Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH:13](OCC)(OCC)OCC.[BH4-].[Na+]>>[CH3:12][O:11][C:7]1[C:6]2[C:2]([NH:1][CH3:13])=[N:3][O:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1cccc2onc(N)c12
Agent: [BH4-]
Agent: [Na+]
Product: CNc1noc2cccc(OC)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 g [11 mmol] of 3-amino-4-methoxy-1,2-benzisoxazole and 22.5 g [151.8 mmol] of triethyl orthoformate are boiled under reflux with exclusion of moisture for 18 hours. After concentrating by rotary evaporation under reduced pressure, the remaining residue is taken up in 50 ml of ethanol and, after the addition of 3.05 g [80.6 mmol] of sodium borohydride, the mixture is stirred first at room temperature for 3 hours and then at 50° C. for 12 hours. The mixture is concentrated, and the residue is dissolved in dichloromethane and washed with water. After drying and concentrating the organic phase, 1.5 g of the compound (XIIa-1) are obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[NH2:10])([O-])=O>C(O)C.C1COCC1.[Pd]>[C:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:8]([NH2:11])[C:9]([NH2:10])=[C:4]([NH2:1])[CH:5]=1
Reactant: Nc1c([N+](=O)[O-])cc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(-c2ccccc2)cc(N)c1N
Temperature: 23 °C
Reaction time: 26 h
Yield: 81.2 %

Procedure:
To a solution of 80 mg (309 μmol) 3,5-dinitrobiphenyl-4-amine in a mixture of 34 mL ethanol and 10 mL THF were added 6.6 mg palladium on charcoal (10%) and the mixture was stirred under an atmosphere of hydrogen for 26 hours at 23° C. After filtration and removal of the solvent the residue was purified by chromatography to yield 50 mg (81%) of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([N:24]1[N:28]=[N:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36]O)=[CH:32][CH:31]=2)=[N:25]1)([CH3:23])[CH3:22].C(Br)(Br)(Br)[Br:39]>C(OCC)C>[Br:39][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:26]2[N:27]=[N:28][N:24]([C:21]([CH3:23])([CH3:22])[CH3:20])[N:25]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)n1nnc(Cc2ccc(CO)cc2)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)n1nnc(Cc2ccc(CBr)cc2)n1
Yield: 62.9 %

Procedure:
Triphenylphosphine (6.5 g, 25 mmol) was added to a solution of 4-[[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]methyl]benzenemethanol (3.0 g, 12.4 mmol) and carbon tetrabromide (8.3 g, 25 mmol) in diethyl ether (150 mL). After 3 hours the reaction mixture was concentrated and the residue purified by chromatography on silica gel eluting with a 9:1 mixture of hexane-ethyl acetate to give 5-[[4-(bromomethyl)phenyl]methyl]-2-(1,1-dimethylethyl)-2H-tetrazole (2.4 g, 7.8 mmol) in 63% yield, mp. 73°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=C(O)/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 109 %

Procedure:
As in Example 115, (E)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid (4.79 g) and 4-nitrophenol (2,5 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.1 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 7.2 g of (E)-5,5-bis (3-chlorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester as an essentially homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH3:26])[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:21]([C:20]1[C:19]([CH3:26])=[N:18][C:17]([NH2:16])=[CH:25][CH:24]=1)=[O:22])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Cc1nc(N)ccc1C(=O)O
Product: Cc1nc(N)ccc1C(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Yield: 88.1 %

Procedure:
Following general amide formation method 1, 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (279 mg, 1.31 mmol, 1.0 eq) was combined with 6-amino-2-methylnicotinic acid (200 mg, 1.31 mmol, 1.0 eq) which gave 3-(6-Amino-2-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400 mg) in 88% yield. MS m/z 346.6 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]4[S:21][C:16]5[CH2:17][O:18][CH2:19][CH2:20][C:15]=5[C:14]=4[C:22](O)=[O:23])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:22]([C:14]2[C:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]=3[S:21][C:13]=2[NH:12][C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:11])=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: O=C(O)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2
Product: O=C(c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2)N1CCOCC1

Procedure:
The title compound was prepared from 2-[(hexahydro-2,5-methano-pentalene-3a-carbonyl)-amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (Example 167B) and morpholine according to the procedure described for Example 166C. 1H NMR (dimethylsulfoxide-d6) δ 1.58-1.62 (m, 4H), 1.75-1.81 (m, 2H), 1.88-1.97 (m, 4H), 2.29 (br s, 2H), 2.66 (t, J=7.0 Hz, 1H), 3.29-3.31 (m, 2H), 3.41 (br s, 4H), 3.71 (br s, 4H), 3.83 (t, J=5.6 Hz, 2H), 4.64 (br s, 2H), 9.74 (br s, 1H). MS (ESI+) m/z 417.2 (M+H)+. Anal. calcd. for C22H28N2O4S: C, 63.44; H, 6.78; N, 7.21. Found: C, 63.29; H, 6.77; N, 6.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:56]=[CH:55][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=2)=[O:47])=[CH:44][C:43]=1[CH3:57]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:56]=[CH:55][C:45]([C:46]([NH:48][C:49]6[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=6)=[O:47])=[CH:44][C:43]=5[CH3:57])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)Nc2ccncc2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)Nc4ccncc4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and 4-bromo-3-methyl-N-pyridin-4-yl-benzamide (41 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-N-pyridin-4-yl-benzamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-258) as a pale yellow powder (22 mg, 9%).
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:15]([S:17]C)=S)[CH2:14][CH2:13][CH2:12][CH2:11][S:10]1.C>C(O)C>[CH3:1][NH:2][C:15]([C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][S:10]1)=[S:17]
Reactant: CSC(=S)C1(c2ccccn2)CCCCS1
Reactant: CN
Solvent: CCO
Product: CNC(=S)C1(c2ccccn2)CCCCS1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (7.5 cc) is added dropwise and in the course of 15 minutes to a solution of methyl 2-(pyrid-2-yl)-tetrahydrothiopyran-2-carbodithioate (9 g) in ethanol (60 cc), kept at a temperature of about 20° C. The solution is then stirred for 16 hours at a temperature of about 20° C. The resulting crystals are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. A crystalline crude product (7.8 g) is thus obtained, which is redissolved in boiling ethanol (96 cc); decolourising charcoal (0.4 g) is added to the solution thus obtained, which is filtered hot, and the filtrate is then cooled for 30 minutes at 0° C. The resulting crystals are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 45° C. N-Methyl-2-(pyrid-2-yl)-tetrahydrothiopyran-2-carbothioamide (6.3 g), melting at 153° C., is thus obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[C:23](B(O)O)([CH3:25])=[CH2:24]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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:23]([C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1)([CH3:25])=[CH2:24]
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: C=C(C)B(O)O
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: C1COCCO1
Product: C=C(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
0.56 g (0.0015 Mol) 4-(2-Bromo-6-pyrrolidin-1-yl-pyridine-4-sulfonyl) -phenylamine, 0.171 g (0.00015 Mol) Pd(PPh3)4 and 0.191 g (0.0021 Mol) isopropenyl boronic acid were stirred at reflux for 18 h in a mixture of dioxane (10 ml) and 2N Na2CO3 (4 ml). Then the solvent was evaporated, the residue was taken up in ethyl acetate, washed with water and brine and dried over Na2SO4. After chromatography on SiO2 with ethyl acetate hexane 1:2 the product containing fractions were evaporated and the residue taken up in hexane. The suspension was stirred for 1 h and then filtered. The residue on the filter was washed with hexane (10 ml) and dried in a high vacuum. It was obtained 0.265 g (52%) 4-(2-isopropenyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine as a light yellow solid; mp.: 200-201° C.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][NH2:14])=[CH:8][CH:7]=2.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[F:16][C:3]([F:2])([F:15])[C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][NH:14][C:23]([C:22]1[CH:21]=[N:20][C:19]([C:18]([F:29])([F:17])[F:28])=[CH:27][CH:26]=1)=[O:24])=[CH:8][CH:7]=2
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nc1
Temperature: 5 °C
Reaction time: 0.21 h
Yield: 60.7 %

Procedure:
{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5A, 646 g, 71% free amine equivalent), 6-trifluormethylnicotinic acid (429.7 g), diisopropylethylamine (1500 mL) and tetrahydrofuran (5.1 L) were placed in a flask equipped with an addition funnel, thermometer, and nitrogen inlet. The mixture was stirred vigorously for 10-15 min. The mixture was cooled to ˜5° C. and propylphosphonic anhydride (3.2 L of 50 wt % solution) added slowly. The mixture was stirred at ˜15° C. for 2 hrs. The mixture was cooled to ˜5° C. and quenched by the addition of water (505 mL) slowly. The pH was adjusted to 5-6 by adding 20 wt % K3PO4 (2.9 L). The mixture was diluted with EtOAc (3.2 L) and the temperature adjusted to 15-20° C. The phases were separated and the organic mixture was washed sequentially with water (1.5 L) and then 5 wt % sodium bicarbonate solution (2.6 L). The mixture was filtered and the solvent removed to minimum volume under vacuum. Isopropyl alcohol (2.0 L) was added and the mixture filtered, and the solvent removed under vacuum two times. Isopropyl alcohol (980 mL) was added and the mixture heated to 70-80° C. Water (1.5 L) was added while maintaining temperature above 65° C. and monitoring turbidity. The temperature was adjusted to 65° C., seeded with product (4.5 g) and the mixture held at 65° C. for 30 min. The mixture was cooled to ˜5° C. overnight and the product was isolated by filtration, washing the solids with cold 10% IPA in water (1 L), then dried in a vacuum oven to give the title compound (529 g);
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]([C:13]1[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][OH:12].N1C=CN=C1>ClCCl>[Si:5]([O:12][CH2:11][CH:10]([C:13]1[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:9])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)n1c(C(O)CO)cc2ccccc21
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(C(O)CO[Si](C)(C)C(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
TBSCl (1.3 g, 8.9 mmol) in dichloromethane (20 mL) was added dropwise at 0° C. over 10 minutes to a solution of tert-butyl 2-(1,2-dihydroxyethyl)-1H-indole-1-carboxylate (2.0 g, 7.2 mmol) and imidazole (1.20 g, 17.4 mmol) in DCM (30 mL). After being stirred at room temperature for 1 hour, the mixture was washed with water (2×50 mL) and brine, dried, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give an oil, which was further purified by prep-HPLC to afford tert-butyl 2-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)-1H-indole-1-carboxylate (500 mg, 18% yield) as an oil. LCMS (ESI) m/z: 318.3 [M-56-17]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2[C@H](O)C[C@@H]1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1c2ccccc2[C@H](OCc2ccccc2)C[C@@H]1C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
20 mg of cis-1-acetyl-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 2 mL of tetrahydrofuran, and 3 mg of sodium hydride was added to the solution under ice cooling. The mixture was stirred for 30 minutes under ice cooling. 15 of benzyl bromide was further added to the solution, and the resulting mixture was stirred for one whole day. Water was added to the reaction liquid, and the mixture was extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:hexane=1:2), and thus 9 mg (yield 31%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Al](C)C.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]([C@H:31]1[CH2:35][CH2:34][O:33][C:32]1=[O:36])[CH2:26][CH2:25][CH2:24]2>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]([C@@H:31]([CH2:35][CH2:34][OH:33])[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:36])[CH2:26][CH2:25][CH2:24]2
Reactant: COC(=O)NS(=O)(=O)c1ccc(N)cc1
Reactant: O=C1OCC[C@@H]1N1CCCc2cc(Cl)ccc21
Agent: C[Al](C)C
Solvent: ClCCl
Product: COC(=O)NS(=O)(=O)c1ccc(NC(=O)[C@H](CCO)N2CCCc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of the methyl 4-aminophenylsulfonylcarbamate (111 mg, 0.48 mmol) and CH2Cl2 (1 mL) under N2, at 0° C., was added trimethylaluminum (0.24 mL, 0.48 mmol) dropwise over 20 minutes. The solution was stirred at ambient temperature for 30 minutes. The solution was cooled to 0° C. followed by the dropwise addition of (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)dihydrofuran-2(3H)-one (100 mg, 0.40 mmol) in CH2Cl2 (1.0 mL) over 30 minutes. The solution was stirred at ambient temperature for 19 h. The solution was cooled to 0° C. and quenched by slow addition of aqueous 1.0 M HCl. The organic portion was washed with 1.0 N aqueous HCl (2×1.0 mL) and evaporated to dryness under reduced pressure. The crude product of (R)-methyl 4-(2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxybutanamido)phenylsulfonylcarbamate was used without purification in the next step.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:13][C:14]([C:27]#[N:28])=[N:15][C:16]=1[NH:17][CH2:18][CH:19]1[CH2:26][CH2:25][C:22]2([CH2:24][CH2:23]2)[CH2:21][CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH3-][C:41]#N.[Na+]>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:41])[CH2:34][CH2:33]2)=[N:13][C:14]([C:27]#[N:28])=[N:15][C:16]=1[NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][C:22]2([CH2:23][CH2:24]2)[CH2:25][CH2:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1nc(NCC2CCC3(CC2)CC3)c(C(=O)NCc2ccccc2)c(OCCC2CCNCC2)n1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CC3)CC4)c2C(=O)NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyano-4-(2-piperidin-4-yl-ethoxy)-6-[(spiro[2.5]oct-6-ylmethyl)amino]-pyrimidine-5-carboxylic acid benzylamide (0.19 mmol) in THF (2 mL) is added formaldehyde solution (100 μL), and the resulting solution is stirred for 0.5 h at room temperature. After cooled to 0° C., 1 M NaBH3CN solution in THF is added dropwise, and the reaction mixture is stirred for 2 h at room temperature. The reaction is quenched by the addition of H2O, and extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column to give 2-cyano-4-[2-(1-methylpiperidin-4-yl)ethoxy]-6-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid benzylamide as a colorless oil; 1H-NMR (CDCl3), δ 0.17-0.30 (4H, m), 0.89-0.94 (2H, m), 1.14-1.29 (3H, m), 1.40-1.50 (2H, m), 1.58-1.78 (9H, m), 1.95-2.01 (3H, m), 2.38 (3H, s), 2.95-2.98 (2H, m), 3.42 (2H, t), 4.46 (2H, t), 4.56 (2H, d), 7.31-7.39 (5H, m), 8.13 (1H, t), 10.16 (1H, t).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[S:13][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CCOC(=O)c1csc(Cc2ccc([N+](=O)[O-])cc2)n1

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (1.50 g), ethyl bromopyruvate (1.64 g) and ethanol (50 mL) was heated under reflux for 30 min. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 2-(4-nitrobenzyl)-1,3-thiazole-4-carboxylate was obtained as pale-yellow crystals (1.79 g, yield 81%) from a fraction eluted with hexane-ethyl acetate (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 122-123° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:37]([O:39][CH2:40][CH3:41])=[CH2:38])CCC>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>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([C:37]([O:39][CH2:40][CH3:41])=[CH2:38])[N:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(C(=O)OC)cc(Cl)n1
Temperature: 100 °C
Yield: 84 %

Procedure:
Add 2,6-dichloro-isonicotinic acid methyl ester, tetrakis(triphenylphosphine)palladium(0) (0.763 g, 0.66 mmol), triphenylphosphine (0.346 g, 1.32 mmol), tributyl(1-ethoxyvinyl)tin (5.0 g, 13.9 mmol) and toluene (30 mL), to a sealed flask flushed with nitrogen. Heat at 100° C. overnight and cool to room temperature. Filter the mixture through a filtering agent, concentrate and purify (silica gel chromatography eluting with 25:75 ethyl acetate:hexanes) to give the title compound (84%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[OH:3][CH:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(=O)n(C)c2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(=O)n(C)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
To a solution of 5-(5-acetylthiophen-2-yl)-1-methylpyridin-2(1H)-one (0.65 g, 2.78 mmol) in THF (8 mL) and MeOH (8 mL) was added NaBH4 (0.26 g, 6.97 mmol) under nitrogen. The mixture was stirred at rt for 10 min, quenched with ammonium chloride solution (15 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were washed with brine solution (2×50 mL), dried over sodium sulphate and evaporated to obtain the crude compound. Purification by flash chromatography (100-200μ; 100% ethyl acetate) afforded 5-(5-(1-hydroxyethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one (0.5 g, 76% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 7.69 (d, 1H), 7.07 (d, 1H), 6.83 (d, 1H), 6.43 (d, 1H), 5.51 (bs, 1H), 4.88 (q, 1H), 3.45 (s, 3H), 1.38 (d, 3H); LC-MS m/z calcd for [M+H]+ 236.07 found 236.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[NH2:13]C(N)=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:8])[NH:13][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: NC(N)=O
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1)C(=O)NC2=O
Temperature: 150 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
Xylene (15 ml) was added to 4-methylphthalic anhydride (3.0 g) and urea (1.2 g), and the mixture was stirred overnight at 150° C. The reaction mixture was cooled to room temperature, and precipitated crystals were collected by filtration and washed with ethanol and water. The crystals were dried under reduced pressure to give 4-methylphthalimide (2.4 g, Y.:82%) as white crystals.