96, 34.67, 29.75, 24.01; MS: (M+H)+ 169 362.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]O>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[O:23][CH3:22])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: COc1ccccc1CO
Product: COc1ccccc1CN1C(=O)C(CCO)Oc2ccccc21

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with the methanesulfonate ester of 2-methoxybenzyl alcohol, in 47% overall yield as a light yellow gum after flash chromatography, eluting with EtOAc/hexanes, IR (Neat) 3436, 2941, 1583, 1683, 1501, 1466, 1403, 1281, 1246, 1113, 1052, 751 cm-1 ; 1H NMR (CDCl3) δ2.18-2.36 (m, 2H), 2.39 (br t, J=6.0 Hz, 1H), 3.90 (s, 3H), 3.92 (br q, J=5.5 Hz, 2H), 4.85 (dd, J=7.4, 5.7 Hz, 1H), 5.15 (s, 2H), 6.81-7.03 (m, 7H), 7.23 (td, J=8.3, 1.7 Hz, 1H); MH+ at m/z=314; Anal. Calc'd for C18H19NO4.0.2 H2O: C, 68.21; H, 6.17; N, 4.42. Found: C, 68.36; H, 6.18; N, 4.36.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2O)[N:4]([CH3:12])[N:3]=1.CN(C)C=O.P(Cl)(Cl)([Cl:20])=O.C(=O)(O)[O-].[Na+]>ClCCCl.CC(O)C.O>[Cl:20][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH3:12])[N:3]=[C:2]([I:1])[C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1nc(I)c2c(O)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCCl
Solvent: O
Product: Cn1nc(I)c2c(Cl)ncnc21
Temperature: 80 °C

Procedure:
3-Iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (C8) (9.35 g, 33.9 mmol), N,N-dimethylformamide (10.5 mL, 135 mmol) and phosphorus oxychloride (9.57 mL, 102 mmol) were combined in 1,2-dichloroethane (90 mL), and the mixture was heated to 80° C. for 2 hours. After cooling to room temperature, it was added portion-wise with vigorous stirring to a beaker containing a chilled mixture (0 to 5° C.) of sodium bicarbonate (28.7 g, 339 mmol) in 2-propanol (90 mL) and water (90 mL). The resulting mixture was stirred at 0 to 5° C. for 6 hours, and then concentrated in vacuo. The resulting solid was collected via filtration, and washed with water to provide the product as a yellow solid. Yield: 8.45 g, 28.7 mmol, 85%. 1H NMR (500 MHz, DMSO-d6) δ 4.04 (s, 3H), 8.82 (s, 1H).
Reaction SMILES: [SH2:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[C:19](=[O:40])[C:18]2=[O:41])(=[O:12])=[O:11])=[CH:6][CH:5]=1)#[N:3].C(N(CC)CC)C.Cl>O.C(OCC)(=O)C.N1C=CC=CC=1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[C:19](=[O:40])[C:18]2=[O:41])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[S:1])[NH2:3]
Reactant: S
Reactant: N#Cc1ccc(S(=O)(=O)NCCCN2CCN(CC(=O)OC(c3ccccc3)c3ccccc3)C(=O)C2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC(=S)c1ccc(S(=O)(=O)NCCCN2CCN(CC(=O)OC(c3ccccc3)c3ccccc3)C(=O)C2=O)cc1
Reaction time: 5 h

Procedure:
Hydrogen sulfide gas was introduced into a mixture of 0.48 g of diphenylmethyl [4-[3-(4-cyanobenzenesulfonylamino)propyl]-2,3-dioxopiperazin-1-yl]-acetate, 2.4 ml of triethylamine and 4.8 ml of pyridine at room temperature until the mixture was saturated therewith. After stirring at the same temperature for 5 hours, the reaction mixture was added to a mixed solvent of 30 ml of ethyl acetate and 30 ml of water, and the pH was adjusted to 4 with 6N hydrochloric acid. The organic layer was separated and the aqueous layer was re-extracted with 10 ml of ethyl acetate. The combined organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=20:1) to obtain 0.40 g of diphenylmethyl [4-[3-(4-thiocarbamoylbenzenesulfonylamino)propyl]-2,3-dioxopiperazin-1-yl]acetate as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.CC(C)([O-])C.[Na+].Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH3:10][C@H:11]1[NH:12][CH2:13][CH2:14][N:15]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: N#Cc1ccc(Br)cc1
Reactant: C[C@@H]1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@@H]1CN(c2ccc(C#N)cc2)CCN1
Temperature: 100 °C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
4-Bromobenzonitrile (200 mg, 1.099 mmol), (R)-2-methylpiperazine (121 mg, 1.209 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), BINAP (41 mg, 0.066 mmol), and sodium-tert-butoxide (211 mg, 2.199 mmol) were suspended in toluene (5 ml), and then the resulting liquid was stirred at 100° C. under nitrogen stream for 5 hours. 1N aqueous HCl solution (20 ml) was added to the resulting reaction liquid, followed by extraction with MC (10 ml×2). The aqueous layer was neutralized by addition of 5N aqueous NaOH solution, followed by extraction with 5% MeOH/MC (20 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 152 mg of pale yellow oil (69%).
Reaction SMILES: C([BH3-])#N.[Na+].[N:5]1([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1>C(O)(=O)C>[N:5]1([CH2:10][CH2:11][CH2:12][CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH2:14]2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: c1ccc2c(CCCN3CCCC3)c[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc2c(c1)NCC2CCCN1CCCC1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
At 15° C. 508 mg (8.10 mmol) sodium cyanoborohydride was added to 600 mg (2.63 mmol) 3-(3-pyrrolidin-1-yl-propyl)-1H-indole in 7.50 g acetic acid and the mixture was stirred for 1 h at 15° C. After this time another 600 mg sodium cyanoborohydride were added and the mixture was stirred at 15° C. for 3 h. The reaction mixture was evaporated down using the rotary evaporator and combined with 40 mL of a 4M hydrochloric acid solution. The reaction mixture was stirred for 1h at RT. Then the mixture was made basic with potassium carbonate and extracted with ethyl acetate (2×50 mL). The combined organic phases were dried and evaporated down i. vac. The product was reacted further without any further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([F:27])[CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:3][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([F:27])[CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CC1(C)CC(C(Nc2cnc3cc(F)ccc3c2)c2ccc(C(=O)O)cc2)C1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3cc(F)ccc3c2)C2CC(C)(C)C2)cc1
Reaction time: 2 h
Yield: 44.8 %

Procedure:
To a vial containing 4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzoic acid (11.0 mg, 0.0290 mmol) was added 3-aminopropionic acid ethyl ester hydrochloride (4.90 mg, 0.0320 mmol), 1-Hydroxy-7-azabenzotriazole (4.80 mg, 0.0350 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (6.70 mg, 0.0350 mmol). Anhydrous methylene chloride (0.290 mL) was added followed by triethylamine (0.005 mL, 0.0380 mmol). After 2 h, the reaction was diluted with methylene chloride and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give 16.0 mg of crude material. Purification by silica gel flash chromatography (0-70% ethyl acetate in heptane) provided ethyl 3-(4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzamido)propanoate (6.20 mg, 45% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.50 (d, J=2.3 Hz, 1H), 7.75-7.68 (m, 2H), 7.54 (dd, J=9.9, 2.5 Hz, 1H), 7.45-7.41 (m, 2H), 7.38 (dd, J=9.1, 6.0 Hz, 1H), 7.14 (td, J=8.7, 2.7 Hz, 1H), 6.80 (t, J=5.9 Hz, 1H), 6.70 (d, J=2.7 Hz, 1H), 4.40 (s, 1H), 4.23 (dd, J=9.4, 4.1 Hz, 1H), 4.20-4.08 (m, 2H), 3.70 (q, J=6.2 Hz, 2H), 2.62 (t, J=6.0 Hz, 2H), 2.52 (sxt, J=8.8 Hz, 1H), 2.09-1.97 (m, 1H), 1.71 (dd, J=19.7, 0.4 Hz, 2H), 1.63 (dd, J=8.0, 4.1 Hz, 1H), 1.31-1.21 (m, 3H), 1.13 (s, 3H), 1.09 (s, 3H). (M+1): 478.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]5[S:38][CH:39]=[CH:40][N:41]=5)=[O:35])=[CH:29][CH:28]=4)=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[C:42]#[N:43])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[C:42]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[N:23]=[CH:22][CH:21]=[C:20]2[O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([NH:36][C:37]2[S:38][CH:39]=[CH:40][N:41]=2)=[O:35])=[CH:31][CH:32]=1)#[N:43]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)Nc5nccs5)cc4)c3cc2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)cc3)ccnc2cc1OCC1CCNCC1
Yield: 110 %

Procedure:
4-(6-Cyano-4-(4-(3-thiazol-2-yl-ureido)-phenoxy)-quinolin-7-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl-ester (240 mg) was deprotected with trifluoroacetic acid in the same manner as Production Example 670-4 to obtain the title compound (220 mg) as a solid.