Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7].[OH-].[Na+]>C(O)C>[CH2:6]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
Tin (II) chloride dihydrate (51.89 g, 0.230 mol) was added to 1-(ethylsulfonyl)-4-nitrobenzene (10 g, 0.046 mol) in ethanol (250 ml) then heated under reflux for 16 h. The mixture was cooled to room temperature and treated with aqueous sodium hydroxide (2N, 100 ml). The product was then extracted into ethyl acetate (3×150 ml). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The residue was then purified by chromatography column over silica (50% ethyl acetate/50% petroleum ether) to afford 4-(ethylsulfonyl)-benzene amine. δ(1H NMR, DMSO, ppm): 1.00 (3H, t), 2.95 (2H, q), 5.95 (2H, s), 6.55 (2H, d), 7.35(2H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][NH:27][CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C([O-])([O-])=O.[K+].[K+].I[CH:57]([CH3:59])[CH3:58]>CC#N>[CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:57]([CH3:59])[CH3:58])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(C)I
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CNC3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 95 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
Benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (2.3 g, 3.43 mmol) was mixed with K2CO3 (3.3 g, 24 mmol) and 2-iodopropane (5.8 g, 34.3 mmol) in MeCN (25 mL) in a sealed tube, then heated to 95° C. with stirring for 20 h. The reaction mixture was filtered and rinsed with MeCN (30 mL), the filtrate was evaporated in vacuo to afford the desired compound (2.1 g, yield: 88%) as a white solid, which was used for next step without further purification. 1H NMR (500 MHz, MeOD): δH 8.13 (s, 1H), 7.35-7.29 (m, 5H), 7.18 (d, J=3.0 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.64 (d, J=3.0 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 6.41 (dd, J=8.5 and 2.5 Hz, 1H), 6.18 (d, J=2.5 Hz, 1H), 5.33-5.32 (m, 1H), 5.08-5.06 (m, 2H), 4.90-4.89 (m, 1H), 4.64 (s, 2H), 4.15-4.14 (m, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.37-3.36 (m, 0.43H), 3.01-2.98 (m, 0.59H), 2.92-2.88 (m, 1H), 2.70-2.40 (m, 3H), 2.24-2.18 (m, 2H), 2.10-1.80 (m, 3H), 1.75-1.69 (m, 2H), 1.61-1.52 (m, 5H), 1.38 (s, 3H), 0.94 (d, J=6.5 Hz, 3H), 0.81-0.79 (m, 3H) ppm; LC-MS (m/z): 714.0 [M+1]+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[O:1]([CH2:8][CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCOc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCOc1ccccc1)C(=O)O
Yield: 63.8 %

Procedure:
Diethyl 2-phenoxyethylmalonate (1 g) was treated with sodium hydroxide (285 mg, 2 eq) in ethanol (10 ml) and water (5 ml). After 16 h the solution was diluted with water (10 ml), washed with diethyl ether (3×20 ml), acidified to pH 2 (5M hydrochloric acid) and extracted with ethyl acetate (2×20 ml). The combined extracts were washed with water (3×20 ml), saturated brine (20 ml), dried (MgSO4) and evaporated to yield the title compound (510 mg, 64%). νmax (KBr) 2915 (br), 1730 and 1243 cm-1. δH [(CD3)2CO] 2.36 (2H, m, CH2CH), 3.69 (1H, t, J 7.2 Hz, CH), 4.12 (2H, t, J 7.3 Hz, OCH2), 6.94, 7.28 (5H, m, Ph). EIMS M+ 224, DCIMS MNH4+ 242.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27].[N-:28]=[N+:29]=[N-:30].[Na+]>C(#N)C>[N:28]([C:6]1[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]([C:19]2[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=2[F:27])=[C:2]([Cl:1])[N:7]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](Nc1nc(N=[N+]=[N-])nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Yield: 72.3 %

Procedure:
A solution of 0.5 g (1.15 mmol) of sulfone 1 and 0.11 g (1.62 mmol) of sodium azide in acetonitrile was refluxed for 2 hours. Cooling, distillative removal of the solvent and digestion of the residue with water gave 0.33 g of the title compound of m.p. 152-154° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:26]([F:39])=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:26]([F:39])=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(F)cc(-c2nn(Cc3oc4ccc(F)cc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cc(O)cc(F)c1)nn2Cc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.9 %

Procedure:
To a solution of Example 120 (0.075 g, 0.140 mmoles) in dichloromethane (10 ml), BBr3 (1M in dichloromethane, 1.0 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as light brown solid (0.023 g, 31% yield). MP: 127-129° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.18(s,1H), 8.19(s, 1H), 7.74-7.61(m, 3H), 7.38(q, J=7.8 Hz, 1H),7.15(m,3H), 6.84(s,1H), 6.81(d, J=8.8 Hz, 1H), 6.65(d, J=10.8 Hz, 1H), 5.54(s, 2H). Mass: 515.54(M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:32])[CH:20]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:31][C:28]1[CH:29]=[N:30][C:25]([N:22]2[CH2:23][CH2:24][CH:20]([N:19]([CH3:32])[CH3:18])[CH2:21]2)=[CH:26][CH:27]=1
Reactant: CN(C)C1CCN(c2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)C1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 71.2 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-amine (309 mg, 1.5 mmol) to afford the desired product (342 mg, 71%) as a yellow solid: ESI MS m/z 480 [C24H26BrN5O+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:19]([NH:18][C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)=[O:17])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@@H]1CCCN1
Yield: 97.7 %

Procedure:
In 140 ml of methanol was dissolved 4.41 g of compound (30) and the compound was hydrogenated using 426 mg of 10% palladium-carbon as a catalyst. The catalyst was filtered off and the filtrate was concentrated to provide 2.41 g of (S)-N-butyl-2-pyrrolidinecarboxamide (31).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH:15]3[O:21][Si](C(C)(C)C)(C)C)[C:7](=[O:29])[C:6]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[NH:47][C:46](=[O:48])[O:45][N:44]=2)=[CH:33][CH:32]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH:15]3[OH:21])[C:7](=[O:29])[C:6]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[NH:47][C:46](=[O:48])[O:45][N:44]=2)=[CH:33][CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C)(C)C(C)(C)C)CC3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(-c2ccc3c(c2)C(O)CC3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution of 6-butyl-3-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.02 g) in tetrahydrofuran (8 mL) was added tetrabutylammonium fluoride (0.60 g), and the mixture was stirred at 50° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:31])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[N:16]([S:39]([CH3:38])(=[O:41])=[O:40])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]([CH3:31])[N:12]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(S(C)(=O)=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A solution of 2.0 g (0.0045 mole) of 1, 4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]6-methyl-4-(3-nitrophenyl) -5-pyrimidinecarboxylic acid, ethyl ester (see example 2A) in 15 ml of dichloromethane containing 0.71 g (0.0090 mole) of pyridine was cooled to -10° C. and treated slowly with a solution of 0.62 g (0.0054 mole) of methanesulfonyl chloride in 5 ml of dichloromethane. After stirring at room temperature overnight, a small amount of the hydrochloric acid salt of 1, 4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester had precipitated. After filtration, additional dichloromethane was added and the solution was washed with water, 1N hydrochloric acid, sodium bicarbonate and brine. The dried solution was evaporated and the residue was flash chromatographed using dichloromethane to give 2.0 g of an oil.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH:13]([N:26]1[CH2:29][CH:28]([C:30]#[N:31])[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CI.[NH4+].[Cl-]>O1CCCC1.CCCCCC.Cl>[CH:13]([N:26]1[CH2:29][C:28]([CH3:1])([C:30]#[N:31])[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A solution of 2.6 g (0.025 mol) of diisopropylamine in 80 ml of anhydrous tetrahydrofuran is cooled to -78° C. under nitrogen and 10 ml of a 2M solution of n-BuLi in n-hexane are added to it with great care. Stirring is carried out for 30 minutes and a solution of 6.2 g (0.025 mol) of 1-benzhydrylazetidine-3-carbonitrile obtained in stage a) of PREPARATION I in 30 ml of tetrahydrofuran is added to it. After 1 hour's stirring, a solution of 7.0 g (0.05 mol) of methyl iodide in 10 ml of tetrahydrofuran is added dropwise. Stirring is carried out for 1 hour and the reaction mixture is allowed to warm up to ambient temperature. It is left to stand overnight and the basic solution is neutralized by addition of approximately 100 ml of a 20% solution of NH4Cl and a few drops of concentrated HCl. The product is extracted with methylene chloride and the organic phase is concentrated to obtain 6.0 g of 1-benzhydryl-3methyl-3-azetidinecarbonitrile which is crystallized from n-hexane. M.p. 78°-80° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:6][CH:5]=1.Cl.[NH2:26][OH:27].C[O-].[Na+]>CO.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH:22]1[C:23]2[N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:26][OH:27])=[O:2])=[CH:5][CH:6]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: NO
Reactant: COC(=O)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NO)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.5 %

Procedure:
4-Carbazol-9-ylmethylbenzoic acid methyl ester (19) (1.0 g, 3.2 mmol) and hydroxylamine hydrochloride (1.3 g, 19.0 mmol) were placed under argon and dissolved in 5 mL of methanol. To it was added a 25% sodium methoxide solution in methanol (5.48 g, 25.4 mmol) which resulted in the formation of a white precipitate. The reaction was stirred for 24 h at room temperature after which the reaction was diluted with 20 mL ethyl acetate and 20 mL of saturated sodium bicarbonate. The organic layer was isolated and the aqueous layer was further extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude extract was purified by HPLC to yield the title compound (0.41 g, 41%) as an off-white solid. 1H NMR (400 MHz, DMSO): δ 11.09 (s, 1H), 8.97 (s, 1H), 8.18 (d, 2H, J=7.8 Hz), 7.61 (m, 4H), 7.43 (t, 2H, J=8.0 Hz), 7.19 (m, 4H), 5.71 (s, 2H). 13C NMR (100 MHz, DMSO): δ 164.0, 140.2, 141.1, 132.0, 127.3, 126.8, 126.0, 122.3, 120.5, 119.2, 109.5, 45.4. ESI-HRMS (m/z): [M+H]+ calcd. for C21H17NO2, 317.1149. found, 317.1143. Analytical HPLC: Purity=99%, tR=10.69 min, Method A.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:29])=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:30]([O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH3:31]>C(Cl)(Cl)Cl>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:8]([CH3:29])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:36]([NH:35][C:33]([O:32][CH2:30][CH3:31])=[O:34])=[S:37])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(=S)NCCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-(2-aminoethoxymethyl)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.43 g) in dry chloroform (50 ml) was added, dropwise, a solution of ethoxycarbonylisothiocyanate (1.31 g) in dry chloroform (25 ml). The reaction was stirred for 18 hours at room temperature before evaporating the solvent and triturating the residue with ether to afford a solid which was recrystallised from diisopropyl ether to give the title compound, yield 2.6 g, m.pt. 144°.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:16])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]>C(O)(=O)C.[Zn]>[CH3:16][CH:4]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=[CH2:2]
Reactant: CC(=CCBr)CCCC(C)CCCC(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
In 300 ml of hexane were dissolved 50 g of 3,7,11-trimethyl-1-dodecen-3-ol and 0.87 g of pyridine, and 30.8 g of phosphorus tribromide was added dropwise to the solution at 0° to -10° C. After 2 hours of stirring at 0° C., the reaction mixture was poured into water and extracted with hexane. The hexane layer was successively washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 62.5 g of crude 1-bromo-3,7,11-trimethyl-2-dodecene. To a suspension of 14.2 g of zinc in 26 ml of acetic acid was added dropwise 62.5 g of the crude 1-bromo-3,7,11-trimethyl- 2-dodecene and the mixture was stirred at room temperature for 1 hour. Thereafter, the zinc was filtered off and the filtrate was poured into water and extracted with hexane. The hexane layer was washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was further distilled under reduced pressure to give 10.6 g (yield 25%) of 3,7,11-trimethyl-1-dodecene. The physical constants of the compound are as follows.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[C:12]([F:18])=[CH:13][CH:14]=[C:15]([O:16]C)[C:8]=2[CH2:7][CH2:6]1)=O>C(Cl)Cl.B(Br)(Br)Br>[F:18][C:12]1[C:9]2[CH2:10][CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[C:15]([OH:16])=[CH:14][CH:13]=1
Reactant: COc1ccc(F)c2c1CCN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(F)c2c1CCNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2,2-trifluoro-1-(6-fluoro-9-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone (1.22 g, 4.19 mmol, 1 eq.) in DCM (50 mL), 1M boron tribromide solution in dichloromethane (8.38 mL) was added. The mixture was stirred at r.t. for 2 hours. The reaction was carefully quenched with 2N aq. NaOH soln. (50 mL) and stirred at r.t. for 30 min. The reaction mixture was washed with DCM (2×50 mL). The aq. layer was concentrated in vacuo. The residue was purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, basic conditions) and concentrated in vacuo to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24](=[O:54])[C:25]4[C:30]([C:31]=3[C:32]3[S:36][C:35]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OCC6C=CC=CC=6)=O)[CH2:40][CH2:39]5)=[CH:34][CH:33]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12.BrB(Br)Br.CO.[ClH:61]>ClCCl.CC#N.O.C(O)=O>[ClH:61].[ClH:61].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24](=[O:54])[C:25]4[C:30]([C:31]=3[C:32]3[S:36][C:35]([CH2:37][N:38]5[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]5)=[CH:34][CH:33]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCN(C(=O)OCc5ccccc5)CC4)s3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Solvent: CC#N
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCNCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
In a 250 ml round bottomed flask equipped with a magnetic stirrer benzyl 4-((5-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate (460 mg, 0.617 mmol) was suspended in 20 ml of dry dichloromethane then 1M tribromoborane in DCM (5 ml) was added and the mixture was stirred overnight at r.t. MeOH (15 ml) and 1M HCl (5 ml) were added and the mixture was stirred for 30 min then organic solvents were evaporated and the crude was purified by reverse phase chromatography eluting with H2O\MeCN\HCOOH 95:5:0.1% and MeCN\H2O\HCOOH 95:5:0.1%, to give the title compound (254 mg, 0.379 mmol, 61.4% yield) as a whitish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21]5([CH2:26][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)OCC[O:22]5)[CH:5]=[CH:6][C:7]=1[F:8]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCC2(C4)OCCO2)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
To a stirring acetic acid/water solution (4:1, 300 mL) was added N-(3-chloro-4-fluorophenyl)-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine (5.5 g, 14 mmol), and the contents heated at 80° C. for 12 h. The dark colored mixture was cooled to rt, and the solvent was removed under reduced pressure. The crude residue was suspended in aq NaHCO3 (1N, 100 mL), stirred for 10 min., and filtered. The filtered solid was triturated with diethyl ether (100 mL) to afford the desired product (4.8 g, 98%) as a dark yellow solid. 1H-NMR (DMSO-d6) δ 8.53 (s, 1H), 8.46 (s, 1H), 7.87 (dd, 1H), 7.60 (m, 1H), 7.40 (t, 1H), 3.73 (s, 2H), 3.43 (t, 2H), 2.64 (s, 2H); LCMS RT=3.01 min; [M+H]+=348.2.
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>O1CCCC1>[C:1]([NH:10][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)(N)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(NCCCS(=O)(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of cumylamine (10.5 g, 78 mmol) in tetrahydrofuran (75 mL) was slowly added a solution of 1,3-propane sultone (9.2 g, 74 mmol) in THF (20 mL). The mixture was stirred at reflux for 4 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, and washed with THF (2×35 mL). The solid was suspended in EtOH (80 mL). The suspension was stirred at reflux for 15 minutes. The solid product was collected by filtration, washed with EtOH (35 mL) and acetone (35 mL). The resulting solid was dried in vacuo, affording compound DM (5.6 g, 30%). 1H NMR (D2O, 500 MHz) 8 ppm 7.41 (m, 5H), 2.74 (m, 4H), 1.88 (m, 2H), 1.66 (s, 6H). 13C NMR (D2O, 125 MHz) 8 ppm 138.36, 129.44, 129.41, 126.52, 61.56, 48.04, 41.21, 24.80, 21.81. ES-MS 256 (M−1).