Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH2:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH2:3][CH3:4].[C:12](=[S:14])=[S:13].Cl>C1COCC1>[CH2:2]([C:5]1[CH:10]=[CH:9][C:8]([C:12]([SH:14])=[S:13])=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: CCCc1ccc(Br)cc1
Reactant: S=C=S
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCc1ccc(C(=S)S)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a 1000 ml three neck flask provided with a stirrer, thermometer, dropping funnel, and nitrogen gas introducing tube were added 9.4 g (386.8 mmol) of magnesium turnings and 20 ml of THF under nitrogen gas atmosphere, and 200 ml solution of 70.0 g (351.6 mmol) of 4-propylbromobenzene in THF was added dropwise while being stirred in 1 hour while the reaction temperature being adjusted at 45 to 55° C. After finishing of the dropping, it was stirred at 55° C. for 2 hours. The reaction mixture thus obtained was cooled down to a temperature lower than 10° C., 133.8 g (1.75 mol) of carbon disulfide was added dropwise thereto in 50 minutes. After finishing of the dropping, it was further stirred at room temperature for 14 hours. The reaction mixture was cooled down to a temperature lower than 5° C., and then 100 ml of 6N hydrochloric acid was added dropwise thereto to terminate the reaction. It was extracted with 300 ml of diethyl ether, and the extract was washed with water (200 ml) thrice, dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 64.2 g of purplish red oily 4-propyldithiobenzoic acid. 1H-NMR (δ ppm): 0.95 (3H, t, J=7.4 Hz), 1.65 (2H, m), 2.63 (2H, t, J=7.8 Hz), 6.0-6.5 (1H, bs), 7.18 (2H, d, J=8.3 Hz), 7.99 (2H, d, J=8.6 Hz).
Reaction SMILES: N(C1CCCC1)=C=S.[CH:9]1([NH:14][C:15]([NH2:17])=[S:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=O>N.CO.C1COCC1>[CH:9]1([NH:14][C:15]2[S:16][CH:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[N:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)NC1CCCC1
Agent: N
Agent: S=C=NC1CCCC1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2csc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Isothiocyanato-cyclopentane (4 g) in ammonia (37% in water, 8 mL) and methanol (32 mL) was stirred for 16 hours, filtered of and dried. The Cyclopentyl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=289.05 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:25][CH:22]2[CH2:23][CH2:24][O:19][CH2:20][CH2:21]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CCOCC1
Reactant: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2CC2CCOCC2)n1
Reaction time: 0.62 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (4-tert-butyl-thiazol-2-yl)-amide; hydrochloride (0.310 g; 1.070 mmol) in 1,2-dichloroethane (2 mL) was added tetrahydro-pyran-4-carbaldehyde (0.244 g; 2.140 mmol), acetic acid (0.2 mL; 3.497 mmol), and sodium sulfate(5-10 equivalents). The mixture is stirred for 30-45 minutes before adding sodium triacetoxyborohydride (0.454 g; 2.140 mmol) and stirring overnight at room temperature. After this time, the mixture is filtered through a plug of silica/Celite® and concentrated in vacuo. Crude material is purified by preparative HPLC. Product fractions are pooled and concentrated in vacuo to afford title compound as an oil. ESI m/z 352 [M+H]+
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:22][C:23]([F:39])([F:38])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([N:35]1[CH2:34][CH2:33][N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH2:24][C:23]([F:38])([F:22])[F:39])[CH2:37][CH2:36]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(COCc1ccccc1)C(=O)N1CCN(c2ccccc2OCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85333.3 %

Procedure:
A mixture of 3-benzyloxy-2,2-dimethylpropionic acid (1.6 g, 7.5 mmol), benzene (10 mL) and DMF (2 drops) was cooled to between 0° and 5° C. and then oxalyl chloride (0.98 mL, 11.2 mmol) was added slowly. The mixture was stirred 1.5 hours at between 20° and 25° C. and concentrated. The residue was dissolved in benzene (10 mL) and the solution reconcentrated (repeated once). The residue then was dissolved in benzene (6 mL) and the solution was cooled to 0° C. and added to a cold (0° C.) mixture of 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine (2.1 g, 8.24 mmol) and benzene (6 mL). The mixture was cooled 15 hours at 0° C. and then triethylamine (3 mL, 21.3 mmol) was added. The mixture was stirred an additional 20 minutes, diluted with 10 mL of saturated sodium carbonate and extracted with methylene chloride (3×15 mL). The combined extracts were washed with water (1×10 mL), dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (8:2) to give 3-benzyloxy-2,2-dimethyl-1-{4-[2-(2,2,2-trif-luoroethoxy)phenyl]piperazin-1-yl}-1-propanone (2.8 g, 6.4 mol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[C:23]([N+:28]([O-])=[O:29])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.CCCCCC>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[C:23]([NH:28][OH:29])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3c([N+](=O)[O-])nccc23)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3c(NO)nccc23)CC1

Procedure:
A solution of the nitro-isoquinoline from step B (0.81 mmol, 1.86 mmol) and Pd/C (10%, 0.081 g) in methanol (50 mL) was stirred under hydrogen overnight, filtered and evaporated to give a crude oil. Chromatography on silica eluting with a gradient of 20% to 70% of EtOAc/Hexane gave an oil. (0.43 g, 55%). LCMS (+APCI) m/z 423 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[N:29]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[N:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)n1

Procedure:
Example 88 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methyl propanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.08 (d, 1H, J=8.4 Hz), 7.82 (s, 1H), 7.67 (t, 1H, J=7.6 Hz), 7.33–7.27 (m, 4H), 6.88 (d, 1H, J=7.2 Hz), 6.57 (brs, 1H), 3.33 (dd, 2H, J=6.0, 12.0 Hz), 2.94 (d, 2H, J=11.6 Hz), 2.58–2.53 (m, 2H), 2.37 (t, 2H, J=6.4 Hz), 1.97 (t, 2H, J=11.2 Hz), 1.87 (d, 2H, J=13.2 Hz), 1.67–1.58 (m, 4H), 1.57 (s, 6H), 1.28 (d, 6H, J=7.2 Hz); ESMS m/e: 485.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][S:9][C:7]2[NH:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=3[N:6]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc2[nH]c(S)nc2c1
Reactant: Clc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2nc(SCCOc3ccc(Cl)cc3)[nH]c2c1
Yield: 55.4 %

Procedure:
A suspension of 5-methyl-1H-benzoimidazole-2-thiol (492 mg, 3 mmol), 1-(2-bromo-ethoxy)-4-chloro-benzene (777 mg, 3.3 mmol) and K2CO3 (828 mg, 6 mmol) in acetone (1.0 ml) is refluxed for 3 h. It is cooled down and filtered on filter paper. The solvent is removed in vacuo and the crude purified by flash chromatography on silica-gel (AcOEt/heptane, 3:7), yielding the title compound (530 mg) in 55% as an off-white solid: tR=2.02 min (LC-2), ESI-MS (pos.): m/z 319.21 [M+H]+, ESI-MS (neg.): m/z 317.23 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 2.36 (s, 3H, Me), 3.59 (t, 2H, SCH2), 4.23 (t, 2H, CH2O), 6.75 (d, 2Harom), 6.97 (d, 1Harom), 7.13 (d, 2Harom), 7.18 (s, 1Harom), 7.34 (d, 1Harom).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][N:16]2[CH2:21][CH:20]=[CH:19][CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[OH-].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>CCOCC>[C:1]([O:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][N:16]2[CH2:17][CH:18]=[CH:19][CH2:20][CH2:21]2)=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(CN2CC=CCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(Oc1ccc(CN2CC=CCC2)cc1)c1ccccc1
Reaction time: 2 h
Yield: 29 %

Procedure:
Benzoyl chloride (3.0 g.) was added to a vigorously stirred mixture of 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine (4.0 g.) in N-sodium hydroxide solution (22 ml.) and ether (30 ml.). The mixture was stirred for 2 hours after the addition and then 3N-sodium hydroxide solution added to pH10. The subsequent mixture was extracted into ethyl acetate (2×30 ml.) and the combined extracts were dried (MgSO4) and evaporated. The residue was dissolved in acetone (50 ml.) and the solution was treated with concentrated hydrochloric acid to pH2. The solid which precipitated was collected by filtration and recrystallised from isopropanol to give 1-(4-benzoyloxybenzyl)-1,2,3,6-tetrahydropyridine (1.8 g.), m.p. 220°-227° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10]Br)=[O:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:10][C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
2-Bromo-4-methylacetophenone (572 mg, 2.68 mmol) was added to a solution of piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.68 mmol) in dichloromethane (5 ml) and triethylamine (0.45 ml, 3.22 mmol). The mixture was stirred for 3 days at room temperature and solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% hexane:60% EtOAc) to yield the title compound (661 mg, 77%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]C)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.I[Si](C)(C)C.C(=O)(O)O.[CH2:31]([O:35][C:36]([NH:38][CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)=[O:37])[CH2:32][CH2:33][CH3:34]>ClCCl.C(#N)C>[CH2:31]([O:35][C:36]([NH:38][CH:39]1[CH2:43][CH2:42][N:41]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:40]1)=[O:37])[CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCCCOC(=O)NC1CCNC1
Agent: C[Si](C)(C)I
Agent: O=C(O)O
Solvent: ClCCl
Solvent: CC#N
Product: CCCCOC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a solution of 1.0 g (3.4 mmole) of methyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 25 ml dichloromethane was added 0.6 ml (0.8 g, 4.2 mmole) of iodotrimethylsilane while stirring at room temperature under a nitrogen atmosphere. The mixture was warmed to reflux and stirred overnight. The reaction was cooled to room temperature, concentrated, and the residue taken up in 25 ml acetonitrile. To the resulting suspension was added a solution of 1.6 g (8.5 mmole) of 3-butoxycarbonylaminopyrrolidine bicarbonate in 10 ml acetonitrile while under nitrogen. The reaction was warmed to reflux for four hours, then cooled to room temperature. The formed precipitate was filtered, washed with acetonitrile and ether, yielding 1.26 g (82%) of 7-[3-(butoxycarbonyl)amino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 228°-230° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:11]1[CH2:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)C(O)=O.[OH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH:26]=O>C(#N)C>[CH3:26][C:25]([CH:29]1[CH:13]2[CH2:14][CH:15]=[CH:11][CH:12]2[C:9]2[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[NH:8]1)([CH3:28])[CH2:24][OH:23]
Reactant: C1=CCC=C1
Reactant: CC(C)(C=O)CO
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(CO)C1Nc2ccc([N+](=O)[O-])cc2C2C=CCC21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Nitroaniline (9.8 g), 6.5 ml of cyclopentadiene, and 5.5 ml of trifluoroacetic acid were dissolved in 70 ml of acetonitrile, and 10.0 g of hydroxypivalaldehyde was added at 0° C. After 30 minutes stirring at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1) to obtain 4.8 g of the captioned compound. Its physical properties are shown below.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[CH2:39][C:40](Cl)=[O:41]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:40](=[O:41])[CH2:39][N:38]([CH3:43])[CH3:37])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CN(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)CN(C)C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL) was added 2-(dimethylamino)acetyl chloride (38 mg, 0.24 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-2-(dimethylamino)ethanone as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.08 (s, 1H), 7.71 (d, 1H), 7.03 (d, 1H), 6.26 (s, 1H), 4.71-4.67 (m, 2H), 3.81-3.77 (m, 2H), 3.14-3.12 (m, 2H), 2.98 (s, 3H), 2.96 (s, 3H), 2.90-2.83 (m, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 1.87 (d, 2H), 1.76-1.55 (m, 2H); ESMS m/z 501.2 (M+H+).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO.O1CCCC1>[CH:1]1([CH:6]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCC2)oc2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C2CCCC2)oc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
Cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanone (27.15 g) synthesized above was dissolved in a mixed solvent of methanol (40 mL)-tetrahydrofuran (240 mL), and sodium tetrahydroborate (90%, 5.5 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (29.26 g, 100%) as a yellow oil.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][CH2:9][C:10](=[O:16])[CH2:11][C:12](=[O:15])[CH2:13][CH3:14].IC>O>[CH3:4][CH:11]([C:10](=[O:16])[CH2:9][CH3:8])[C:12](=[O:15])[CH2:13][CH3:14]
Reactant: C1CCOC1
Reactant: CCC(=O)CC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCC(=O)C(C)C(=O)CC
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To 0.02 mol sodium hydride was added 100 ml anhydrous tetrahydrofuran, slowly added dropwise 0.02 mol 3,5-heptandione at room temperature. Upon completion, the mixture was stirred for 0.5 hours, then 0.04 mol iodomethane was slowly added dropwise. After stirred at room temperature for 10 hours, 20 ml water was added. White solid was precipitated. The solid was filtered, washed with water, and dried to give 4-methyl-3,5-heptandione as a white solid, and the yield was 94%. m.p. was 91-92° C.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([Cl:29])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1>[Cl-:29].[CH2:20]([P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCC=Cc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: C(=Cc1ccccc1)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 130 °C

Procedure:
88.2 parts of triphenylphosphine was dissolved in 240 parts of xylene and 51.3 parts of cinnamyl chloride was added thereto. The mixture was heated at 130° C. for 4 hr. After the mixture was cooled to 30° C., the resulting colorless crystals were collected by filtration and washed with toluene to obtain 117.4 parts of cinnamyltriphenylphosphonium chloride (compound No. 15).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)=[CH:5][CH:4]=1.[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=2[N:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])=[CH:8][CH:7]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CNCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)CCCN(C)C)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
6-(4-(Bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was suspended in DMF and N1,N1,N3-trimethylpropane-1,3-diamine (5 equiv.) was added to it. The reaction mixture was stirred at room temperature for overnight. On completion of reaction, solvent was removed under reduced pressure and residue was purified by prep. HPLC chromatography to provide the desired compound (30% yield). LCMS: 544.25 (M+1)+; HPLC: 99.96% (@ 254 nm) (Rt; 4.732); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 10.14-9.80 (m, 1H), 8.95 (bs, 1H), 8.40-8.35 (m, 3H), 8.22-8.19 (m, 1H), 7.75-7.69 (m, 2H), 5.91 (s, 1H), 5.35-5.32 (m, 1H), 4.42 (d, 2H, J=3.6 Hz), 3.08-2.98 (m, 6H), 2.80-2.62 (m, 8H), 2.23 (s, 3H), 2.13 (s, 3H), 2.07 (m, 2H). 1.55 (d, 6H, J=6.4 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:13])[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].O>CN(C)C=O>[CH2:8]1[O:9][C:10]2[CH:11]=[CH:12][C:4]([CH2:3][O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]=2[O:7]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: ClCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCCOCc1ccc2c(c1)OCO2
Yield: 24.1 %

Procedure:
60% Sodium hydride (0.6 g) was suspended in dimethylformamide (10 ml), and piperonyl alcohol (1.5 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1-bromo-5-chloropentane(1.8 g) was added, which was followed by stirring at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 0.6 g of 5-((3,4-methylenedioxyphenyl)methoxy)pentyl chloride.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].N1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(OCCOCC)C>>[N:4]1([S:1]([NH2:5])(=[O:3])=[O:2])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: NS(N)(=O)=O
Agent: CCOCCOCC
Product: NS(=O)(=O)N1CCOCC1
Temperature: 120 °C
Reaction time: 11 h
Yield: 76.6 %

Procedure:
5.00 g of sulfamide, 4.09 g of morpholine and 5 ml of 1,2-diethoxyethane were mixed and heated with stirring in an oil bath at 120° C. for 11 hours. The reaction solution was air-cooled to room temperature and the crystal was washed with diethyl ether, washed with methanol and then dried under reduced pressure to obtain 5.98 g of the desired compound as an brownish crystal having a melting point of 158 to 161° C.