Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH2:4][F:5].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:19][C:14]2[C:15]([O:17][CH3:18])=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[N:22][CH:23]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(C(CF)CF)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(C(CF)CF)CC2

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (140 mg, 66%). LCMS (m/e) 573 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.96 (s, 1H), 7.32 (s, 1H), 6.67 (s, 1H), 5.34 (d, 1H, J=7.3 Hz), 5.24 (d, 1H, J=7.0 Hz), 4.77-4.64 (m, 2H), 4.64-4.52 (m, 2H), 4.03-3.93 (m, 1H), 3.89 (s, 3H), 3.31-3.10 (m, 2H), 2.97-2.82 (m, 8H), 2.80 (s, 3H), 2.31-2.16 (m, 2H), 1.92-1.78 (m, 2H), 1.50-1.32 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)#[N:18]>>[OH:28][C:23]1[NH:24][C:25]2[C:21]([C:22]=1[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:6][N:7]=1)=[CH:20][C:19]([C:17]#[N:18])=[CH:27][CH:26]=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCOCC1
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(S(=O)(=O)N4CCOCC4)cn3)c2c1

Procedure:
The title compound was prepared as described for Example 101 using 4-[(6-chloropyridin-3-yl)sulfonyl]morpholine and 5-cyanooxindole. The reaction mixture was quenched with water and the solvents were evaporated in vacuo. Water was added and the mixture was filtered. The solid material was washed with water, methanol, ethyl acetate and diethyl ether to give the title compound. Yield: 44%: MS (ES) m/z 385 (M++1).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH:17]=1)[NH2:16]>C(O)C>[NH2:16][C:15]1[CH:17]=[C:11]([S:9][C:6]2[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][CH:5]=2)[CH:12]=[CH:13][C:14]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1ccc(Br)cc1
Agent: [Na]
Solvent: CCO
Product: Nc1cc(Sc2ccc(Br)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 6262.1 %

Procedure:
Sodium (0.269 g) was added to ethanol (20 ml) and the resultant solution was allowed to cool to ambient temperature then 4-bromothiophenol (2.21 g) was added. The mixture was stirred for 5 minutes then 5-chloro-2-nitroaniline (2 g) was added. The mixture was then heated under reflux under argon for 3 hours then allowed to cool down. The resultant solid was collected by filtration , washed with ethanol then dried to give the title compound (236 g) as a solid. NMR: 6.3 8 (dd, 1H), 6.65 (m, 1H), 7.42 (m, 4H), 7.7 (m, 2H), 7.9 (d, 1H); MS: 327 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K]>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:12]1[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]2[C:8]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCBr
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CCCCCBr

Procedure:
As shown in the above Reaction Scheme 1, 1,5-dibromopentane is reacted with potassium phthalimide in a suitable solvent to give N-(5-bromopentyl)phthalimide (2). The compound (2) is reacted with pyrrolidine in the presence of potassium carbonate and sodium iodide to give N-(5-pyrrolidin-1-ylpentyl)phthalimide (3). The compound (3) is reacted with hydrazine to provide 5-(pyrrolidin-1-yl)pentylamine (4). The compound (4) is reacted with di-t-butyl dicarbonate to give t-butyl (5-pyrrolidin-1-ylpentyl) carbamate (5). Then, the compound (5) is reacted with lithium aluminum hydride in a suitable solvent to give N-methyl-N-[5-(pyrrolidin-1-yl)pentyl]amine (6).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)#[N:4].[CH3:14]I>CN(C)C=O>[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[N:6]=1)#[N:4]
Reactant: CI
Reactant: N#Cc1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(C#N)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.37 g, 60% dispersion in mineral oil) was added to a solution of 3-cyano-1H-indazole (1.20 g, Reference Example 57) in dry dimethylformamide (30 mL) under a nitrogen atmosphere at ambient temperature. The mixture was allowed to stir for 1 hour then treated with methyl iodide (0.85 mL) and stirring was continued for 1 hour. The reaction mixture was then poured into ice-water (15 mL). The precipitated solid was filtered then washed with water and then dried to give the title compound (0.80 g) as a beige solid, m.p. 73° C. 1H NMR [(CD3)2SO]: δ 7.91 (m, 2H); 7.60 (t, 1H); 7.42 (t, 1H); 4.21 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([OH:18])[C:16]#[CH:17].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]([C:17]#[C:16][CH2:15][OH:18])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(NC2CCCC2)n1
Reactant: C#CCO
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCC#Cc1cnc(Cl)nc1NC1CCCC1
Temperature: 67 °C

Procedure:
A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 200 g (0.723 mol, 1.0 eq.) of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (A1f) and 2303 g, (2600 mL) of tetrahydrofuran. The mixture is stirred, heated to reflux (67° C.) and 200 mL of distillate is collected. The sample is cooled to 25° C. and 52.7 g (0.940 mol, 55.6 mL, 1.3 eq.) of propargyl alcohol (A1e), 570.3 g (1.808 mol, 2.5 eq.) of tetrabutylammonium fluoride trihydrate and 25.4 g (0.036 mol, 0.05 eq.) of bis(triphenylphosphine)palladium (II) dichloride are added. The sample is stirred, heated to reflux (67° C.) and maintained at this temperature for 2 h or until 5-7% of the starting material A1f remains as determined by HPLC analysis. The sample is cooled to 25° C. and concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL to remove tetrahydrofuran. 541 g, (600 mL) of ethyl acetate is charged. The sample is again concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL to remove residual tetrahydrofuran. 2706 g (3000 mL) of ethyl acetate and a solution of 63 g of sodium bicarbonate dissolved in 1500 g (1500 mL) of water are added. The sample is stirred at 25° C. for 10 min and the phases are separated. The organic (top) phase is washed once with 1500 g (1500 mL) of water. The sample is stirred for 10 min and the phases are separated. The organic (top) phase is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 625 mL to remove ethyl acetate. 1582 g (2000 mL) of acetone is added to the concentrate. The sample is stirred, heated to reflux (58° C.) and maintained at this temperature for 30 min. It is then cooled to 40° C. and clarified by filtering through a pad of filter cel. The flask and filter cake are washed twice with 158 g (200 mL, 2×100 mL per wash) of acetone. The sample is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 460 mL. It is then cooled to 4° C. and is hold at this temperature for 1 h. The solids are filtered and the filter cake is washed twice with 158 g (2×100 mL) of cold (4° C.) acetone. The solids are dried at 50° C. for 16 h, to afford 85.6 g (47.4%, corrected) of Compound A1d as a tan, crystalline solid, mp=162-163° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[C:27](C)([CH3:32])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH2:4]([O:5][C:6](/[CH:8]=[C:9]1/[C:27]([CH3:28])([CH3:32])[CH2:26][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH2:30][CH2:29]/1)=[O:7])[CH3:3]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\CCN(C(=O)OC(C)(C)C)CC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a suspension of NaH (0.212 g, 5.29 mmol) in THF (2 mL) was added a solution of triethyl 2-phosphonopropionate (1.05 mL, 5.29 mmol) in THF (2 mL) at 0° C. After the mixture was stirred for 1 h at rt, a solution of tert-butyl-3,3-dimethyl-4-oxopiperidine-1-carboxylate (J. Org. Chem., 2001, 66, 2487) (0.600 g, 2.64 mmol) in THF was then added and stirred for 10 h. The resulting mixture was quenched with water and the product portion was extracted with Et2O. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography (gradient: 5% EtOAc/hexane to 40% EtOAc/hexane) to afford the titled compound (784 mg, ˜100%); 1H NMR (CDCl3) δ 5.73 (s, 1H), 4.15 (q, J=6.8 Hz, 2H), 3.52-3.42 (m, 2H), 3.25-3.18 (m, 2H), 3.05 (t, J=5.6 Hz, 2H), 1.47 (s, 9H), 1.29 (t, J=6.8 Hz, 3H), 1.12 (s, 6H)
Reaction SMILES: [OH:1][C@H:2]([CH3:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:22][S:23]([O:1][C@H:2]([CH3:21])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)=[O:4])(=[O:25])=[O:24]
Reactant: COc1ccc(COc2ccc(C(=O)[C@@H](C)O)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccc(C(=O)[C@@H](C)OS(C)(=O)=O)cc2)cc1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
The compound (1.53 g, 5.34 mmol) synthesized in the above (3) was dissolved in dichloromethane (15 mL), and with cooling with ice, methanesulfonyl chloride (0.62 mL, 8.0 mmol) and triethylamine (1.11 mL, 8.0 mmol) were added in that order. The reaction solution was stirred for 20 minutes with cooling with ice. The reaction solution was poured into aqueous saturated sodium hydrogencarbonate solution, and extracted with chloroform. The organic layer was washed with aqueous saturated ammonium chloride solution and water in that order, then dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting pale yellow solid was washed with chloroform and n-hexane to obtain the entitled compound (1.8 g, 93%) as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[CH3:31][O:30][C:28]([N:18]1[CH2:17][CH2:16][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:20][CH2:19]1)=[O:29]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C2CCNCC2)cc1OC1CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine (1.00 mmol, 0.275 g) and pyridine (1.65 mmol, 0.130 g; 133 μL) in dry CH2Cl2 (10 mL) at 0° C. was added methyl chloroformate (1.10 mmol, 0.104 g; 85 μL) dropwise over 5 minutes. The resulting solution was warmed to room temperature and stirred for 1 hour. The reaction was diluted with CH2Cl2 (70 mL) and extracted with water (70 mL). The aqueous phase was extracted with CH2Cl2 (70 mL), the combined organics washed with water (70 mL), dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by flash chromatography (SiO2 : 1) CH2Cl2, 2) 5% EtOAc/CH2Cl2) to afford the title compound as a colorless oil (0.190 g, 57%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21]([O:23]C)=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@H:11]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
(2S,4R)-1-tert-Butyl 2-methyl 4-(benzyloxy)pyrrolidine-1,2-dicarboxylate (2.78 g, 8.29 mmol) was dissolved in a 1:1 mixture of MeOH and THF (30 ml) and 2N NaOH (12.5 ml, 26 mmol) was added. After stirring at room temperature for 2 h, the organic solvents were evaporated under reduced pressure and the aqueous phase was extracted twice with dichloromethane. The aqueous phase was then cooled at 0° C. and then acidified with concentrated chlorhydric acid. This phase was extracted twice with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 2.01 g (76% yield) of the final compound were obtained, pure enough to perform the next synthetic step.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11](I)([F:13])[F:12]>CN(C)C=O.O.[Cu]>[F:10][C:11]([F:13])([F:12])[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: FC(F)(F)I
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(C(F)(F)F)c1

Procedure:
A solution of 5-iodo-m-xylene (2.3 g) in dimethylformamide (DMF)(30 ml) and copper bronze (0.65 g) in a stainless steel tube is cooled and treated with trifluoromethyliodide (15 g). The tube is sealed and heated at 130°-140° C. in a rocking autoclave for 6 hours. After cooling and venting, the reaction mixture is diluted with water and extracted with n-hexane (2×200 ml). The combined hexane extracts are washed with aqueous NaHCO3 and water. After drying over MgSO4, the solvent is removed under reduced pressure. The residue is subjected to chromatography over silica gel to yield purified 5-(trifluoromethyl)-m-xylene.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)C>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:25][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Reactant: CN1CCN(CCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCN(CCOc2ccc(-n3nc(C(C)(C)C)cc3N)cc2)CC1
Reaction time: 1.25 h
Yield: 15.1 %

Procedure:
To a solution of Intermediate 13b (1.15 g, 5.0 mmol), 2-(4-methyl-piperazin-1-yl)-ethanol (864 mg, 6.0 mmol), and triphenylphosphine (2.62 g, 10.0 mmol) in THF (10 mL), was added diisopropyl azodicarboxylate (2.0 g, 10.0 mmol) dropwise and stirred for 75 min. The mixture was diluted with diethyl ether (50 mL) and extracted with 10% aqueous citric acid soln (2×). The combined aqueous layers were basified with solid potassium carbonate until pH=9. The aqueous layer was then extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried (NaSO4) and evaporated in vacuo. Purification by FCC using 0-12% [9:1 MeOH/880 ammonia] in DCM. The resulting product was crystallised (diethyl ether) to give the title compound (270 mg, 0.756 mmol, 15%). LCMS (Method 1): Rt 2.31, 1.72 min, m/z 358/359 [MH+].
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][O:10][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Temperature: 65 °C
Yield: 91.5 %

Procedure:
To a solution of 5-iodosalicylaldehyde (6.68 g, 26.9 mmol) (Aldrich) in N,N-dimethylformamide (150 mL) was added anhydrous K2CO3 (11.17 g, 80.7 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (7.74 g, 32.3 mmol, Aldrich). The reaction mixture was heated at 65° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde as a yellow oil (Yield 10 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([NH2:15])=[C:6]2[C:10]=1[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7]2.[O:17]=[C:18](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7][C:6]=2[C:5]([N:15]=[C:18]=[O:17])=[C:4]([F:16])[CH:3]=1
Reactant: CCN1c2c(Cl)cc(F)c(N)c2CS1(=O)=O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCN1c2c(Cl)cc(F)c(N=C=O)c2CS1(=O)=O

Procedure:
To a mixture of 7-chloro-1-ethyl-5-fluoro-1,3-dihydro-2,1-benzisothiazol-4-amine-2,2-dioxide (1.30 g, 4.91 mmol), diphosgene (1.17 g, 1.2 eq) in p-dioxane (20 mL), triethylamine (0.6 g, 1.2 eq) was added and the resulting reaction mixture was heated at reflux for overnight. The precipitated triethylamine hydrochloride was filtered off and the solvents were removed in vacuo and dried to give the title compound of Step A as a brown semisolid. 1H NMR (CDCl3, 400 MHz): δ7.21 (d,1H, J=9.5 Hz), 4.28 (s,2H), 3.94 (q,2H), 1.22 (t,3H, J=7.5 Hz).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17]O>>[C:1]([O:12][CH2:17][CH2:16][CH2:15][N:14]([CH3:19])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 3-dimethylamino-1-propanol as starting materials to give the aimed compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH2:24][CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH2:24][CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(CCc3cscn3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(CCc3cscn3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
Tert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[2-(1,3thiazol-4-yl)ethyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.16 g, 0.3 mmol) was dissolved in absolution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-[2-(1,3-thiazol-4-yl)ethyl]-1(2H)-isoquinolinone hydrochloride (0.13 g, 92.9%) as an amorphous solid.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[N:5]2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:42][C@@H:43]([CH3:60])[CH2:44][N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:57]=[C:56]([F:58])[C:53]([C:54]#[N:55])=[C:52]([Cl:59])[CH:51]=2)=[N:46]1>C(Cl)Cl>[Cl:59][C:52]1[CH:51]=[C:50]([C:47]2[CH:48]=[CH:49][N:45]([CH2:44][C@@H:43]([NH:42][C:9]([C:6]3[CH:7]=[CH:8][N:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)=[O:11])[CH3:60])[N:46]=2)[CH:57]=[C:56]([F:58])[C:53]=1[C:54]#[N:55]
Reactant: O=C(O)c1ccn(C2CC2)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccn(C2CC2)n1
Reaction time: 8 h

Procedure:
1-Cyclopropyl-1H-pyrazole-3-carboxylic acid (0.30 g, 1.29 mmol) was dissolved in DCM (20 ml). EDCI (0.692 g, 3.61 mmol), HOBt (0.487 g, 3.61 mmol) and DIPEA (0.932 g, 7.22 mmol) were added at 0° C. to the solution. The resulting mixture was stirred at 0° C. for 15 min. (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.502 g, 1.8 mmol) dissolved in DCM (2 ml) was added and the mixture was stirred overnight. The reaction mixture was quenched by the addition of water and extracted with DCM. The organic layer was evaporated and the residue was purified by flash chromatography. Yield: 400 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.97-1.17 (m, 7H), 3.74-3.80 (m, 1H), 4.26-4.41 (m, 3H), 6.53 (d, 1H), 7.01 (d, 1H), 7.82-7.87 (m, 3H), 7.96 (s, 1H), 8.14 (d, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13].N1C=CC=CC=1>ClCCl>[NH:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[NH:13][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: CCOC(=O)NN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)NNC(=O)Oc1ccccc1
Yield: 90.4 %

Procedure:
Phenyl chloroformate (32.34 g, 0.207M) in dichloromethane (100 ml) was reacted with ethyl carbazate (20.8 g, 0.2M) in dichloromethane (150 ml) and pyridine (16.63 g, 0.21M) to give ethyl phenyl hydrazine-1,2-dicarboxylate (40.5 g). After chromatography on silica gel using dichloromethane and ethyl acetate, recrystallization from toluene gave colourless solid m.p. 89.5-90.5. (Found C 53.8%, H 5.5%, N 12.7%; C10H12N2O4 requires C 53.6%, H 5.4%, N 12.5%). The infra-red spectrum (0.5% in dichloromethane) showed bands at 3360 cm-1 (NH), 1775 and 1745 cm-1 (>C=O), and 1600 cm-1 (aromatic ring). Oxidation of the diester (5 g) in dichloromethane (25 ml) with t-butyl hypochlorite and evaporation of the solvent gave a red oil which was extracted with petroleum spirit (b.p. 30°-40° C.) to isolate ethyl phenyl azodicarboxylate (4 g). (Found C 53.9%, H 4.6%, N 12.4%, C10H10N2O4 requires C 54.1%, H 4.5%, N 12.6%). The infra-red spectrum (0.4% in dichloromethane) showed bands at 1792 with a shoulder at circa 1780 cm-1 (>C=O) and 1600 cm-1 (aromatic ring) and no >NH band at 3360 cm-1.