Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:8]=2[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=O)[CH3:24])=[CH:19][C:18]=3[F:26])[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH2:2]1>CCO.[Ni]>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:8]3[CH:27]=[C:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:29]=[CH:30][C:7]=3[CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:10])[CH2:12][CH2:13]2)=[C:18]([F:26])[CH:19]=1)[CH3:24]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3C3=CCOCC3)CC2)c(F)c1
Agent: [Ni]
Solvent: CCO
Product: CCc1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3C3CCOCC3)CC2)c(F)c1
Yield: 41 %

Procedure:
1-(4-{4-[2-(3,6-Dihydro-2H-pyran-4-yl)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-3-fluoro-phenyl)-ethanone (Example 72) is hydrogenated in EtOH in presence of Raney nickel under a hydrogen pressure of 100 bar at 100IC for 18 h. Filtration, evaporation of the solvent and purification of the residue by preparative HPLC on a C-18 column with a H2O/MeCN gradient provided [4-(4-Ethyl-2-fluoro-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(tetrahydro-pyran-4-yl)-phenyl]-methanone in 41% yield as colourless crystals (M+H+: 475.5.).
Reaction SMILES: CS[C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]=1.[F:21][CH2:22][C:23]([NH:25][NH2:26])=O>CN(C)P(=O)(N(C)C)N(C)C>[F:21][CH2:22][C:23]1[N:4]2[C:5]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:6]=3[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][CH2:9][C:3]2=[N:26][N:25]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: NNC(=O)CF
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: FCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A solution of 8 g of 2-(methylthio)-5-phenyl-7-chloro-3H-1,4-benzodiazepine and 3.68 g of 2-fluoroacetic acid hydrazide [cp. M. A. Phillips, Agr.Vet.Chem. 2, 86-87 (1961), C. A. 57, 12314 (1962)] in 80 ml of hexamethylphosphoric acid triamide is heated for 8 hours at 140° The solvent is then distilled off in vacuo, and the residue distributed between methylene chloride and water. The organic phase is separated, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, and concentrated by evaporation. The residue is recrystallized from ethyl acetate/petroleum ether to obtain 1-(fluoromethyl)-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine, M.P. 153°-154°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[CH2:11]([Mg]Br)[CH3:12].C1COCC1.CCCCCC.CCOC(C)=O>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:11][CH3:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC(O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3,4-difluorobenzaldehyde (5.0 g, 35.2 mmol) in diethyl ether (35 mL) in a round bottom flask was added a solution of ethylmagnesium bromide in THF (38.0 mL, 38.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h when TLC analysis indicated that the reaction was complete (Rf=0.5, 8:1 hexane/EtOAc). The reaction was quenched carefully by adding 38 mL of water. It was extracted with diethyl ether (2×30 mL), washed with brine and the organic layer was dried over NaSO4. The solvent was removed in vacuo after filtration and 1-(3,4-difluorophenyl)propan-1-ol was obtained as a yellow oil (crude wt.=6.0 g) which looked >90% pure by NMR. It was used in the next step without purification.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].Cl[CH2:16][CH2:17][O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN1C(=O)CCC1>[C:4]([O:6][CH2:16][CH2:17][O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)OCCCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)OCCOC(=O)/C=C/C(=O)OC
Yield: 85.3 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.39 g, 3.0 mmol) in NMP (8 mL) was reacted with CsHCO3 (0.69 g, 3.6 mmol) and ethyl (chloroethoxy)formate (0.64 g, 4.2 mmol) to afford 0.63 g (85% yield) of the title compound (39) after isolation and purification. 1H NMR (CDCl3, 400 MHz): δ 6.89 (d, J=15.6 Hz, 1H), 6.82 (d, J=15.6 Hz, 1H), 6.84 (q, J=5.6 Hz, 1H), 4.23 (q, J=7.2 Hz, 3H), 3.81 (s, 3H), 1.58 (d, J=5.6 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H). MS (ESI): m/z 247.01 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][C:17]#[N:18])[CH3:13].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:19])[C:16]([C:17]#[N:18])=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH3:13]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To a stirred solution of 1,4-dioxa-spiro[4.5]decan-8-one (261) (5.0 g, 32.01 mmol) and cyano-acetic acid ethyl ester (3.99 g, 35.31 mmol) in toluene (50 mL) were added acetic acid (0.3 mL, 5.09 mmol) and ammonium acetate (123 mg, 1.60 mmol). A Dean Stark trap and reflux condenser were attached to the reaction flask and the mixture was heated to reflux and stirred for 16 h. Thereafter, the reaction mixture was cooled to 0° C. and quenched with saturated aqueous NaHCO3 (100 ml). The aqueous layer was extracted with ethyl acetate (2×200 ml) and the combined organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The crude yellow oil was re-crystallized with 20% ethyl acetate in hexane to afford pure cyano-(1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester (262) (3.2 g, 39.78%) as a light yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(CC)CC)C.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC>O1CCOCC1>[N:10]1[CH:9]=[CH:8][N:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=12
Reactant: Ic1ccc2nccn2c1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: c1ccn2ccnc2c1
Temperature: 90 °C

Procedure:
The obtained 2-[4′-(2″-hydroxyethoxy)]phenyl]-6-iodoimidazo[1,2-a]pyridine was dissolved in dioxane, and triethylamine is added thereto. Then, bis(tributyltin) and a catalytic amount of tetrakis-triphenylphosphine palladium are added thereto. This reaction mixture is heated at about 90° C. and reacted for about 24 hours, and then a solvent is distilled off and chromatographic purification is performed to obtain 6-tributylstannyl-2-[4′-(2″-hydroxyethoxy)]phenyl]imidazo[1,2-a]pyridine as the target compound (FIG. 2-2, Step 1). The amount of bis(tributyltin) to be used in this instance may be an amount satisfying a condition where it is excessive relative to the reaction substrate, specifically, it is about 1.5 times in molar ratio relative to the reaction substrate 2-[4′-(2″-hydroxyethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)c(F)c1
Temperature: 50 °C
Yield: 64 %

Procedure:
To a mixture of 0.34 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 6 ml of chloroform, 0.48 g of 65% m-chloroperbenzoic acid was added at room temperature. The solution was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate, and then washed with a saturated aqueous solution of sodium hydrogencarbonate twice and a saturated sodium chloride solution once, sequentially. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.23 g of 3-fluoro-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 26”).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Br[C:8]1[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH2:3]1
Reactant: N[C@H]1CCNC1
Reactant: CCOC(=O)c1sc(Br)nc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@H](N)C2)nc1C
Yield: 83.9 %

Procedure:
A solution of (3S)-3-aminopyrrolidine (0.16 mL, 1.80 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (300 mg, 1.20 mmol) and diisopropylethylamine (0.42 mL, 2.40 mmol) in DMF (12 mL) was stirred at 90° C. for 75 minutes. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=5/1) to obtain 257 mg of the title compound as a pale yellow solid (84%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9].[C-:16]#[N:17].[Na+]>CS(C)=O.O>[C:16]([CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])#[N:17]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CCl
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)nc1CC#N
Reaction time: 2 h

Procedure:
A solution of 48.6 g (0.2 mole) of 4-chloromethyl-5-methyl-2-phenylimidazole hydrochloride [see Cornforth & Huang, J. Chem. Soc., 731 (1948)] in 200 ml of DMSO is added (over 20 minutes) to a rapidly stirred solution of sodium cyanide, prepared by dissolving 29.4 g (0.6 mole) of sodium cyanide in 70 ml of water and adding 200 ml of DMSO, at 0° to 5° C. [slightly modified procedure of W. Schultze, J. Prakt. Chem. 19, 91-100 (1922)]. The reaction mixture is stirred in the cold for 2 hours and then poured onto a slight excess of cracked ice which causes a semicrystalline gum to separate (Crop A). The gum is quickly filtered off and to the filtrate is added sufficient aqueous sodium carbonate (10%) to give a volume of 2 liters. The mixture is allowed to stand overnight during which time a second crop (about 12-13 g) crystallizes (Crop B). Extraction of the mother liquor with ethyl acetate gives an aditional (about 2-3 g) yield (Crop C). Crop A is recrystallized from benzene-Norite B. Crop C is recrystallized from benzene. The resulting crystals are combined with Crop B. Repeated recrystallizations from benzene gives a pure product of 4-cyanomethyl-5-methyl-2-phenylimidazole, m.p., 132°-140° C. Treatment with a mineral acid, e.g., sulfuric, hydrobromic and the like, affords the corresponding acid addition salts.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(#N)C>[CH3:21][O:20][C:3]1[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:1][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCc1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 15.7 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (155 mg, 1.126 mmol) and 4-bromomethyl-benzenesulfonamide (84 mg, 0.337 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 15.7%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[N:10]2)=[C:5]([CH3:18])[CH:4]=1.B(Br)(Br)Br>ClCCl.CO.O>[N:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][C:5]=2[CH3:18])[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2
Reactant: COc1ccc(-n2cc3ccccc3n2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1cc(O)ccc1-n1cc2ccccc2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A solution of 2-(4-methoxy-2-methylphenyl)-2H-indazole (500 mg, 2.1 mmol) in dichloromethane (10 mL) was cooled to −78° C. Added boron tribromide (2.6 g, 10.5 mmol) and reaction was stirred at −78° C. for 1 hour. Reaction was warmed to room temperature are stirred overnight. The reaction was diluted with methanol and water, and extracted with ethyl acetate (3×30 mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 4-(2H-indazol-2-yl)-3-methylphenol (350 mg, 74%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ): 9.82 (s, 1H), 8.51 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.25-7.30 (m, 2H), 7.07-7.11 (m, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.75 (dd, J=8.4, 2.4 Hz, 1H), 2.06 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=2)[N:7]=1)(=[O:12])=[O:11]
Reactant: CC(C)CN(Cc1cccc(Br)n1)S(=O)(=O)c1ccccc1Cl
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1cccc(-c2cccc(S(C)(=O)=O)c2)n1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(6-bromo-pyridin-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-[6-(3-methanesulfonyl-phenyl)-pyridin-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 492.9 ([M+H]+)
Reaction SMILES: Cl[C:2]([O:4][CH2:5]C)=[O:3].[NH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:11]1>N1C=CC=CC=1>[CH3:5][O:4][C:2]([NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:11]1)=[O:3]
Reactant: NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
Ethyl chloroformate (0.19 g) was added dropwise to a stirred solution of 1-(2-aminoethyl)-3-(1-imidazolylmethyl)indole (0.48 g) in pyridine (5 ml) at room temperature. The solution was stirred at room temperature for 3 hours and then evaporated. The residue was stirred with aqueous sodium bicarbonate solution and the solid product was filtered off, washed with water, dried and crystallised from ethyl acetate/petrol (b.p. 60°-80° C.) to give 1-(2-methoxycarbonylaminoethyl)3-(1-imidazolylmethyl)indole (0.32 g), m.p. 78°-79° C. Found: C, 62.22; H, 5.99; N, 17.72. C16H18N4O2.1/2H2O requires: C, 62.52; H, 6.23; N, 18.23%.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([CH2:17][C:18]3[NH:19][C:20]([C:36]4[S:37][CH:38]=[CH:39][N:40]=4)=[N:21][C@@H:22]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[Cl:35])[C:23]=3[C:24]([O:26][CH3:27])=[O:25])[CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[C:41](O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:27][O:26][C:24]([C:23]1[C@H:22]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[Cl:35])[N:21]=[C:20]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[NH:19][C:18]=1[CH2:17][N:16]1[CH:14]2[CH2:15][N:8]([C:6](=[O:5])[CH3:41])[CH2:9][CH:10]1[CH2:11][O:12][CH2:13]2)=[O:25]
Reactant: COC(=O)C1=C(CN2C3COCC2CN(C(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=C(CN2C3COCC2CN(C(C)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 9-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (280 mg, 0.47 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL) dropwise in ice-bath. The mixture was stirred at room temperature for 16 hours. The mixture was neutralized with a saturated aqueous sodium bicarbonate solution and then extracted with CH2Cl2 (20 mL×2). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL×2), and then dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (R)-6-(7-acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound AC) as light yellow oil (230 mg, 98%) which was used for next step without further purification. MS: calc'd (MH+) 492, measured (MH+) 492.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:23]([F:26])([F:25])[F:24])=[CH:11][C:12]=2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:27]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C.BrBr>[Br:27][C:11]1[C:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:23]([F:25])([F:24])[F:26]
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(p-chlorophenyl)sulfonyl]-5-(trifluoromethyl)pyrrole (2.15 g, 5.12 mmol), bromine (0.29 mL, 5.63 mmol) and sodium acetate (0.46 g, 5.63 mmol) in acetic acid is stirred at room temperature for 4 hours, treated with additional bromine (3 drops), stirred overnight at room temperature and poured into water. The resultant aqueous mixture is filtered to obtain a solid. Flash column chromatography of the solid using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as a white solid (1.88 g, mp >230° C.).
Reaction SMILES: [CH:1]([N:3]=[C:4]=[O:5])=[CH2:2].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[N-]=C=O>C(OCC)(=O)C>[CH:1]([NH:3][C:4](=[O:5])[O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:2]
Reactant: C=CN=C=O
Reactant: OC1CCCCC1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CNC(=O)OC1CCCCC1
Temperature: 40 °C

Procedure:
69 parts of vinyl isocyanate and 89.5 parts of ethyl acetate are introduced into a reaction vessel and heated to 40° C. A mixture of 110 parts of cyclohexanol and 89.5 parts of ethyl acetate (containing 0.02% of dibutyl-tin dilaurate as the catalyst) is added in the course of 1 hour. The mixture is then allowed to react for a further 2 hours at 40° C. A light yellow solution is obtained, from which the reaction product separates out, as crystals, on cooling. Blocked isocyanate content: 11.7%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:6]1[CH:7]=[C:8]([C:12](OC)=[O:13])[CH:9]=[N:10][CH:11]=1)([OH:5])[CH3:4].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[F:17][C:2]([F:1])([F:16])[C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[O:13])[CH:9]=[N:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: COC(=O)c1cncc(C(C)(O)C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(O)(c1cncc(C=O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of the title compound from Step B (0.14 g, 0.56 mmol) in toluene (3.23 mL) and dichloromethane (3.23 mL) was added a solution of di-isobutyl aluminum hydride in toluene (1.0 M, 1.29 mL, 1.29 mmol). After 10 min, the reaction was quenched with water (1 mL), allowed to warm to room temperature, and dried over magnesium sulfate. Concentration of the filtrate under reduced pressure provided the title compound: 1H NMR (500 MHz, CDCl3) δ 10.16 (s, 1 H), 9.08 (s, 1 H), 9.07 (s, 1 H), 8.41 (s, 1 H), 3.30 (br s, 1 H), 1.88 (s, 3 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:7]=2[N:6]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C:22]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:7]=2[N:6]=1)(=[O:24])[CH3:23]
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN)nc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NCCCc1nc2cc(C3=NNC(=O)CC3C)ccc2[nH]1
Yield: 89 %

Procedure:
##STR59## 050 g (1.75 mmol) of 6-[2-(3-aminopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone are boiled with 0.34 ml (3.50 mmol) of acetic anhydride in 20 ml of glacial acetic acid for 45 minutes. The cooled solution is extensively concentrated by evaporation under vacuum and the residue is taken up with 10 ml of water. The resulting solution is adjusted to pH 9 with 10% ammonia. After concentration of this solution by evaporation to about one-third of its volume and cooling in an ice bath, a yellowish solid crystallizes, and this solid is suction filtered and then boiled up in 30 ml of acetonitrile. The solid obtained as residue is suction filtered, washed with 10 ml of acetonitrile and dried under vacuum. 0.51 g (89%) of colourless crystals melting at 244° to 246° C. are obtained.
Reaction SMILES: O=[C:2]([CH3:20])[CH2:3][N:4]([C:12](=[O:19])[CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[C:5]([CH3:11])([CH3:10])[C:6]([O:8]C)=[O:7].C[O-].[Na+].O.[OH-].[K+]>C(O)C>[CH3:20][C:2]1[CH2:3][N:4]([C:5]([CH3:11])([CH3:10])[C:6]([OH:8])=[O:7])[C:12](=[O:19])[C:13]=1[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1
Reactant: COC(=O)C(C)(C)N(CC(C)=O)C(=O)Cc1ccsc1
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(c2ccsc2)C(=O)N(C(C)(C)C(=O)O)C1
Yield: 65.9 %

Procedure:
To a solution of methyl 2-[N-(2-oxopropyl)thiophene-3-yl-acetylamino]isobutyrate (7.6 g) in absolute ethanol (50 mL) was added 95% sodium methoxide (1.6 g), and the mixture was heated at reflux for 30 minutes. To the solution were added water (3.5 mL) and 85% potassium hydroxide (0.88 g), and the mixture was heated at reflux for 1 hour. After distilling off the solvent, the residue was poured into ice-water and washed with diethyl ether. It was adjusted to pH 2-3 with concentrated hydrochloric acid and the precipitated crystals were filtered, washed with water and dried to give 4.47 g of 2-[4-methyl-2-oxo-3-(thiophen-3-yl)-3-pyrrolin-1-yl]isobutyric acid.