Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:31]=[C:30]([C:32]#[C:33][CH3:34])[CH:29]=[C:28]2[CH:35]=[O:36])[CH2:24][C@@H:23]1O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC1C=CC=CC=1)=S.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C(#N)C.CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:31]=[C:30]([C:32]#[C:33][CH3:34])[CH:29]=[C:28]2[CH:35]=[O:36])[CH2:24][CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC#Cc1cc(C=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC#Cc1cc(C=O)n([C@H]2CC[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 22.2 %

Procedure:
To a solution of 1-(2-deoxy-5-O-trityl-β-D-ribofuranosyl)-4-(1-propynyl)pyrrole-2-carbaldehyde (392 mg, 797 μmol) in acetonitrile were added 4-dimethylaminopyridine (975 mg, 7.98 mmol) and phenyl chlorothioformate (470 μl, 3.40 mmol) in an argon atmosphere, and the reaction mixture was stirred at room temperature. After 23 hours, the reaction solution was concentrated under reduced pressure, and purified by column chromatography on silica gel (50-67% CH2Cl2 in hexane) to give an intermediate (193 mg, containing minor amounts of impurities). To a solution of this intermediate in toluene (10 ml) were added tri-n-butyltin hydride (165 μl, 612 μmol) and α,α′-azobisisobutyronitrile (15 mg, 92 μmol), and the reaction mixture was refluxed for 5 hours in an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel (eluent: 50-80% CH2Cl2 in hexane) to give the title product (84 mg, 58%).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.CCCCCC.[CH3:21][N:22]([CH3:38])[CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](N(OC)C)=[O:33])=[N:30][CH:31]=1.C(O)(C)C>C1COCC1.O>[CH3:21][N:22]([CH3:38])[CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([C:2]2[CH:14]=[CH:13][C:5]([O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)=[CH:4][CH:3]=2)=[O:33])=[N:30][CH:31]=1
Reactant: Ic1ccc(OC2CCCCO2)cc1
Reactant: CON(C)C(=O)c1ccc(OCCN(C)C)cn1
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)nc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a solution of 2-(4-iodophenoxy)tetrahydro-2H-pyran (1.1 eq) in THF was added a solution of nbutyllitium in hexane (1.1 eq) at −78° C. The mixture was stirred at −78° C. for 20 min. To the mixture was added a solution of 5-(2-(dimethylamino)-ethoxy)-N-methoxy-N-methylpicolinamide (1.0 eq) in THF at −78° C. After 2 h, isopropanol and water was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate. The extract was washed with 0.5 N HCl, sodium bicarbonate (sat.), and brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel) to give the subtitle compound (47% yield).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:25][CH3:26])=[C:17]3[O:21][C:20]([CH2:22][O:23][CH3:24])=[CH:19][C:18]=23)=[O:12])=CC=1)([O-])=O.[NH2:27][C:28]1[N:32]([CH3:33])[CH:31]=[N:30][C:29]=1[C:34]#[N:35]>O>[C:34]([C:29]1[N:30]=[CH:31][N:32]([CH3:33])[C:28]=1[NH:27][C:11]([C:13]1[CH:14]=[CH:15][C:16]([O:25][CH3:26])=[C:17]2[O:21][C:20]([CH2:22][O:23][CH3:24])=[CH:19][C:18]=12)=[O:12])#[N:35]
Reactant: Cn1cnc(C#N)c1N
Reactant: COCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)ccc(OC)c2o1
Solvent: O
Product: COCc1cc2c(C(=O)Nc3c(C#N)ncn3C)ccc(OC)c2o1
Reaction time: 0.67 h
Yield: 74.8 %

Procedure:
Prepared from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid 4-nitro-phenyl ester (250 mg) and 5-amino-1-methyl-1-H-imidazole-4-carbonitrile (171 mg). The reaction was stirrred for 1 hour and 40 minutes. Water (1 ml) was added and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 10% methanol in dichloromethane afforded the title compound as a pale yellow solid (178 mg).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:18]=[CH:17][C:16]2[C:6](=[C:7]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:8]3[C:12](=O)[O:11][C:10](=[O:14])[C:9]=3[CH:15]=2)[CH:5]=1.Cl>C(COC)OC.C1COCC1>[Cl:3][C:4]1[CH:18]=[CH:17][C:16]2[C:6](=[C:7]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:8]3[CH2:12][O:11][C:10](=[O:14])[C:9]=3[CH:15]=2)[CH:5]=1
Reactant: O=C1OC(=O)c2c1cc1ccc(Cl)cc1c2-c1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C1OCc2c1cc1ccc(Cl)cc1c2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a suspension of sodium borohydride (0.5 g) in dimethoxyethane (20 ml), a solution of 6-chloro-4-(4-chlorophenyl) naphtho[2,3-c]furan-1,3-dione (1.0 g) in THF (20 ml) was added dropwise, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into 1N hydrochloric acid to stop the reaction; the product was extracted with ethyl acetate. After being washed with water, the extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: hexane−ethyl acetate=3:1) and recrystallized from THF to yield the title compound (300 mg).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][C:3](=O)[CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCC(CC2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C1CN2CCC(CC2)N1

Procedure:
1,4-Diazabicyclo[3.2.2]nonan-3-one (5.12 g; 36 mmol) was dissolved in tetrahydrofuran (50 ml), litium aluminium hydride 2.28 g (60 mmol) was added to the solution and the reaction mixture was refluxed for 36 hours. After cooling the reaction mixture to mom temperature, water (2.3 ml) was added dropwise and the mixture was filtered. The solvent was removed from the filtrate by rotavapor at reduced pressure. The formed substance was distilled with Kugelrohr (0.5 mBar, 70° C.). Yield of the title compound 3.11 g (68%).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)(=O)C.I(C1C=CC=CC=1)=O.B(F)(F)F.CCOCC.[CH2:26]([O:28][C:29](=[O:38])[CH2:30][C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32])C>CO>[CH3:26][O:28][C:29](=[O:38])[CH:30]([O:3][CH3:1])[C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)C1CCCC1
Agent: FB(F)F
Agent: O=Ic1ccccc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(OC)C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared using a method analogous to that described in Tetrahedron 1998, 44, 1603-1607: To a suspension of iodosobenzene diacetate (5.2 g, 16.3 mmol) in MeOH (40 mL) was added BF3.OEt2 (2.1 mL, 16.3 mmol). The resulting mixture was added to 3-cyclopentyl-3-oxo-propionic acid ethyl ester (3.0 g, 16.3 mmol) and stirred at rt overnight. The mixture was concentrated to half the total volume, quenched with satd. aq. NaHCO3, and extracted with CHCl3 (2×). The combined organic layers were dried and concentrated and the crude residue purified (EtOAc/hexanes) to yield a colorless oil (1.5 g, 43%). 1H NMR (MeOD): 4.4 (s, 1H), 3.8 (s, 3H), 3.5 (s, 3H), 3.3-3.2 (m, 1H), 1.9-1.5 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:22][CH:23]=2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=2
Reactant: CCOC(=O)CBr
Reactant: CCCCOc1nc(N)c2nc(Br)n(Cc3ccc(O)cc3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(Br)n(Cc3ccc(OCC(=O)OCC)cc3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
8-Bromo-2-butoxy-9-(4-acetoxybenzyl)adenine (0.29 g, 0.67 mmol) obtained in accordance with the method of Reference example 4 was added to methanol (10 ml) and 5% sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 4 hours. After the mixture was neutralized with concentrated hydrochloric acid, the resulting solid was filtered and washed with methanol to give 8-bromo-2-butoxy-9-(4-hydroxybenzyl)adenine (0.19 g, 0.49 mmol, yield: 73%) as a white solid. Thus obtained 8-bromo-2-butoxy-9-(4-hydroxybenzyl)adenine (0.05 g, 0.13 mmol) and potassium carbonate (0.02 g, 0.14 mmol) were added to DMF (10 ml), and then thereto was added ethyl bromoacetate (0.04 g, 0.24 mmol). The mixture was stirred at room temperature for 18 hours. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜50/1) to give 8-bromo-2-butoxy-9-(4-ethoxycarbonylmethoxybenzyl)adenine (0.06 g, 0.12 mmol, yield: 96%) as a white solid. And then the captioned compound was obtained in accordance with the method of Example 1, Yield: 80%.
Reaction SMILES: [N+](=[CH2:3])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[CH2:18]([N:25]1[CH2:30][C@@H:29]([OH:31])[CH2:28][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[C@H:26]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCOCC>[CH2:18]([N:25]1[CH2:30][C@@H:29]([O:31][CH3:3])[CH2:28][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[C@H:26]1[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Product: COC(=O)[C@H]1C[C@H](OC)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
Diazomethane was generated (from 5 g of Diazald) and distilled together with ether into a mixture of 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (0.60 g, 0.0016 mol) and around 1 g of silica gel in 10 mL of ether. After distillation, the mixture was stirred at rt overnight. The mixture was diluted with methylene chloride, filtered to remove silica gel. The filtration was concentrated to dry and the resulting residue was applied on column, eluting with 0 to 40% EtOAc in Hexane, to yield the methyl ether compound (20 mg, 3.2%). MS (ESI): (M+H)+=398.1.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9](=[O:27])[N:10]([CH2:25][CH3:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([C:19](=[O:23])[CH2:20][CH2:21][CH3:22])=[C:13]([CH3:24])[CH:12]=2)=[O:7])(C)(C)C.Cl(O)(=O)(=O)=O>C(OCC)C>[CH2:25]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:19](=[O:23])[CH2:20][CH2:21][CH3:22])=[C:13]([CH3:24])[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:7])=[O:5])[C:9]1=[O:27])[CH3:26]
Reactant: CCCC(=O)c1cc2c(O)c(C(=O)OC(C)(C)C)c(=O)n(CC)c2cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CCCC(=O)c1cc2c(O)c(C(=O)O)c(=O)n(CC)c2cc1C

Procedure:
7.13 g of 1-ethyl-6-butyryl-4-hydroxy-7-methylcarbostyril-3-carboxylic acid tert-butyl ester are suspended in 100 ml of diethyl ether and, while stirring, 2.0 ml of 70% strength perchloric acid are carefully added. The reaction mixture is stirred for 10 minutes at 30°, cooled by means of an ice bath and suction-filtered and the residue is washed twice with a little diethyl ether and subsequently with hexane, then allowed to dry at room temperature. In this manner 1-ethyl-6-butyryl-4-hydroxy-7-methylcarbostyril-3-carboxylic acid having a melting point of 157°-158° is obtained.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:6]([O:43][CH3:44])=[C:7]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:30][CH2:29]2)=[O:17])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1.C(N(CC)CC)C.[CH2:52]([S:55](Cl)(=[O:57])=[O:56])[CH2:53][CH3:54].N1C=CC=CC=1>ClCCl>[C:11]([C:9]1[CH:10]=[C:5]([NH:4][S:55]([CH2:52][CH2:53][CH3:54])(=[O:57])=[O:56])[C:6]([O:43][CH3:44])=[C:7]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:32][CH2:33]2)=[O:17])[CH:8]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)C4CCCN4C)CC3)c2n1C
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1cc(C(C)(C)C)cc(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@@H]5CCCN5C)CC4)c3n2C)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg of 1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(3-amino-5-tert-butyl-2-methoxy-phenyl)-amide trihydrochloride are dissolved in 2 ml dichloromethane and mixed successively with 210 μl triethylamine, 80 μl propylsulphonic acid chloride and 70 μl pyridine. The mixture is stirred for 2 hours at ambient temperature, a further 80 μl of propylsulphonic acid chloride are added and the mixture is stirred for a further 12 hours. The solvents are eliminated in vacuo and the residue is purified by preparative HPLC (method 3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][N:19]([CH3:29])[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[C@@H:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCCl.CCOCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][N:19]([CH3:29])[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])=[O:21])[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C1CCCCC1)C(=O)OCC[Si](C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCCl
Product: CN(C[C@@H](NC(=O)OC(C)(C)C)C(=O)C1CCCCC1)C(=O)OCC[Si](C)(C)C
Temperature: 70 °C
Yield: 98.1 %

Procedure:
To a solution of (1R,2R)-2-(t-butoxycarbonylamino)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol (0.76 g, 1.76 mmol) in 1,2-dichloroethane (4 mL) was added Dess-Martin periodinane (1.05 g, 2.29 mmol), and the resulting mixture was heated in a CEM microwave reactor at 70° C. for 3 min. Completion of reaction was confirmed by TLC. The mixture was diluted with ether (20 mL), washed with 1 N aq NaOH (2×10 mL) and brine, dried over Na2SO4, and concentrated to give crude (R)-2-(t-butoxycarbonylamino)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-one (0.74 g), which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20].CCOCC>CN(C=O)C>[O:11]=[C:10]1[C:4]2[S:3][C:2]([NH:1][C:22]([NH:21][CH2:19][CH3:20])=[O:23])=[N:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 90 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A solution of 2-amino-7-oxo-4,5,6,7-tetrahydro-benzothiazole 3 (11.56 g, 68.7 mmol) in anhydrous DMF (200 mL) was treated with triethylamine (19.2 mL, 137 mmol, 2.0 eq) and ethyl isocyanate (10.9 nL, 137 mmol, 2.0 eq). The reaction mixture was heated at about 90° C. with stirring for about 3 hours. The DMF solvent was distilled off under reduced pressure. A sticky brown residue was obtained. Treatment with Et2O (100 mL) gave a precipitate, which was filtered off and washed with more Et2O (50 mL). The light brown colored solid was dried under vacuum to give 13.97 g (85%) of 4. The material was used in the following synthesis without further purification. 1H NMR (DMSO) δ 10.95 (br s, 1H, NH), 6.66 (br s, 1H, NH), 3.16 (p, 2H, J=7.2 Hz, CH2), 2.79 (t, 2H, J=6.1 Hz, CH2), 2.45 (t, 2H, J=6.5 Hz, CH2), 2.05 (p, 2H, J=6.4 Hz, CH2), 1.07 (t, 3H, J=7.2 Hz, CH3); LC/MS 240 (MH+); RP-HPLC RT 2.27 minutes.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH3:20][CH:21]([SH:23])[CH3:22]>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][S:23][CH:21]([CH3:22])[CH3:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)S
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)SCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To benzyl bromoacetate (100 mg, 0.437 mmol) in dimethyl formamide (2 mL) is added triethylamine (67 uL, 0.481 mmol) and 2-propanethiol (41 uL, 0.437 mmol). After stirring at rt during 2 h, the solvent is evaporated, the residue is treated with dichloromethane and water. The organic phase is dried and evaporated to give a crude compound before purification by preparative HPLC (Column Waters C18 ODB 5 μm 19×50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min 100% ACN) to yield the title compound.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Br:22])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Brc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3Br)CC2)c(OC)nc1C
Yield: 58 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:13][CH2:12][C@@H:11]([O:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:14])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](CO)OCOCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)OCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.6 %

Procedure:
To a stirred solution of (2S)-2-[(benzyloxy)methoxy]propan-1-ol (Banfi, L., et al., J. Org. Chem. (1984), 49:3784-90) (11.40 g, 0.058 mol) in dichloromethane (50 mL) and pyridine (20 mL) was added p-toluenesulfonyl chloride (11.0 g, 0.057 mol) at 0° C. The reaction mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate and washed with water, 5% hydrochloric acid solution, water and brine; dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford (S)-2-(benzyloxymethoxy)propyl 4-methylbenzenesulfonate (17.10 g, 84%): 1H NMR (300 MHz, CDCl3) δ7.77 (d, J=8.3 Hz, 2H), 7.36-7.25 (m, 7H), 4.71 (s, 2H), 4.59-4.48 (m, 2H), 4.02-3.93 (m, 3H), 2.41 (s, 3H), 1.19-1.11 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](=[O:12])[NH:4][CH:3]=1.[CH3:13]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+].[Ag+]>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: O=c1[nH]cc(Br)c2c1CCCC2
Reactant: CI
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ncc(Br)c2c1CCCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
47.7 g (209 mmol) of 4-bromo-5,6,7,8-tetrahydro-2H-isoquinolin-1-one are dissolved in 1 l of chloroform and, after addition of 77.8 g (282 mmol) of silver(I) carbonate and 53.5 ml (118.7 g, 836 mmol) of methyl iodide, stirred at 50° C. for 3 h. After cooling, the suspension is filtered through Celite, concentrated and chromatographed on silica gel using n-heptane with addition of 2% ethyl acetate. A colorless oil (42.5 g, 84% yield) is obtained.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=4)=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=4)=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1ncc(Oc2ccc(CO)cc2)s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a stirred solution of 2-(4-Cyclopropanesulfonyl-phenyl)-N-[5-(4-formyl-phenoxy)-thiazol-2-yl]-2-(tetrahydro-pyran-4-yloxy)-acetamide (Example A74; 0.2 g, 0.36 mmol) in 10 mL methanol, sodium borohydride (0.027 g, 0.73 mmol) was added in portions at 0° C. After complete addition reaction mixture was stirred for 1 hr at 0° C. to 10° C. Completion of the reaction was confirmed by TLC, then methanol was evaporated on rotavapour. Reaction mixture was diluted with ethyl acetate (3×20 mL), organic layer was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. Purified by PREP TLC to afford title compound (0.110 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[C:16]3[NH:23][C:24]([NH:26][C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)=[O:25])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CC(O)C>[N:28]1[CH:29]=[CH:30][N:31]=[CH:32][C:27]=1[NH:26][C:24]([NH:23][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)[CH:14]=2)[N:19]=[CH:18][CH:17]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nccc(NC(=O)Nc4cnccn4)c3c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(Nc1cnccn1)Nc1ccnc2ccc(C3CCNC3)cc12
Temperature: 25 °C
Yield: 124.6 %

Procedure:
To a solution of 50 mg of tert-butyl-3-[4-(3-pyrazin-2-yl-ureido)-quinolin-6-yl]-pyrrolidine-1-carboxylate (example 43) (0.120 mmol) in 5 ml of DCM was added 1 ml of 6M HCl solution in propanol-2 with stirring at room temperature. After reaction over night the solvent and excess HCl was removed in vacuum, and the residue was co-distilled at least three times with propanol-2. 50 mg of the desired product were obtained as powder as the di-hydrochloride salt (yield: quant.).