Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][SiH:2]([CH3:6])[O:3][CH2:4][CH3:5].[Br:7][CH2:8][CH2:9][CH:10]=[CH2:11]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru]>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][Si:2]([CH3:6])([CH3:1])[O:3][CH2:4][CH3:5]
Reactant: C=CCCBr
Reactant: CCO[SiH](C)C
Agent: [Ru]
Agent: [C-]#[O+]
Product: CCO[Si](C)(C)CCCCBr
Temperature: 80 °C

Procedure:
800 g of 4-bromo-1-butene were reacted with 15% excess of dimethylethoxysilane (939 ml). In a 2 l reactor 0.5 g of Ru3(CO)12 and 800 ml of 4-bromo-1-butene were brought under nitrogen and 939 ml of dimethylethoxysilane were added under nitrogen and the mixture was brought at 65° C. After 0.5 h the bath temperature was raised to 80° C. and the mixture was allowed to react overnight. After distillation 1329 g (93.7%) of 4-bromobutyl-dimethyl-ethoxysilane were isolated.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C:17](=O)[C:16](=[O:19])[N:6]2[C:7]=1[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9].Cl.[NH2:21][OH:22].N1C=CC=CC=1.C(Cl)Cl>CN(C)C=O>[OH:22][N:21]=[C:17]1[C:16](=[O:19])[N:6]2[C:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])=[C:2]([CH3:1])[CH2:3][S:4][C@H:5]12
Reactant: NO
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=O)[C@H]2SC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=NO)[C@H]2SC1
Yield: 79.2 %

Procedure:
In dimethylformamide (5 ml) are dissolved 2,2,2-trichloroethyl 3-methyl-7-oxo-3-cephem-4-carboxylate (691 mg) and hydroxylamine hydrochloride (139 mg), followed by addition of pyridine (162 μl) and methylene chloride (10 ml). The mixture is refluxed in a Dean-Stark trap packed with Molecular Sieve 3A for 45 minutes. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in ethyl acetate. The resultant solution is washed with water and aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is subjected to silica gel (20 g) column chromatography and elution is carried out with 5-13% ethyl acetatehexane to give 2,2,2-trichloroethyl 7-hydroxyimino-3-methyl-3-cephem-4-carboxylate as an oil (570 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H]([C@@H]([C@@H](CO)O)O)O)O.COC([C@@H](NC([C@@H](N)CC(O)=O)=O)CC1C=CC=CC=1)=O.[C:34]12([CH3:44])[C:40]([CH3:42])([CH3:41])[CH:37]([CH2:38][CH2:39]1)[CH2:36][CH:35]2[OH:43].C[C@H]1C[C@@H](O)[C@H](C(C)C)CC1>C(O)C.OCC(CO)O>[C:34]12([CH3:44])[C:40]([CH3:41])([CH3:42])[CH:37]([CH2:38][CH2:39]1)[CH2:36][C:35]2([CH2:3][CH2:2][OH:1])[OH:43]
Reactant: CC1(C)C2CCC1(C)C(O)C2
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Solvent: OCC(O)CO
Solvent: CCO
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2
Reaction time: 1 h

Procedure:
Thereafter, the warm aqueous mixture is filtered by using 100 mesh sieve and residues from the first filtration are extracted with. 20 l of water at a temperature of 80°-100° C. for 1 hour and condensed and under the reduced. Pressure to produce about 15 l of a natural substance extract. After 76.7 g of Bezoar bovis and 63.3 g of Moschus are dried on a silicagel desiccator for 24 hours and ground into microparticle size in a grinder to form a microparticle mixture by using 140 mesh sieve to make a Bezoar bovis powder and a Moschus powder, respectively. 5 Kg of conc-glycerin, 5 Kg of sugar and 35 Kg of d-sorbitol or 35 Kg of "ASPARTAME" and 10 Kg of Mel are solved with 10 l of distilled warm water for 15 minutes to make a sweetening solution. 5 l of distilled water is added to 110.0 g of genus Gelatin and the aqueous mixture is heated to produce a Gelatin solution. And 63.3 g of Borneol, and 0.5 l of L-menthol are solved with 3.5 l of ethanol to produce a Borneol-ethanol solution.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([CH:14]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH2:26])([C:10]([O:12]C)=O)[C:6]([O:8][CH3:9])=[O:7].CN(C)C=O.Cl>CO>[CH3:9][O:8][C:6]([C:5]1([CH3:4])[CH:14]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[CH:18][C:17]=2[NH:26][C:10]1=[O:12])=[O:7]
Reactant: COC(=O)C(C)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)C1(C)C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccc(OC)cc1
Yield: 88.3 %

Procedure:
A 25% (by weight) sodium methoxide in methanol solution (14.2 ml; 625 mmole; 4.6 eq.; d=0.945) and α-methyl-[2-(2-amino-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (5.96 g; 13.56 mmole) in methanol (30 ml) and dry dimethylformamide (35 ml) were refluxed (~95° C.) overnight. 1N Hydrochloric acid was added with stirring producing a white precipitate that was collected by suction-filtration, washed with water (three times) and dried in vacuo giving 4.88 g of a white solid which contained an impurity as shown by NMR. The impurity disappeared after the sample stood overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O=[C:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.[O-]S([O-])(=O)=O.[Mg+2].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH3:12][C:11]1[NH:10][N:9]=[CH:8][C:7]=1[C:5]1[S:4][C:3]2[C:13](=[O:14])[NH:15][C:17]3([CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)[NH:1][C:2]=2[CH:6]=1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1CCC2(CC1)NC(=O)c1sc(-c3cn[nH]c3C)cc1N2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl) thiophene-2-carboxamide (0.111 g, 0.50 mmol), ethyl 4-oxocyclohexanecarboxylate (0.34 g, 2.00 mmol), MgSO4 (0.120 g, 1.00 mmol), CSA (0.012 g, 0.05 mmol) and DMA (3 mL) was stirred at 100° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to EtOAc then to 80:20 EtOAc/MeOH). The obtained residue was triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (96 mg, 51%, a mixture of 3:2 cis/trans isomers, absolute structure not determined) as yellow solid:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[CH:17]=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.[C:41](O)([C:43]([F:46])(F)F)=O>C(Cl)Cl>[F:46][C:43]1[CH:41]=[CH:17][CH:16]=[CH:15][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[CH:27]=3)[CH2:23][C:22](=[O:39])[NH:21][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)nn1
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (2′-fluoro-3-{3-[3-(6-methyl-pyridazin-3-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert-butyl ester (Example M13) (292 mg, 0.541 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (181 mg).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH:13]=[CH:12][N:11]=[N:10]1.[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CS(C)=O.O>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:9]1[CH:13]=[CH:12][N:11]=[N:10]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1c[nH]nn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccnn2)c(F)c1
Temperature: 90 °C
Yield: 50 %

Procedure:
A slurry of dibasic potassium phosphate, 38.0 g (0.218 mol), and 1H-1,2,3-triazole, 7.53 g (6.3 mL, 0.109 mol), in 325 mL dimethylsulfoxide was treated dropwise with 3,4-difluoronitrobenzene, 17.3 g (12.1 mL, 0.109 mol), with heating to 90° C. for 18 h. The mixture was cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (4×50 mL). Drying (Na2SO4) and concentrating in vacuo afforded a light yellow solid. This material was chromatographed over 600 g 230-400 mesh silica gel eluting with methylene chloride, 1% (v:v), 2% (v:v) and 5% (v:v) methanol-methylene chloride to afford 11.38 g (50%) of 3-Fluoro-1-nitro-4-(1H-1,2,3-triazol-1-yl)benzene as a light yellow solid, mp=123-124.5° C., along with 9.66 g (43%) of regioisomer 3-Fluoro-1-nitro-4-(2H-1,2,3-triazol-2-yl)benzene as a light yellow solid, mp 137-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH2:9][C:10]([NH2:11])=[O:14])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCC(=O)c1ccc(Cl)cc1
Product: NC(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The crude 3-(4-chloro-phenyl)-3-oxo-propionitrile obtained above was stirred with 100 mL of sulfuric acid at room temperature for 4 hours. The mixture was poured into 500 mL of ice-water and stirred for 30 minutes. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 5.73 g of 3-(4-chloro-phenyl)-3-oxo-propionamide as a brown solid which was used in next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH3:15][NH:16][CH2:17][CH2:18][OH:19]>>[O:4]=[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][N:16]([CH3:15])[CH2:17][CH2:18][OH:19]
Reactant: CNCCO
Reactant: O=C(CCl)N1CCc2ccccc2C1
Product: CN(CCO)CC(=O)N1CCc2ccccc2C1

Procedure:
The procedure is similar to that described in Example 6a), reacting 4.78 g (23 mmol) of 2-(2-chloroacetyl)-1,2,3,4-tetrahydroisoquinoline and 3 g (40 mmol) of 2-(methylamino)ethanol.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C@H:14]([NH2:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[NH:18][CH:17]=1>CO>[CH3:13][C@H:14]([NH:27][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[NH:18][CH:17]=1
Reactant: COc1ccc2[nH]cc(C[C@H](C)N)c2c1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CO
Product: COc1ccc2[nH]cc(C[C@H](C)NC[C@H](O)c3ccc4nnnn4c3)c2c1
Yield: 54.4 %

Procedure:
A solution of 350 mg of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 429 mg of (S)-1-methyl-2-(5-methoxy-1H-indol-3-yl)ethyl amine (R. A. Glennon et al., Biol. Psychiatry, 18, 493 (1983) in 8 ml of methanol was heated at reflux under nitrogen for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue (765 mg) was purified twice by preparative TLC on silica gel (95:5:0.5 CH2Cl2 :MeOH:NH4OH) to give 419 mg of (R)-α-[[(1(S)-methyl-2-(5-methoxy-1H-indol-3-yl)ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:10][NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Cl:1])[CH3:14])[CH3:18]
Reactant: Cc1cccc(NN)c1Cl
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)C(C)=NNc1cccc(C)c1Cl

Procedure:
The title compound was prepared in accordance with the general method of example 25b) from (2-Chloro-3-methyl-phenyl)-hydrazine and ethyl pyruvate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[CH3:21][N:22]=[C:23]=[S:24].NC(N)=S>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]([NH:22][CH3:21])=[S:24])=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Reactant: CN=C=S
Agent: NC(N)=S
Product: CNC(=S)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1

Procedure:
Proceeding in analogy to the method described in example 19 and starting from 500 mg (1.63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (see example 17) and 220 mg (3.0 mmol) of methyl isothiocyanate allowed 245 mg of the desired thiourea to be isolated.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>C(O)C>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[NH:12][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Cc1csc2c(Cl)ncnc12
Solvent: CCO
Product: Cc1csc2c(NC3Cc4ccccc4C3)ncnc12
Yield: 75 %

Procedure:
4-chloro-7-methylthieno[3,2-d]pyrimidine (74 mg, 0.40 mmol) and 2-aminoindan (270 mg, 2.0 mmol) in dry ethanol (3 ml) were heated to reflux under an argon atmosphere for 1 hour. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (83 mg, 0.30 mmol) having the following physical properties:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[NH2:35])[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].CO[CH:39]1[CH2:43][CH2:42][CH:41](OC)O1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[N:35]3[CH:39]=[CH:43][CH:42]=[CH:41]3)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: Nc1ccc(F)cc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: COC1CCC(OC)O1
Product: O=C(NC1(C(=O)NC2CCN(c3cc(F)ccc3-n3cccc3)CC2O)CCCCC1)c1cc2ccccc2o1

Procedure:
The mixture of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-amino-5-fluorophenyl)piperidin-3-ol (2 g) obtained in Step 1 and 0.96 ml of 2,5-dimethoxytetrahydrofuran was refluxed for 1 hour and concentrated under reduced pressure. The resulting residue was diluted with 70 ml of dichloromethane, washed with a saturated sodium bicarbonate solution and brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.8 g of the titled compound as white color.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:20][C:21]([CH3:23])=[O:22]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1/[CH:4]=[CH:20]/[C:21](=[O:22])[CH3:23]
Reactant: CC(C)=O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)/C=C/c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
In a 250 ml single neck flask was charged 10 g (57 mmoles, 1.0 eq) of 2,6-dichlorobenzaldehyde dissolved in 100 ml of acetone. To this was added 2.28 g (5.7 mmoles, 0. 10eq.) of a 10% aqueous sodium hydroxide solution, dropwise and during the course of addition, temperature was kept no higher than 25°C., while the mixture was agitated continuously for 2 h. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to afford of (E)-4-(2,6-dichlorophenyl)-3-buten-2-one as a faintly yellow oil which was used directly in the following procedure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: COc1ccc(O)c(Br)c1
Reactant: BrCC1CC1
Product: COc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-methoxy-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[C:7](=O)[C:6]=2[CH:19]=1.O1CCCC1.C(O)(=O)C.S(=O)(=O)(O)O>O1CCOCC1.C(O)C>[OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH2:7][C:6]=2[CH:19]=1
Reactant: O=c1c(-c2cccc(Cl)c2)coc2cc(O)c(O)cc12
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1cc2c(cc1O)OCC(c1cccc(Cl)c1)C2

Procedure:
As example 39, but using 6,7-dihydroxy-3-(3-chlorophenyl)-4H-1-benzopyran-4-one (1.2 g) instead of 6,7-dihydroxy-3-(3-methylphenyl)-4H-1-benzopyran-4-one. Tetrahydrofuran and acetic acid are used instead of dioxan/ethanol and sulphuric acid. The resulting oil crystallizes to give 3,4-dihydro-6,7-dihydroxy-3-(3-chlorophenyl)-2H-1-benzopyran.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:23][CH:22]=1.O[Li].O>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][NH:28][C:29]([CH:31]2[CH2:32][CH2:33]2)=[O:30])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(NCc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1)C1CC1
Yield: 91.1 %

Procedure:
Dissolve 7-chloro-6-{4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (335 mg, 0.698 mmol) in MeOH (10 mL). Add LiOH.H2O (293 mg, 6.98 mmol) and stir overnight. Partition the reaction mixture between chloroform and water. Separate the aqueous phase and extract three times with chloroform and once with chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g, pre-packed cartridge) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15; 50 mL/min) to obtain 7-chloro-6-{-4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (244 mg, 91%). MS (APCI+) m/z: 384 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:11]2[CH:12]=[C:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[O:9][C:8]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=O.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:12][C:11]=3[C:7]=2[C:5]2[NH:4][CH2:3][CH2:2][N:1]=2)=[CH:28][CH:27]=1
Reactant: CC(C)Oc1cc2c(C(=O)NCCN)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Oc1cc2c(C3=NCCN3)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of N-(2-aminoethyl)-2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxamide (1.2 g, 2.99 mmol) in toluene (75 mL) at room temperature under nitrogen was added POCl3 (2.79 mL, 29.9 mmol). The reaction mixture was heated to 100° C. and maintained at same temperature overnight. The reaction mixture was concentrated completely under vacuum, and the residue diluted with water, basified with NaHCO3. The product was extracted with EtOAc (100 mL×3), washed with brine, dried over Na2SO4 and concentrated to obtain 2-(2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-yl)-4,5-dihydro-1H-imidazole as a yellow solid. Yield: 1.0 g (87%). LCMS: (ES+) m/z=384.28 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 nm); M phase A: 5 mM Ammonium Acetate:MeCN (95:5); M phase B: 5 mM Ammonium Acetate:MeCN (5:95)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C:9]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:38][C:39](=[O:40])[N:41]([CH3:43])[CH3:42])[CH:14]=2)[C:9]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CN(C)C(=O)CCl
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(OCC(=O)N(C)C)cc12
Temperature: 85 °C

Procedure:
To a stirred solution of 6-hydroxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester (70 mg, 0.17 mmol) in N,N dimethylformamide (2 mL) was added potassium carbonate (237 mg, 1.71 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.088 mL, 0.86 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the crude product was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 30% ethyl acetate/hexane) afforded 6-dimethylcarbamoylmethoxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester. To a stirred solution of 1-(3-isopropoxy-benzoyl)-7-methoxy-6-(2-pyrrolidin-1-yl-ethoxy)-isoquinoline-4-carboxylic acid ethyl ester (73.0 mg, 0.14 mmol) in ethanol (1.0 mL) and tetrahydrofuran (0.5 mL) was added 4N aqueous sodium hydroxide (0.144 mL, 0.56 mmol) at room temperature. The mixture was heated at 60° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane and water. The aqueous phase was acidified to pH=3 by addition of 1N hydrochloride solution and then was extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product recrystallized from ethyl acetate to afford 1-(3-isopropoxy-benzoyl)-7-methoxy-6-(2-pyrrolidin-1-yl-ethoxy)-isoquinoline-4-carboxylic acid as a light brown solid (28 mg, 37% yield). HR-MS m/e calcd for C23H21N1O6 (M−H+) 440.1340, found 440.1347; 1H NMR (300 MHz) compatible.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33]>>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Clc1ccccc1OCCCBr
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3Cl)cc2)C(O)C1

Procedure:
Analogously to Method I, 5.84 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 6.00 g of 1-(3-bromopropoxy)-2-chlorobenzene are reacted. The title compound is obtained as a white solid. Rf=0.62 (1:2 EtOAc-heptane); Rt=5.33.