Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:23][C:24]([CH3:40])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32]CC2C=CC=CC=2)[CH3:25])[C:5](=[O:22])[N:6]([C:8]2[CH:9]=[C:10]([CH:17]=[C:18]([F:21])[C:19]=2[CH3:20])[C:11]([NH:13][CH:14]2[CH2:16][CH2:15]2)=[O:12])[CH:7]=1.C([O-])=O.[NH4+]>[Pd]>[CH:14]1([NH:13][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([N:6]3[CH:7]=[CH:2][N:3]=[C:4]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[OH:32])([CH3:25])[CH3:40])[C:5]3=[O:22])[C:19]([CH3:20])=[C:18]([F:21])[CH:17]=2)[CH2:15][CH2:16]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC(C)(C)c2ccccc2OCc2ccccc2)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Temperature: 75 °C
Yield: 99.8 %

Procedure:
To 3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Example 252i, 9.84 g) was added 10% Pd/C (1.729 g) and ammonium formate (14.35 g). The reaction was heated at 75° C. for 2 h then filtered through celite and washed with ethanol. The filtrate was collected and the volatiles removed in vacuo and the resulting crude product was taken up in dichloromethane and washed with water. The organic layer dried (MgSO4) and the solvent removed in vacuo and the residue triturated with diethyl ether to afford subtitle product (7.08 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:29][N:30]1[C:42]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[C:34]([S:43](Cl)(=[O:45])=[O:44])[CH:35]=2>C(Cl)(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:43]([C:34]3[CH:35]=[C:36]4[C:31](=[CH:32][CH:33]=3)[N:30]([CH3:29])[C:42]3[CH2:41][CH2:40][CH2:39][CH2:38][C:37]4=3)(=[O:44])=[O:45])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cn1c2c(c3cc(S(=O)(=O)Cl)ccc31)CCCC2
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc3c(c2)c2c(n3C)CCCC2)CC1

Procedure:
To a solution of 1 g (0.0034 Mol) of 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxoethylamine and 1.1 g (0.011 Mol) of triethylamine in 30 ml of chloroform are added dropwise, at ambient temperature and with stirring, 0.96 g (0.0034 Mol) of 9-methyl-1,2,3,4-tetrahydro-carbazol-6-sulphonic acid chloride dissolved in 10 ml of chloroform. After 12 hours' stirring the mixture is evaporated down in vacuo and the residue obtained is chromatographed over a silica gel column (eluant: ethyl acetate/methanol=9:1). The eluate having an Rf value of 0.3 is collected and evaporated down in vacuo.
Reaction SMILES: [CH:1]1([CH2:11][C:12](=O)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[NH2:15][CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[OH:18].[BH4-].[Na+]>CO>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([CH:17]([OH:18])[CH2:16][NH:15][CH:12]([CH3:13])[CH2:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][O:2]2)=[CH:24][CH:23]=1
Reactant: NCC(O)c1ccc(O)cc1
Reactant: CC(=O)CC1OCCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(CC1OCCc2ccccc21)NCC(O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
In 15 ml of anhydrous methanol were dissolved 2.93 g (15.5 mmol) of (isochroman-1-yl)acetone [Chem. Pharm. Bull., 36, 1758 (1988)] and 1.57 g (10.3 mmol) of 2-amino-1-(4-hydroxyphenyl)ethanol [U.S. Pat. No. 2,585,988 (1952)], and the resulting solution was stirred for 3 hours at room temperature. Methanol was evaporated, and anhydrous benzene was added to the mixture, and water formed was removed off by azeotropic distillation. To the resulting mixture was added 15 ml of anhydrous methanol. Subsequently, 567 mg (15 mmol) of sodium borohydride was gradually added under ice cooling, and the resulting mixture was stirred for 3 hours at room temperature. The methanol was evaporated off, and then 10% sulfuric acid aqueous solution was added to the residue, and the mixture was washed with ether. The resulting mixture was rendered basic with the addition of saturated aqueous potassium hydrogencarbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated off, and the residue was subjected to silica gel column chromatography (ethyl acetate :triethylamine=20:1) to give 2.8 g (83%) of crystals of Compound 1.
Reaction SMILES: [CH2:1]([CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:2][CH:3]=C.I([O-])(=O)(=O)=[O:17].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[O:15]=[C:12]1[N:11]2[CH:5]([CH2:1][CH2:2][CH:3]=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2=[N:14][O:13]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCC1CCCCc2noc(=O)n21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCCC1CCCCc2noc(=O)n21
Temperature: 25 °C

Procedure:
To a solution of the product of Example 18 in dioxane and water is added sodium periodate and osmium tetraoxide. The reaction is stirred at room temperature and monitored by thin layer chromatography. Water is added to the reaction mixture and the solution is extracted with CH2Cl2. The organic layer is dried over magnesium sulfate, filtered, and stripped of all solvent under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].Cl[CH2:13][C:14](=O)[CH3:15]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:13]=[C:14]([CH3:15])[N:8]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C(N)=O)c1
Reactant: CC(=O)CCl
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc(C)co2)c1
Yield: 64.6 %

Procedure:
To a solution of 3-methoxybenzamide (1.5 g, 9.9 mmol) in toluene (15 mL) was added 1-chloropropan-2-one (1.37 g, 14.9 mmol), and the mixture was stirred at reflux for 16 h. The mixture was cooled and concentrated to give crude product, which was purified via silica gel chromatography eluted with ethyl acetate/petroleum ether (1:5) to give 2-(3-methoxyphenyl)-4-methyloxazole (1.21 g, 64.6% yield) as yellow syrup. LCMS MH+ 190.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O>ClC1C=CC=CC=1>[NH2:11][C:9]1[S:10][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N:8]=1
Reactant: NC(=S)Nc1ccc(Cl)cc1
Solvent: Clc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: Nc1nc2ccc(Cl)cc2s1
Reaction time: 3 h
Yield: 85 %

Procedure:
186.5 parts of 4-chlorophenylthiourea were suspended with stirring in 850 parts of chlorobenzene, and 185 parts of sulfuryl chloride were added uniformly with stirring at a temperature of 40°-45° C. within about 3 hours. After the immediately starting gas development had ceased, the suspension formed which could be stirred with difficulty only was liberated from the chlorobenzene by steam distillation. The remaining suspension of 2-amino-6-chlorobenzothiazolium chloride was adjusted to pH 8 with 25% ammonia solution, thus causing the crude 2-amino-6-chlorobenzothiazole to agglomerate to a tacky mass. By decantation and drying, 146.3 parts of 2-amino-6-chlorobenzothiazole containing about 85% of pure product were obtained (=124.4 parts of 100% product, 67.4% of th.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:23]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(NCC)C>[NH2:23][C@H:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Solvent: CCNCC
Product: COC(=O)[C@H](N)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Yield: 71.3 %

Procedure:
A solution of 1.695 g (3.10 mmol) of methyl(2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl){[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethanoate in 10 mL of diethylamine was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with a gradient starting with ethyl acetate/hexanes (1:2) and ending with chloroform/methanol (9:1) to provide 0.717 g of methyl(2R)-amino(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)ethanoate as a colorless oil. Electrospray Mass Spec 325.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:14](OC)=[O:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][OH:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2
Reactant: COCN1c2cc(C(=O)OC)ccc2Sc2nccnc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCN1c2cc(CO)ccc2Sc2nccnc21
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Into a solution of 350 g of methyl 10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate in methylene chloride (2.5 l) was added dropwise under a nitrogen atmosphere 3.2 l of a 1.01 M solution of diisobutylaluminum hydride in toluene while maintaining the system at a temperature not exceeding 15° C. Then the reaction mixture was poured into ice and stirred for 1 hour. After filtering off the insoluble matter, the filtrate was washed with water. After distilling off the solvent under reduced pressure, the crude crystals thus obtained were washed with diisopropyl ether to thereby give 250 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)=[O:21]
Reactant: CN1CC=C(c2c[nH]c3ccncc23)CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(C(=O)c3c(Cl)cccc3Cl)c3ccncc23)CC1

Procedure:
from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole (20 mg, 0.094 mmol), 2,6-dichlorobenzoyl chloride (27 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.S([O-])(O)(=O)=O.[K+].O>C1COCC1.[Li]CCCC.CCCCCC>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(S(=O)(=O)n2cc(C(=O)O)c3ccccc32)cc1
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
To a solution of 300 mg of 1H-indole-3-carboxylic acid in 9 mL of THF, 2.68 mL of 1.60 M n-BuLi hexane solution was added dropwise while the inner temperature was kept at −50° C. or lower by cooling in a dry ice-acetone bath, and the resulting mixture was stirred at the same temperature for 5 minutes, then at 0° C. for 1 hour. The solution was cooled in a dry ice-acetone bath and a solution of 461 mg of 4-methoxybenzenesulfonyl chloride in 1 mL of THF was added dropwise. The solution was stirred at 0° C. for 3 hours. To the solution, 20 mL of 5% aqueous potassium hydrogen sulfate solution and 40 mL of water were added in this order, and then the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. To the residue was added 5 mL of ethyl acetate, and the resulting mixture was stirred at room temperature for 15 minutes. The white crystals formed were collected by filtration to obtain 509 mg of 1-[(4-methoxyphenyl)sulfonyl]-1H-indole-3-carboxylic acid as a white solid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]1([CH2:19][C:20]([NH:22][C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:19][C:20]2[O:31][C:29](=[O:30])[C:23]3([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[N:22]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cc1ccccc1)NC1(C(=O)O)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1OC(Cc2ccccc2)=NC12CCCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
633 mg (3.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 784 mg (3 mmol) of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid obtained in Reference Example 2 in 20 ml of methylene chloride. After the mixture was stirred at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 625 mg (86%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COCC(=O)c1ccc(Br)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COCC(O)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a mixture of 1-(6-bromopyridin-3-yl)-2-methoxyethanone (15.85 g), tetrahydrofuran (15 mL) and ethanol (15 mL) was slowly added sodium borohydride (0.97 g) at room temperature, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (15.26 g, yield 96%) was obtained as a yellow oil from a fraction eluted with ethyl acetate. MS: 234 (MH+).
Reaction SMILES: [C:1]([NH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][C:26]([OH:31])([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)([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.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1.CO>C1COCC1>[C:1]([NH:20][CH:21]1[CH:22]2[CH2:23][CH:24]3[CH2:25][C:26]([O:31][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([C:33]5[O:32][C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=6[N:34]=5)=[CH:42][CH:43]=4)([CH2:27][CH:28]1[CH2:29]3)[CH2:30]2)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: OC12CC3CC(C1)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C3)C2
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(C(NC2C3CC4CC2CC(OCc2ccc(-c5nc6ccccc6o5)cc2)(C4)C3)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To KH (35%; (0.34 g;0.0029 mole) in THF (8 ml) under N2 and cooled in an ice bath is added N-trityl-5-hydroxytricyclo-[3.3.1.13,7 ]decan-2-amine (1.0 g; 0.0025 mole) This forms a pale yellow solution and is stirred at room temperature for 1 hour. The reaction mixture is then cooled in ice and 4-(benzoxazol2-yl)benzyl bromide (0.7 g; 0.0025 mole) is added all at once. The mixture is stirred for 1/2 hour with ice cooling and then 31/2 hours at room temperature then cooled in ice and MeOH is added to quench the KH. The mixture is evaporated to dryness. Purification is accomplished on HPLC, eluting with a gradient system staring with 10% and ending with 20% ethyl acetate/hexane to obtain N-trityl-5-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-2-amine which is used directly in step F.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([N:11]1[C:20]([CH3:21])=[C:19]([C:22](=[O:36])[NH:23][C@@H:24]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:18]2[C:13](=[C:14]([F:37])[CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:38])[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[Br:40]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[N:7]([N:11]1[C:20]([CH2:21][Br:40])=[C:19]([C:22](=[O:36])[NH:23][C@@H:24]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:18]2[C:13](=[C:14]([F:37])[CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:38])[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCN(C(=O)OC(C)(C)C)n1c(C)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCN(C(=O)OC(C)(C)C)n1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O

Procedure:
(4-{[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-propyl-carbamicacid tert-butyl ester (0.2 g, 0.4 mmol; prepared as described in example 8), carbon tetrachloride (50 mL), N-bromosuccinimide (0.072 g, 0.41 mmol) and benzoyl peroxide (10 mg, 0.04 mmol) are warmed at 80° C. for 2 hours. The reaction mixture was cooled and washed with 10 ml of water. The organic phase was dried over MgSO4 and was rotovaped to give 0.3 g. crude product. The product was chromatographed on silica gel with Etac:Hept, 30:70 as eluent to give 0.15 g. the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].Br[CH2:12][CH:13]1[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH2:15][O:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:12][CH:13]1[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH2:15][O:14]1)[CH3:2]
Reactant: CC1COC(CBr)OC1C
Reactant: CCOC(CCN)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CCNCC1OCC(C)C(C)O1)OCC
Temperature: 25 °C

Procedure:
3,3-Diethoxypropylamine (0.11 mole), 2-bromomethyl-4,5-dimethyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17](OC)[C:18]([CH:20]=2)=[O:19])[C:13]2[C:12]([O:24][CH3:25])=[C:11]([O:26][CH3:27])[C:10]([O:28][CH3:29])=[CH:9][C:8]=2[CH2:7][CH2:6]1)=[O:3].[CH3:30][NH2:31]>C(O)C>[CH3:1][C:2]([NH:4][CH:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([NH:31][CH3:30])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3]
Reactant: CN
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Solvent: CCO
Product: CNc1ccc2c(cc1=O)C(NC(C)=O)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 84.3 %

Procedure:
A mixed solution of colchicine (5.00 g, 12.5 mmoles), an aqueous 40% methylamine solution (10 ml, 130 mmol) and ethyl alcohol (10 ml) was subjected to reaction at 120° C. for 20 hours under stirring in a sealed tube. The solvent was distilled off, water (10 ml) was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was separated, washed with water and dried. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography [chloroform: methanol (20:1)]. Thereby, 4.20 g of N-methylcolchiceinamide was obtained as yellow crystals (yield 84%). ##STR13##
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2Cl)[CH:6]=1)=[O:4].[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[NH:32][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH3:22])=[CH:31]3)[CH:6]=1)=[O:4]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN(Cc1ccccn1)C(=O)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N(C)Cc5ccccn5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid methyl-pyridin-2-ylmethyl-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 428 (MH+); HPLC Rf: 4.30 min.; HPLC purity: 97%.
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:39]([OH:52])[CH2:40][C@H:41]([C:45](=[O:51])[NH:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:42]([CH3:44])[CH3:43])[CH2:10][C@@H:11]([CH:36]([CH3:38])[CH3:37])[CH2:12][NH:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[NH:27][N:26]=[N:25][N:24]=2)=[CH:17][C:16]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=O)(C)(C)C.[ClH:53]>O1CCOCC1>[ClH:53].[NH2:8][C@H:9]([C@@H:39]([OH:52])[CH2:40][C@H:41]([C:45](=[O:51])[NH:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:42]([CH3:43])[CH3:44])[CH2:10][C@@H:11]([CH:36]([CH3:38])[CH3:37])[CH2:12][NH:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[NH:24][N:25]=[N:26][N:27]=2)=[CH:17][C:16]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@H](CNC(=O)c1ccc(OCc2nnn[nH]2)cc1OCCCCOC)C(C)C)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@H](CNC(=O)c1ccc(OCc2nnn[nH]2)cc1OCCCCOC)C(C)C)C(C)C

Procedure:
In a manner analogous to that described in Example 21), reaction of (2S,4S,5S,7S)-N-[4-(tert-butoxycarbonyl)amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonyl]-2-(4-methoxybutoxy)-4-(1H-tetrazol-5-ylmethoxy)-benzamide (88 mg) in a 4N hydrochloric acid solution in dioxane at 0° C. for 6 hours, rapid concentration of the solvent under a high vacuum and lyophilisation yield (2S,4S,5S,7S)-N-(4-amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonyl)-2-(4-methoxybutoxy)-4-(1 H-tetrazol-5-ylmethoxy)-benzamide hydrochloride: Rf (W)=0.06. HPLC Rt =11.5 min. MS(FAB) m/e 634 (M+ +1).