Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:25][CH:26]1[N:31]([CH2:32][C:33]([NH:35][NH2:36])=[O:34])[CH:30]([CH3:37])[CH2:29][O:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:36][NH:35][C:33](=[O:34])[CH2:32][N:31]3[CH:26]([CH3:25])[CH2:27][O:28][CH2:29][CH:30]3[CH3:37])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC1COCC(C)N1CC(=O)NN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1COCC(C)N1CC(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 2 h
Yield: 6.8 %

Procedure:
To the solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 0.569 mmol) and 2-(3,5-dimethylmorpholino)acetohydrazide (0.106 g, 0.569 mmol) in THF (10 mL) were added T3P (0.543 g, 0.854 mmol) followed by DIPEA (0.110 g, 0.854 mmol) at −60° C. and stirred for 2 h. The reaction mixture was transferred into 25 mL iced-water and extracted with ethyl acetate (2×25 mL) and the combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford the crude product, which was purified by chromatography (0-3% MeOH/CH2Cl2) to give 0.02 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-(3,5-dimethylmorpholino)acetyl)acrylohydrazide (Yield: 7%). 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.83 (s, 1H), 9.56 (s, 1H), 8.54-8.56 (m, 2H), 8.25-8.30 (m, 1H), 7.49-7.51 (d, J=10.4 Hz, 1H)), 6.01-6.04 (d, J=10.4 Hz, 1H), 3.44-3.57 (m, 2H), 3.28-3.34 (m, 2H), 3.21 (s, 1H), 3.15 (s, 1H), 2.84-2.88 (m, 2H), 0.93-1.04 (m, 6H): LCMS m/z 521.18 [M+H]+, tR 1.898 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:24])[CH3:23])=[CH:14][C:13]=2[CH3:27])=[CH:7][CH:6]=1)[CH3:2].[CH:29](=O)[CH3:30].C([BH3-])#N.[Na+].[C:36](O)(=O)[CH3:37]>C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:25])([CH3:26])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:23])[CH3:24])=[CH:14][C:13]=2[CH3:27])[CH2:36][CH2:37][CH2:29][CH3:30])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Reactant: CC=O
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CCCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1C)C(C)(C)CCN2C(C)C
Yield: 52 %

Procedure:
A solution of 4-(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-7-ylamino)-benzoic acid ethyl ester (Compound 46, 64.4 mg, 0.1692 mmol), acetaldehyde (37.2 mg, 0.8462 mmol), sodium cyanoborohydride (53.2 mg, 0.8462 mmol), acetic acid (0.125 mL), and acetonitrile (1 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.44) to give the title compound (71.2 mg, 52%) as a solid: 1H NMR (300 MHz, CDCl3): δ1.15 (d, 6 H, J=6.5 Hz), 1.27 (t, 3 H, J=7.1 Hz), 1.31 (s, 6 H), 1.35 (t, 3 H, J=7.1 Hz), 1.74 (t, 2 H, J=6.0 Hz), 1.96 (s, 3 H), 3.15 (t, 2 H, J=6.0 Hz), 3.68 (d, 2 H, J=5.9), 3.98 (sp, 1 H, J=6.5 Hz), 4.31 (q, 2 H, J=7.1 Hz), 6.43 (s, 1 H), 6.49 (d, 2 H, J=8.9 Hz), 7.08 (s, 1 H), 7.84 (d, 2 H, J=8.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(OC)ccc4nc3OC)CC2)c1
Yield: 81 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 81%). MS(ESI) m/z 454 (M+1).
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][CH:12]=1)([O-])=O.[CH2:19](O)C>[Pd]>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:11][CH:12]=1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cn1
Reactant: CCO
Agent: [Pd]
Agent: NN
Solvent: O
Product: COC(=O)CCCc1ccc(N)cn1
Reaction time: 1 h

Procedure:
Hydrazine hydrate (10 ml) in ethanol (20 ml) was added over 30 minutes to a stirred suspension of 4-(5-nitropyrid-2-yl)butanoic acid (7.5 g, 0.036 mole) and 10% palladium on carbon (1 g) in ethanol (100 ml). The solution was stirred for 1 hour, filtered through hyflo and the filtrate was evaporated to dryness. The residue was dissolved in methanol (250 ml) containing concentrated sulphuric acid (20 ml) and the resulting solution was refluxed for 4 hours, cooled and the solvent was removed under reduced pressure. The residue was dissolved in water (100 ml), basified and extracted with chloroform (3×100 ml). The chloroform extracts were combined, dried over magnesium sulphate, and evaporated to dryness. The residue was distilled in a kugelrohr apparatus (oven temp. 145° C. at 0.05 mmHg) to give the title compound 3.84 g as a straw coloured oil.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26]Cl)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I-:50].[Na+]>C(#N)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][I:50])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCI
Temperature: 60 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
To a solution of chloromethyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate (7.8 g, 11 mmol) in acetonitrile (100 mL), was added sodium iodide (6.5 g, 44 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1% MeOH in CH2Cl2), to give 7.84 g of iodomethyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[CH2:12]([N+:19](C)(C)C)[C:13]1C=CC=C[CH:14]=1.C(#N)C=C>C(O)(C)(C)C>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH2:13][C:12]#[N:19]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Sc1nc2ccccc2s1
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: C=CC#N
Product: N#CCCSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
2-Mercaptobenzothiazole (25.0 g; 0.15 moles) was mixed with t-butanol (125 ml) and benzyltrimethylammonium hydroxide (40% in methanol; 3 ml). Acrylonitrile (15.9 g; 0.30 moles) was added dropwise and the mixture stirred at room temperature for 7 days. The product was removed by filtration and recrystallized from benzene.
Reaction SMILES: [CH3:1][N:2]([C:10]1[C:11]2[CH:18]=[CH:17][N:16]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:12]=2[N:13]=[CH:14][N:15]=1)[CH:3]1[CH2:9][O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:29][C:30]1[CH:31]=[C:32]([NH:37][CH2:38][C:39](O)=[O:40])[CH:33]=[C:34]([Cl:36])[CH:35]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:29][C:30]1[CH:31]=[C:32]([NH:37][CH2:38][C:39]([N:5]2[CH2:4][CH:3]([N:2]([CH3:1])[C:10]3[C:11]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:9][O:8][CH2:7][CH2:6]2)=[O:40])[CH:33]=[C:34]([Cl:36])[CH:35]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CNCCOC4)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4COCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-methyl-N-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-amine ((0.114 g (0.283 mmol) 107.5, (3,5-dichloro-phenylamino)-acetic acid (0.0685 g (0.311 mmol) 107.b, and 1-hydroxybenzotriazole hydrate (9 mg (0.057 mmol) were dissolved in DMF (4 mL). The resulting solution was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (60 mg, 0.311 mmol) and DIEA (100 uL (0.566 mmol) and stirred at rt for 24 hr. The mixture was diluted with H2O and extracted with EtOAc (2×) and 1:1 EtOAc/THF (2×). The combined organics were washed with 10% citric acid and brine, dried over MgSO4, filtered, and concentrated, absorbing onto 3 g SiO2. Purification by flash column chromatography (ISCO 12 g SiO2, 40% EtOAc/hex then gradient to 100% EtOAc) afforded (2-(3,5-dichlorophenylamino)-1-(6-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1,4-oxazepan-4-yl)ethanone (0.179 g) 107.6 as a white solid. LCMS (ESI) m/z: 603.20 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][C@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].N[C@H](CO[C@H](C1C=CC(F)=CC=1)C)CO.[C:31](O)(=[O:40])[C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33]>C(O)(C)C>[OH:33][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31]([O:4][CH2:3][C@H:2]([NH2:1])[CH2:5][O:6][C@H:7]([C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH3:8])=[O:40]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: C[C@H](OC[C@H](N)CO)c1ccc(F)cc1
Agent: C[C@H](OC[C@@H](N)CO)c1ccc(F)cc1
Solvent: CC(C)O
Product: C[C@H](OC[C@@H](N)COC(=O)[C@H](O)c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a stirred solution of the 80:20 mixture of (R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol & (S)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (2.94 g) in isopropanol (3 ml) was added a solution of D-(−)-mandelic acid (2.10 g) in isopropanol (2 ml). The solvent was evaporated and replaced with ethyl acetate to afford white crystals which were collected by filtration. The crystals were dissolved in hot EtOAc (65 ml) at 80° C. and the mixture was allowed to cool slowly. Crystals appeared on reaching a temperature of 70° C. and the suspension was then stirred at room temperature for 16 h. The crystals were collected by filtration and redissolved in hot EtOAc (80 ml) at 80° C. and the mixture was allowed to cool slowly until cyrstallisation started and then the resulting suspension was stirred at room temperature for 16 h. The crystals were collected by filtration to afford pure (R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (R)-hydroxy-phenyl-acetate (3.08 g, 61%) as a white solid. 1H NMR (300 MHz, DMSO, δ ppm): 1.34 (d, J=6.3 Hz, 3H), 3.13 (m, 1H), 3.23 (m, 1H), 3.37 (m, 4H), 3.83 (m, 1H), 4.46 (q, J=6.3 Hz, 1H), 4.54 (s, 1H), 7.20 (m, 5H), 7.35 (m, 4H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11](N)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.[OH:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].N([O-])=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([O:23][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(-c2nc(N)cc3cccnc23)c1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 8-(3-methylsulfanyl-phenyl)-[1,7]naphthyridin-6-ylamine (2.05 g, 7.68 mmol) in DMF (30 ml) at 0° C. is added triflic acid (20 ml) slowly. Sodium nitrite (1.06 g) is then added slowly over 15 minutes and the reaction mixture allowed to warm to room temperature. After stirring for 23 hours the reaction is complete by HPLC. The mixture is then diluted with ethyl acetate and washed with water, 2 N sodium carbonate and brine. The organic layer is dried over magnesium sulfate and concentrated. The product is purified by silica gel chromatography, eluting with 30% ethyl acetate in isohexane. The product is obtained as an amorphous solid. MS (ES+) 400.9948
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH2:18])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.O=[C:34]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36].C([BH3-])#N.[Na+]>C(O)C>[C:35]([C@@H:34]([NH:18][C@H:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:11])[CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
10 g (0.0268 mol) of tert-butyl Nε -benzyloxycarbonyllysinate hydrochloride are dissolved in 150 cm3 of anhydrous ethanol; 2.71 g (0.0268 mol) of triethylamine, 20.6 g (0.1 mol) of ethyl 2-oxo-4-phenylbutyrate and 20 g of 4Å molecular sieve are added. The mixture is stirred for one hour at 20° C. A solution of 1.68 g (0.0268 mol) of sodium cyanoborohydride in 20 cm3 of ethanol is then added in the course of 4 hours, after which stirring is continued for 18 hours at 20° C. The mixture is filtered and taken to dryness, the residue is redissolved in 200 cm3 of ethyl acetate and the solution is then washed twice with 100 cm3 of a 10% strength aqueous citric acid solution and then with water until the washing liquors are neutral. The mixture is dried over magnesium sulfate and evaporated. 28.7 g of an oil are collected, and this is purified by chromatography on silica gel (eluent: methylene chloride/acetone 95:5). After the removal of impurities and then the (S, R) isomer, 4.1 g of tert-butyl (S)-Nα -[(S)-1-carbethoxy-3-phenylpropyl]-Nε -benzyloxycarbonyllysinate are collected, and used without further treatment in the following stage.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([Br:28])=[CH:20][C:19]=1[C:29]([OH:31])=O.[Cl:32][C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH2:48])[CH2:42][CH2:41]1>O1CCCC1>[Br:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([O:17][CH3:16])=[C:19]([C:29]([NH:48][CH2:47][CH2:46][N:43]2[CH2:42][CH2:41][N:40]([C:34]3[CH:35]=[CH:36][CH:37]=[C:38]([Cl:39])[C:33]=3[Cl:32])[CH2:45][CH2:44]2)=[O:31])[CH:20]=1
Reactant: COc1c(C(=O)O)cc(Br)c2ccccc12
Reactant: NCCN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C(=O)NCCN2CCN(c3cccc(Cl)c3Cl)CC2)cc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
Triethylamine (1.24 mL, 8.87 mmol) and isobutyl chloroformate (0.50 mL, 3.9 mmol) are added to 1-methoxy-4-bromo-2-naphthoic acid (European Published Patent Application EP 0 539 281A1) (1.0 g, 3.55 mmol) in dry tetrahydrofuran (20 mL) at 0° C. and allowed to stir for 1 hour. To this mixed anhydride is added 4-(2,3-dichlorophenyl)-l-piperazineethanamine (0.97 g, 3.55 mmol) in dry tetrahydrofuran (5 mL) and stirring continued for 18 hours, gradually allowing the mixture to warm to room temperature. The reaction mixture is washed with saturated sodium chloride (NaCl), dried (sodium sulfate), and concentrated to give 0.27 g of the title compound as a white solid; mp 137° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].O.[OH-].[Li+:36]>CCO.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].[Li+:36]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C)cn2)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)[O-])cc3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 106.1 %

Procedure:
Crude ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-((5-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (Intermediate 59) (238 mg) in EtOH (2 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (26 mg, 0.620 mmol). The solution was stirred at ambient temperature for 5 h. A further portion of lithium hydroxide monohydrate (4 mg, 0.095 mmol) was added and the mixture left at ambient temperature overnight. The mixture was concentrated to dryness to give crude lithium 4-((2S,4R)-1-acetyl-2-methyl-4-((5-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate as a brown foam (240 mg) which was used directly in the next step without further purification. LCMS: (Formate, 2 min), Rt=0.65 min, MH+416.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[S:21]([CH3:24])(=[O:23])=[O:22])C1C=CC=CC=1.Cl>O1CCOCC1.CO.[Pd]>[CH3:24][S:21]([C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]=1[NH2:8])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(-c2ccncc2)ccc1N
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of benzyl-(2-methanesulfonyl-4-pyridin-4-yl-phenyl)-amine (2.0 g) in dioxane/methanol 1:1 (100 ml) was added 2N HCl (5 ml) and palladium black (1.0 g). The reaction mixture was hydrogenated at 1.1 bar and rt for 18 h. The catalyst was filtered off over a microfilter and washed with methanol. The filtrate was evaporated to dryness to obtain the desired compound (1.45 g) as a yellowish solid. MS (ISP): 249.1 (M+H)+
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N1C=CC=CC=1>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:33]3[CH2:34][CH2:35][CH:30]([CH2:29][OH:28])[CH2:31][CH2:32]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: OCC1CCNCC1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCC(CO)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 4-(hydroxymethyl)piperidine and pyridine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 408 (M+H+, 100).
Reaction SMILES: [CH2:1]1[C@@:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[C:17]2=[O:27])=[CH:12][CH:11]=1.[CH3:28][C:29]1([O:32][CH2:31]1)[CH3:30].[Br-].[Li+].CN1C(=O)CCC1>O.C(OCC)(=O)C>[OH:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:27])[N:16]([C:13]1[CH:14]=[CH:15][C:10]([N:2]3[CH2:3][CH2:4][C@:5]4([CH2:9][CH2:8][N:7]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[CH2:6]4)[CH2:1]3)=[CH:11][CH:12]=1)[CH2:25][CH2:24]2
Reactant: CC1(C)CO1
Reactant: O=C1c2ccc(O)cc2CCN1c1ccc(N2CC[C@]3(CCNC3)C2)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)CN1CC[C@]2(CCN(c3ccc(N4CCc5cc(O)ccc5C4=O)cc3)C2)C1
Temperature: 65 °C

Procedure:
A mixture of 2-[(S)-4-(2,7-diaza-spiro[4.4]non-2-yl)-phenyl]-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.50 g), isobutylene oxide (0.10 g), lithium bromide (0.12 g) and NMP (1 mL) was heated at 65° C. for 5 hours. The cooled reaction mixture was distributed between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. In this way the product was obtained with molecular weight 435.57 (C26H33N3O3); MS (ESI): 436 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].O.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>O1CCCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1]
Reactant: CN(C)CCCCCCO
Reactant: COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1COCCCCCCN(C)C
Reaction time: 0.75 h

Procedure:
6-(Dimethylamino)hexanol (8.80 g, 60.6 mmol) was dissolved in an anhydrous 2:1 mixture of tetrahydrofuran and dimethylfornamide (150 mL) and the solution was cooled in an ice bath. Sodium hydride (60% in oil, 3.23 g, 80.8 mmol) was added in portions and after 5 min. the water bath was removed. After 45 min., 2-methoxybenzyl chloride (6.28 g, 40.4 mmol) was added. After 4 h, the reaction mixture was quenched with 1 M sodium thiosulfate and tetrahydrofuran was removed in vacuo. The reaction mixture was washed with ethyl acetate and the aqueous phase was basified with 3 M sodium hydroxide, followed by extraction with ether. The ether layer was dried over potassium carbonate, filtered and acidified with 4 M hydrochloric acid in dioxane. The reaction mixture was concentrated in vacuo and the residue was crystallized form ethanol/ether to give O-(2-methoxybenzyl)-6-dimethylaminohexanol as the hydrochloride salt (10.4 g, 85%). MS (M-Cl)+266.3.