Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]([CH2:12][NH2:13])[CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22](Cl)=[O:23])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:20]([O:21][C:22](=[O:23])[NH:13][CH2:12][CH:9]1[CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1)[C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1CCc2ccccc2CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCc2ccccc2CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of 1-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methanamine (100 mg, 0.472 mmol) in tetrahydrofuran (5 ml) was added benzyl chloridocarbonate (0.074 ml, 0.520 mmol) and diisopropylethylamine (0.181 ml, 1.039 mmol). The mixture was stirred overnight at 25° C., and then concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 100% EtOAc in hexanes over 10 column volumes to provide the title compound (133 mg, 0.430 mmol, 91% yield). Mass spectrum (ESI) 310.1 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27]C)=[O:26])[C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([OH:27])=[O:26])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of dimethyl 4-[2-(5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylmalonate (1.28 g, 3.21 mmol) in a mixture of methanol (12.9 ml) and tetrahydrofuran (6.4 ml) is added a 2 mol/L aqueous solution of sodium hydroxide (8.01 ml, 16.03 mmol). The mixture is stirred for 2 hours at room temperature, and then the solvent was removed under a vacuum. The residue is dissolved in water and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (1.17 g, 95%). HRMS calcd for C22H24O6: 384.4290. Found: 384.4291. MA calcd for C22H24O6: C, 68.74%; H, 6.29%. Found: C, 68.69%; H, 6.31%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:21]=[C:20](Cl)[N:19]=1>CN1C(=O)CCC1>[Cl:17][C:18]1[N:19]=[C:20]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:21]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:23]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)n(C)c12
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)c2cc(Cl)nc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12

Procedure:
0.33 g (1.5 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.20 g (0.49 mmol) 6-(2,6-dichloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred in 3 mL NMP for 3 h at 120° C. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:35])[N:18]([O:27]CC4C=CC=CC=4)[C:19](=[O:26])[N:20]3[CH:23]3[CH2:25][CH2:24]3)=[CH:15][C:14]=2[F:36])[CH2:9]1)(C)(C)C.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3]>FC(F)(F)C(O)=O>[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:35])[N:18]([OH:27])[C:19](=[O:26])[N:20]3[CH:23]3[CH2:24][CH2:25]3)=[CH:15][C:14]=2[F:36])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3C2CC2)C1
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3C2CC2)C1
Reaction time: 3 h
Yield: 106.4 %

Procedure:
A solution of [1-(3-benzyloxy-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Example G-3, 0.10 g, 0.22 mmol) in trifluoroacetic acid (TFA, 3.0 mL) was reacted with a 1.0 M solution of boron tris(trifluoroacetate) (1.1 mL, 1.1 mmol) in TFA and allowed to stir for 3 hours. The mixture was then concentrated and the residue rediluted in methanol and concentrated. This process was repeated two times. The residue was then triturated from diethyl ether and filtered to provide 0.075 g of the title compound as a solid, mp 244-245° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Cl:19])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[N:4][C:5]([O:9][CH3:10])=[C:6]([Cl:19])[C:7]=1[CH3:8]
Reactant: COc1cc(C)c(Br)c(C)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1nc(C)c(Br)c(C)c1Cl
Temperature: 80 °C
Reaction time: 14 h

Procedure:
3-bromo-6-methoxy-2,4-dimethylpyridine obtained in Preparation Example 22 (800 mg) was added to DMF (4 mL). NCS (494 mg) was added to the solution, and the mixture was stirred at 80° C. for 14 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5% to 30%). The title compound (930 mg) was obtained.
Reaction SMILES: NC1C=C([O:8]C)C=CC=1CCCO.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=1>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:8])=[O:25])=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=1
Reactant: COc1ccc(CCCO)c(N)c1
Reactant: COc1ccc(CCCO)c([N+](=O)[O-])c1
Product: COc1ccc(/C=C/C(=O)O)c([N+](=O)[O-])c1

Procedure:
In particular, 3-(2-amino-4-methoxyphenyl)propan-1-ol may be prepared by hydrogenation of 3-(4-methoxy-2-nitrophenyl)propan-1-ol obtained by reduction of (2E)-3-(4-methoxy-2-nitrophenyl)acrylic acid, resulting from the condensation of malonic acid with 4-methoxy-2-nitrobenzaldehyde. The latter may prepared by hydrolysis of 1-(dibromomethyl)-4-methoxy-2-nitrobenzene obtained by dibromination of 4-methyl 3-nitroanisole. Similarly, 2-[3-(dimethylamino)propyl]-5-methoxyaniline may be prepared by hydrogenation of the product resulting from the reaction between dimethyl amine and 3-(4-methoxy-2-nitrophertyl)propyl methanesulfonate. The latter may be obtained by methanesulfonylation of 3-(4-methoxy-2-nitrophenyl)propan-1-ol as described in the scheme below.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:33](O)=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C.[Si]([O:43][CH:44]([CH3:50])[CH2:45][NH:46][CH2:47][CH2:48][CH3:49])(C(C)(C)C)(C)C>>[NH2:8][C:9]1[CH2:10][C:11]([C:33]([N:46]([CH2:45][CH:44]([OH:43])[CH3:50])[CH2:47][CH2:48][CH3:49])=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Reactant: CCCNCC(C)O[Si](C)(C)C(C)(C)C
Product: CCCN(CC(C)O)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedures as described in Example 101 (Steps H and I) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MS APCI(+) m/z 475 (M+1) detected; 1H-NMR (400 MHz, CDCl3) δ 7.67 (d, 2H), 7.60 (d, 2H), 7.49 (s, 1H), 7.29-7.34 (m, 2H), 6.87 (s, 1H), 4.11 (br s, 1H), 3.48-3.71 (m, 7H), 3.29 (dd, 1H), 2.93 (d, 1H), 2.80 (d, 1H), 1.86-2.01 (m, 4H), 1.61-1.74 (m, 2H), 1.22 (d, 3H), 0.91 (t, 3H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:17]([O:19]C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH:14]([CH3:16])[CH3:15])[CH:8]=1)(=[O:3])[CH3:2].[CH3:21][O:22][C:23](=[O:37])[CH:24]([NH:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH2:25][CH2:26][S:27][CH3:28].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>[OH-].[Na+].CO.CN(C=O)C.O.C(N(CC)CC)C>[C:1]([NH:4][C@H:5]([C:17]([NH:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([NH:29][C@H:24]([C:23]([O:22][CH3:21])=[O:37])[CH2:25][CH2:26][S:27][CH3:28])=[O:36])=[O:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH:14]([CH3:15])[CH3:16])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(CCSC)NC(=O)CCCCN
Reactant: COC(=O)[C@H](Cc1ccc(N)c(C(C)C)c1)NC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)CCCCNC(=O)[C@H](Cc1ccc(N)c(C(C)C)c1)NC(C)=O
Reaction time: 5 h

Procedure:
A mixture of methyl N-acetyl-4-amino-3-isopropylphenylalaninate in 1N NaOH (4 mL) and methanol (2 mL) was stirred for 5 hours, concentrated under reduced pressure, taken up in a mixture of ethyl acetate and ethanol (3×30 mL, 1:1), dried (Na2SO4), filtered and concentrated under reduced pressure. MS (ESI) m/z=−263 (M−H)−. To a mixture of the residue (239 mg, 0.833 mmole), 2-(5-amino-pentanoylamino)-4-methylsulfanyl-butyric acid methyl ester (298 mg, 1.0 mmole), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (240 mg, 1.25 mmole) and N-hydroxybenzotriazole (169 mg, 1.25 mmole) in DMF (3 mL) was added triethyl amine (116 μL) and the mixture was stirred for 16 hours. The mixture was diluted with water and extracted with ethyl acetate (2×25 mL) then with chloroform (2×25 mL). The combined organics were dried (MgSO4), filtered, concentrated under reduced pressure and purified on silica gel eluting with 30% methanol/ethyl acetate to provide the titled compound (316 mg). MS (ESI) m/z=+509(M+H)+, 531 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:9])=[CH:3][C:2]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(F)c(Br)c1
Reactant: CCB(CC)c1cccnc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(F)c(-c2cccnc2)c1
Temperature: 80 °C
Yield: 46.4 %

Procedure:
A mixture of 3-bromo-4-fluorophenylamine (7.92 g, 41.7 mmol), diethyl(3-pyridyl)borane (6.74 g, 45.9 mmol), tetrakis(triphenylphosphine)palladium(0) (0.96 g, 0.83 mmol) and potassium carbonate (17.26 g, 125 mmol) in 1,2-dimethoxyethane (30 ml) and water (15 ml) was heated at 80° C. for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (500 ml) and water (500 ml). The organics were washed with brine (400 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with dichloromethane on a gradient of ethyl acetate (0%-20%) gave 4-fluoro-3-(pyridin-3-yl)phenylamine (3.64 g, 46%) as a colourless oil that solidified on standing to afford a white solid: δH (360 MHz, CDCl3) 3.65 (2H, s), 6.65-6.72 (2H, m), 6.99 (1H, dd, J 9 and 9), 7.33-7.37 (1H, m), 7.84-7.86 (1H, m), 8.58 (1H, d, J 4), 8.76 (1H, m).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH2:29][CH2:28][CH2:27]2>>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:29][CH2:28][CH2:27]2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: Clc1ccc2c(c1)CCCN2
Product: O=C(O)c1ccnc(-c2cn(CCN3CCCc4cc(Cl)ccc43)cn2)c1
Yield: 9 %

Procedure:
The title compound was prepared in 9% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 6-chloro-1,2,3,4-tetrahydroquinoline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.74 (2H, t, J=5.1 Hz), 2.64 (2H, t, J=6.5 Hz), 3.06 (2H, t, J=5.5 Hz), 3.63 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=6.0 Hz), 6.62 (1H, d, J=8.9 Hz), 6.92 (1H, s), 6.94 (1H, t, J=8.7 Hz), 7.49 (1H, d, J=4.8 Hz), 7.69 (1H, s), 7.81 (1H, s), 8.23 (1H, s), 8.46 (1H, d, J=4.1 Hz). [M+H] Calc'd for C20H19ClN4O2, 384. Found, 384.
Reaction SMILES: [CH2:1]([O:6][CH:7]1[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1)[C:2]([CH3:5])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)C>[C:23]([N:11]1[CH:7]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:8][CH2:9][C:10]1=[O:12])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)COC1CCC(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)COC1CCC(=O)N1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
2.2 g of 5-neopentyloxy pyrrolidin-2-one in 30 cm3 of ethyl ether is added at ambient temperature to a solution of 2.6 g of sodium bis trimethylsilylamide in 160 cm3 of ethyl ether. After 30 minutes, the solution is cooled to 0° C. and 1.89 g of benzoyl chloride diluted with 20 cm3 of ethyl ether is added. After leaving the solution for 30 minutes at 0° C. then allowing to return to ambient temperature, and concentrating to dryness under reduced pressure, the residue is chromatographed on silica (eluent: hexane-ethyl acetate 7-3). After crystallization from ethanol, 1.45 g of expected product is obtained. m.p.=83°-85° C.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[S:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(O)(=O)C.[Zn]>[CH2:1]([CH:8]1[NH:12][C:11](=[S:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=S)NC1=Cc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NC(=S)NC1Cc1ccccc1

Procedure:
5-Benzylidene-2-thiohydantoin (24.5 g, 0.12 mol) was dissolved in 150 mL of acetic acid in a flask equipped with a thermometer, a mechanical stirrer, a reflux condenser, and argon pressure. Zinc dust (11.8 g, 0.18 mol) was added, and the flask was immersed in a 130° bath. After 2.5 hr at reflux, HPLC analysis showed no starting material. The mixture was allowed to cool to 50°, and a 500 mL portion of methanol was added. The mixture was returned to reflux, for about 5 min and was then allowed to cool to 63°. The hot mixture was filtered through Whatman #4 paper. The filtrate was concentrated to a paste in vacuo. The residue was mixed with 400 mL of a 3:7 mixture of isopropanol:dichloromethane. The solution was filtered and washed with 1×200 mL and 1×100 mL of water and 1×100 mL of saturated aqueous sodium chloride. After the solution had been filtered through 1 PS paper, it was concentrated at aspirator pressure and high vacuum to yield 17.5 g (71%). HPLC analysis indicated a purity of 78% at 210 nm. NMR (d6-DMSO) δ 12.1 (bs, 1H), 10.7 (bs, 1H), 7.8 (s, 5H), 5.2 (t, 1H), 3.6 (d, 2H).
Reaction SMILES: C(NC1SC=C(C2C=CC=CC=2)C=1C(OCC)=O)(=O)C.C([NH:24][C:25]1SC=C[C:29]=1[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])(=O)C>>[C:33]1([S:30]([CH2:29][C:25]#[N:24])(=[O:31])=[O:32])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)Nc1sccc1S(=O)(=O)c1ccccc1
Agent: CCOC(=O)c1c(-c2ccccc2)csc1NC(C)=O
Product: N#CCS(=O)(=O)c1ccccc1

Procedure:
In place of the 2-acetylamino-3-ethoxycarbonyl-4-phenylthiophene used in Example 4 there is used an equivalent amount of 2-acetylamino-3-phenylsulphonylthiophene (which was obtained by condensing phenylsulphonylacetonitrile with 2:5-dihydroxy-1:4-dithiane in ethanol containing piperidine and subsequently acetylating) whereby 2-amino-3-phenylsulphonyl-5-nitrothiophene (m.pt 155° - 157° C) is obtained.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[N:17][CH:16]=[CH:15]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[N:17][CH:16]=[CH:15]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2cnccc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2cnccc2c1)c1ccccc1
Yield: 28.9 %

Procedure:
Benzenesulphonyl chloride (4.9 g, 0.028M) in CH2Cl2 (15 ml) was added dropwise over 10 minutes to a cooled stirred mixture of 6-aminoisoquinoline (4.0 g, 0.028M) and pyridine (2.37 g, 0.03M) in CH2Cl2 (150 ml). The reaction mixture was stirred overnight at room temperature and was then washed with H2O. The CH2Cl2 solution was dried over MgSO4 and was then chromatographed on a silica gel column. After evaporation the residue was recrystallised from isopropanol to yield 6-phenylsulphonamidoisoquinoline (2.28 g, 33%), m.p. 204°-6° C.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][CH2:20]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][CH2:20]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(N3CCSCC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(N3CCSCC3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
Cyclohexyl[3-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl]methanone (0.83 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (10 mL) and methanol (1 mL), and sodium borohydride (90%, 0.2 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (0.18 g, 22%) as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[C:18]3[CH3:26])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][C@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:16]=2)[C:21](=[O:25])[NH:20][CH:19]=1
Reactant: Cc1c[nH]c(=O)c2ccc(O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c(=O)c2ccc(O[C@H]3CCCNC3)cc12
Reaction time: 2 h

Procedure:
The crude (S)-3-(4-Methyl-1-oxo-1,2-dihydroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 2 ml of DCM and excess TFA added (0.2 ml). After stirring for 2 hours the solvent was removed under reduced pressure and the residue dissolved in methanol and partially purified by ion exchange chromatography. Further purification by prep-HPLC gave (S)-4-methyl-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one, El-MS: m/z=259.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(CNC(=O)OCc1ccccc1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)CNC(=O)OCc1ccccc1

Procedure:
22.6 g of 3-benzyloxycarbonylamino-2(R,S)-methylpropionic acid are left to stand for 24 hours in 230 ml of methanol with a few drops of concentrated sulfuric acid. The reaction mixture is concentrated by evaporation and the residue is purified by FC (220 g of silica gel, dichloromethane). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.60.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:19][CH2:18][C:17]([NH2:39])([C:20](=[O:38])[NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][N:26]=[C:25]3[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:25]2[C:24]3[C:28](=[CH:29][CH:30]=[C:22]([NH:21][C:20]([C:17]4([NH2:39])[CH2:18][CH2:19][NH:15][CH2:16]4)=[O:38])[CH:23]=3)[NH:27][N:26]=2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
4M HCl/dioxane (2 ml) was added to a solution of 3-Amino-3-[3-(4-fluoro-phenyl)-1H-indazol-5-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1P) (60 mg, 0.088 mmol) in MeCl2 (1 ml) at room temperature then stirred for 1 hour at room temperature. The solvent was evaporated. Hexanes (20 ml) was added and supernatant decanted. The residue was dried yielding title compound 2P as a white solid (20 mg, 69%). ESMS (MH 340).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:23][C:24]([O:26]C)=O)[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O.[NH2:29][NH2:30]>CO>[NH:29]([C:24](=[O:26])[CH2:23][N:15]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[NH2:30]
Reactant: COCCOc1ccc(S(=O)(=O)N(CC(=O)OC)c2ccc(C)cc2)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: COCCOc1ccc(S(=O)(=O)N(CC(=O)NN)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude carboxylic acid methyl ester resulting from the precedent step, e.g. methyl ({[4-(2-methoxyethoxy)phenyl]sulfonyl}-4-methylanilino)acetate (1 mmol), was dissolved in MeOH (3.5 mL). Hydrazine hydrate was added (0.385 mL). The reaction mixture was stirred overnight at room temperature. Solvents were evaporated. The crude product was dissolved in ethyl acetate (4 mL) and was washed with water (4 mL). Aqueous phase was extracted with ethyl acetate (3×2 mL) and with methylene chloride (2×2 mL). Combined organic phases were dried over magnesium sulfate, filtrated and solvents were evaporated. The desired product, e.g. N-(2-hydrazino-2-oxoethyl)-4-(2-methoxyethoxy)-N-(4-methylphenyl)benzenesulfonamide was isolated as a light yellow oil, in 86% purity by HPLC (MaxPlot detection between 230 and 400 m). This intermediate was used in the next step without further purification.