Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].C(N(CC)CC)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]=C=O)=[CH:44][CH:43]=1>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:12][CH2:13]2)=[O:7])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3cc([N+](=O)[O-])ccc23)CC1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc([N+](=O)[O-])ccc23)CC1

Procedure:
To a solution of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-nitroquinoline (360 mg, 1 mmol) in CH2Cl2 (1 mL) is added trifluoroacetic acid (1 mL). After 1½ h at room temp., the mixture is concentrated, and the residue is dissolved in CH2Cl2 (20 mL) and treated with triethylamine (0.56 mL, 4 mmol) and 4-fluorophenyl isocyanate (0.16 mL, 1.4 mmol). After 1½ h stirring at room temp., the reaction mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by reversed phase HPLC with water-MeCN-TFA yielding the title product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1.[OH-:22].[Na+].[OH:24]O.O>C(O)(=O)C.[Na]>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1)(=[O:24])=[O:22]
Reactant: CCCCCCCCCCCCOc1ccc(SC)cc1
Reactant: [OH-]
Reactant: OO
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C

Procedure:
95.4 g of dodecyl 4-methylthiophenyl ether was dissolved in 400 ml of acetic acid, and further a dilute sodium hydroxide solution containing 0.5 g of sodium tangstate was added thereto. The resulting solution was heated at 80° C. with stirring. To the solution 66.3 g of 35% hydrogen peroxide was dropwise added. After the conclution of the addition, the reaction mixture was stirred for 2-hours under heating, and, after cooling, water was added to filtrate a precipitated crude crystal. The crude crystal was recrystalized by using methanol to obtain 101.5 g of dodecyl 4-methylsulfonylphenyl ether crystal.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[C:15](=[S:17])=[S:16].Br[CH2:19][CH2:20][C:21]([F:25])=[C:22]([F:24])[F:23]>CS(C)=O.O>[CH3:13][C:10]1([CH3:14])[CH2:9][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:3][C:15](=[S:17])[S:16][CH2:19][CH2:20][C:21]([F:25])=[C:22]([F:24])[F:23])[C:12]=2[O:11]1
Reactant: FC(F)=C(F)CCBr
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Cc2cccc(NC(=S)SCCC(F)=C(F)F)c2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydroxide (3.7 ml, 20M) was added to a stirred solution of 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (10 grams, 0.061 mole) in dimethyl sulfoxide (31 ml). Upon completion of addition, carbon disulfide (6.06 grams, 0.08 mole) was added. The reaction mixture was stirred for one hour at ambient temperature, then cooled to 0° C. at which time 4-bromo-1,1,2-trifluoro-1-butene was added dropwise. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (400 ml) and extracted with diethyl ether. The extract was dried (sodium sulfate) and concentrated under reduced pressure leaving a residue. This residue was passed through a column of silica gel, eluting with hexane:diethyl ether (9:1). Appropriate fractions were combined and concentrated under reduced pressure, yielding (3,4,4-trifluoro-3-butenyl) N-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)dithiocarbamate (Compound A12). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[OH-].[Na+]>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccc1CO
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)N(NC(=O)c1ccccc1CO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
0.7 g of N'-t-butyl-N-(2-hydroxymethylbenzoyl)-hydrazine and 1.1 g benzoyl chloride are combined in 10 ml of 5% NaOH and stirred at room temperature for 1.5 hours. The solids are filtered off, washed with water, then ether, to afford 0.6 g of white solid N'-t-butyl-N-(2-(benzoyloxymethyl)benzoyl)-N'-benzoylhydrazine. m.p. 190°-191° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[C:11](Cl)=[O:12])[C:5]=1[CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)([CH3:26])[CH3:25])=[CH:20][CH:19]=1.C1C[O:37]CC1>N1C=CC=CC=1>[CH2:1]([C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[C:11]([OH:17])=[O:12])[C:5]=1[CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].[CH2:1]([C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[C:11]([OH:37])=[O:12])[C:5]=1[CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].[OH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)([CH3:26])[CH3:25])=[CH:22][CH:23]=1
Reactant: C=CCC1=C(CC=C)C2CC1CC2C(=O)Cl
Reactant: C1CCOC1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: C=CCC1=C(CC=C)C2CC1CC2C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
130 g of diallyl-bicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are added dropwide at 20° C. within 30 minutes to a solution of 62.7 g of bisphenol A in 200 ml of pyridine. The mixture is then stirred for 1 hour at 80° C. and then worked up as described in Example 2. This gives 162 g (95% of theory) of a brown, liquid resin with η25 =3,165 mPas. By gel permeation chromatography (THF), the molecular weight is found to be 610 (Mn) or 691 (Mw).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[ClH:28].O1CCOCC1.C(OCC)C>C(Cl)Cl>[ClH:28].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)CNCC3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.4 g, 3.7 mmol) in DCM (3 mL) was added 4.0M HCl in dioxane (4.6 mL, 18.56 mmol) and stirred at rt for 3 h, Diethylether (200 mL) was then added and the mixture was stirred at rt for 30 min and then filtered and washed with diethylether and dried to give the title compound (1.3 grams).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14](=O)[CH3:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].B.C1COCC1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Agent: B
Solvent: C1CCOC1
Product: CCc1c[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a solution of 3-acetyl-1H-indole-6-carboxylic acid methyl ester (0.65 g, 3.0 mmole) in THF (30 mL) was added BH3-THF (1.0M, 9 mL, 9 mmol). The solution was heated to reflux and then more BH3-THF (5 mL) was added. After allowing to cool and stirring for 2 hr at room temperature, the solvent was removed and the remaining material was diluted in ethyl acetate (100 mL) and washed with dilute NaHCO3 (200 mL). The organic layer was dried (MgSO4), filtered and concentrated. The remaining material was subjected to flash chromatography (25% ethyl acetate/hexanes) to collect 0.45 g (74% yield) of 3-ethyl-1H-indole-6-carboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH3:17])[C@@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:10].[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.CN[C@H]1CCCC[C@@H]1NC.[C:45]([O-:48])([O-])=[O:46].[Cs+].[Cs+]>[Cu]I.O1CCOCC1>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[O:10])[C@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.[C:45]([OH:48])([C:26]([F:29])([F:28])[F:27])=[O:46]
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: c1cn[nH]c1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: O=C(O)C(F)(F)F
Temperature: 140 °C

Procedure:
A mixture of rac-cis-(2-bromo-5-methylphenyl)(3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanone (0.0326 g, 0.0693 mmol), pyrazole (0.0094 g, 0.139 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.004 g, 0.0277 mmol), Cs2CO3 (0.045 g, 0.139 mmol) and CuI (0.003 g, 0.0139 mmol) and dioxane (1.0 mL) was degassed and heated overnight at 140° C. The reaction was cooled to RT, and acidified with TFA to pH4-5. The solvent was removed in vacuo to obtain the crude which as purified by preparative-HPLC to obtain the title compound as a TFA salt. ESI-MS (m/z): 458, [M+1]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)[CH3:21]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([C:19]#[C:18][C:15]2[CH:14]=[CH:13][C:12]([C:9]3([NH:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:10]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=1)[CH3:21]
Reactant: C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 127, 65.0 mg, 0.27 mmol) and ethyl-4-iodo benzoate (Reagent A, 68.0 mg, 0.27 mmol) in triethyl amine (8 mL) was treated with copper(I)iodide (16.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis (triphenylphosphine)palladium(II) (58 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 90 mg (90%) of the title compound as an orange solid.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][C@@H:9]([NH:13][C:14]1[C:23]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=2[C:21]2[C:20](=[O:29])[NH:19][CH:18]=[CH:17][C:16]=2[NH+:15]=1)[CH:10]([CH3:12])[CH3:11].C(N(CC)CC)C.[Br:37]NC(=O)CCC(N)=O>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:37][C:17]1[C:16]2[N:15]=[C:14]([NH:13][C@H:9]([CH3:8])[CH:10]([CH3:11])[CH3:12])[C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[C:21]=2[C:20](=[O:29])[NH:19][CH:18]=1
Reactant: CC(C)[C@@H](C)Nc1[nH+]c2cc[nH]c(=O)c2c2cc(F)ccc12
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@@H](C)Nc1nc2c(Br)c[nH]c(=O)c2c2cc(F)ccc12
Reaction time: 2 h

Procedure:
To a solution of 6-{[(1R)-1,2-dimethylpropyl]amino}-9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-5-ium trifluoroacetate (53 mg, 0.13 mmol) in DMF (3 mL) were added triethylamine (18 uL, 0.13 mmol) and N-bromosuccinamide (27 mg, 0.15 mmol). The solution was stirred for 2 hr then diluted with EtOAc and sat. NaHCO3. The organic layers were separated, dried with MgSO4, filtered, and concentrated. The resulting crude mixture was purified by silica column chromatography 100% Hex. to 100% EtOAC to afford 4-bromo-6-{[(1R)-1,2-dimethylpropyl]amino}-9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (600 MHz, CD3OD) δ 9.55 (d, 1H), 8.37 (m, 1H), 7.66 (s, 1H), 7.36 (m, 1H), 4.65 (m, 1H), 2.1 (m, 1H) 1.30 (d, 3H), 1.0 (m, 6H). LRMS (ESI) calc'd for (C17H18Br2FN3O) [M+H]+, 378.1; found 378.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC=CC=1.C(Cl)(Cl)Cl.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>CCOCC>[N:1]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: N#CCCCCCCBr
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: N#CCCCCCCN1CCCCC1

Procedure:
In a flask equipped with a dropping funnel and a cooler was placed a mixture of 8.94 g of piperidine, 7.7 ml of benzene and 1.5 ml of chloroform. The mixture was refluxed by heating, and to the mixture was dropwise added 9.50 g of 7-bromoheptanenitrile. After the addition was complete, the mixture was further refluxed by heating for 4 hours and then cooled under ambient condition. To the mixture was added ether, and the resulting mixture was stirred for a while. The reaction mixture was filtered to remove insolubles. The insolubles were washed with ether. The filtrate and washings were combined and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 7-piperidinoheptanenitrile as a colorless oil, yield: 8.92 g (theoretical yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][NH:16][C:17]([C:19]3[NH:28][C:22]4=[CH:23][N:24]=[C:25]([Cl:27])[CH:26]=[C:21]4[CH:20]=3)=[O:18])OCC[O:11]2)=[CH:6][CH:5]=1>CC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:11])[CH2:15][NH:16][C:17]([C:19]2[NH:28][C:22]3=[CH:23][N:24]=[C:25]([Cl:27])[CH:26]=[C:21]3[CH:20]=2)=[O:18])=[CH:8][CH:9]=1
Reactant: COc1ccc(C2(CNC(=O)c3cc4cc(Cl)ncc4[nH]3)OCCO2)cc1
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(C(=O)CNC(=O)c2cc3cc(Cl)ncc3[nH]2)cc1
Temperature: 25 °C

Procedure:
Aqueous hydrochloric acid (2.1 mL, 2M) was added to a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-(4-methoxyphenyl)[1,3]dioxolan-2-ylmethyl]amide (Preparation 49, 160 mg, 0.41 mmol) in acetone (20 mL). The mixture was heated under reflux for 90 min then allowed to cool to rt. The suspension was filtered then washed with acetone and air dried, to give the title compound as a pale yellow solid. δH (d6 DMSO): 3.86 (3H, s), 4.79 (2H, d), 7.08 (2H, d), 7.23 (1H, s), 7.77 (1H, s), 8.03 (2H, d), 8.58 (1H, s), 9.14 (1H, t), 12.31 (1H, br s). m/z (ES+) 344 [M+H]+; RT=3.34 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[C:7]#[N:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OCc1ccccc1

Procedure:
5-Bromo-2-hydroxybenzonitrile, benzyl bromide and potassium carbonate were reacted in DMF at room temperature to obtain 2-(benzyloxy)-5-bromobenzonitrile. EI: 287, 289.
Reaction SMILES: [ClH:1].[CH2:2]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:24]3[CH:23]=[C:22]([C:25](=[O:27])[CH3:26])[S:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+].O>CO>[ClH:1].[CH2:2]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:24]3[CH:23]=[C:22]([CH:25]([OH:27])[CH3:26])[S:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1cc2c(N3CCN(CCc4ccccc4)CC3)cccc2s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1cc2c(N3CCN(CCc4ccccc4)CC3)cccc2s1
Reaction time: 0.33 h

Procedure:
To partially dissolved 1-[4-(4-phenethyl-piperazin-1-yl)benzo[b]thiophen-2-yl]-ethanone hydrochloride (0.92 g, 2.5 mmol, product from Example 42) in methanol (70 mL) is added sodium borohydride (0.19 g, 5.0 mmol). After 0.33 h, the reaction is clear and homogeneous. The reaction is worked up after 2 h by pouring into water (10 mL), extracting with dichloromethane (3×75 mL), and concentrating the sodium sulfate dried extracts in vacuo. The product (Rf of 0.3 in ethyl acetate) is dissolved in acetonitrile (50 mL), treated with 1.0M hydrochloric acid (2.5 mL), concentrated in vacuo, then reconcentrated from acetonitrile:methanol to give a white solid. After vacuum drying for 9 h at 70° C., the title compound is isolated as a white solid (0.865 g). 1H NMR (d6 -DMSO): 11.48 (1H, bs), 7.61 (1H, d, J=8.0 Hz), 7.40-7.23 (7H), 6.95 (1H, d, J=7.6 Hz), 5.76 (1H, bs), 5.07 (1H, q, J=6.2 Hz), 3.69 (2H, bd, J=10.6 Hz), 3.53 (2H, m), 3.45-3.25(6H), 3.17 (2H, m), 1.50 (3H, d, J=6.4 Hz) ppm. 13C NMR (d6 -DMSO): 152.13, 146.05, 139.74, 137.10, 133.35, 128.67, 126.79, 124.47, 117.62, 116.20, 112.54, 64.86, 56.19, 51.18, 48.45, 48.24, 29.29, 25.68 ppm. IR (KBr): 3351, 2575, 2554, 2446, 1570 cm-1. CIMS (methane): 367 (92%), 349 (100%), 275 (82% ).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[N:40](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:7]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:22])=[O:21])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.O>C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:7]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:22])=[O:21])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(COCc2ccccc2C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(COCc2ccccc2C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.8 %

Procedure:
A mixture of 450 mg of 2-butyl-5-[(2-carboxyphenyl)methoxymethyl]-4-chloro-1-[[2'-(1-triphenylmethyltetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl]-1H-imidazole, 7.5 ml of acetic acid, 3.7 ml of H2O and 2 ml of THF is stirred at room temperature for 10 hours. The solvent s are evaporated off under reduced pressure and the residue is taken up in H2O, alkalinized with 10% NaOH, an insoluble part is filtered off, the resulting solution is extracted with ether and acidified to pH 4.5 with 5N HCl. The obtained precipitate is filtered and washed with H2O. 0.2 g of a white solid are obtained (70% yield). M.p. 109°-111° C. 1H NMR (CDCl3), δ: 0.84 (t, 3 H); 1.27 (m, 2 H); 1.54 (m, 2 H); 2.39 (t, 2 H); 4.43 (s, 2 H); 4.60 (s, 2 H); 5.14 (s, 2 H); 6.80-8.12 (m, 12 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[OH:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11]>>[OH:8][C:9]([CH3:15])([CH3:14])[C:10]([O-:12])=[O:11].[CH2:1]([N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH3:9])[CH3:2]
Reactant: COC(=O)C(C)(C)O
Reactant: CCN(CC)CC
Product: CC(C)(O)C(=O)[O-]
Product: CC[N+](C)(CC)CC
Reaction time: 8 h

Procedure:
Into a 5-L SUS316 autoclave equipped with an electromagnetic stirrer, were charged 505 g (5.0 mol) of triethylamine and 2950 g (25 mol) of methyl 2-hydroxyisobutyrate, and heated under stirring. After the contents of the autoclave reached 120° C., the temperature was kept there for 8 h to proceed the reaction. The reaction pressure was 0.1 MPa (Gauge). After the reaction was completed, the reaction liquid was cooled and low-boiling components were removed from the reaction liquid by distillation to obtain triethylmethylammonium 2-hydroxyisobutyrate in 87.4 mol % yield based on triethylamine.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:39]([C:40]2[C:41]([CH2:54][O:55][Si:56]([CH:63]([CH3:65])[CH3:64])([CH:60]([CH3:62])[CH3:61])[CH:57]([CH3:59])[CH3:58])=[N:42][N:43]([CH2:45][CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:44]=2)[N:38]=[C:37]([C:66]([CH3:69])([CH3:68])[CH3:67])[CH:36]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:66]([C:37]1[CH:36]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:39]([C:40]2[C:41]([CH2:54][O:55][Si:56]([CH:57]([CH3:59])[CH3:58])([CH:63]([CH3:65])[CH3:64])[CH:60]([CH3:61])[CH3:62])=[N:42][N:43]([CH2:45][CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:44]=2)[N:38]=1)([CH3:68])([CH3:67])[CH3:69]
Reactant: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl)(C(C)C)C(C)C
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
Intermediate B (0.23 g, 0.61 mmol) was treated with a solution of Intermediate 74g (0.47 g, 0.68 mmol) in 1,4-dioxane (3.4 mL) then DIPEA (0.13 mL, 0.74 mmol) was added. The mixture was stirred at 70° C. overnight. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7% MeOH in DCM, to give the title compound (0.34 g, 60%). LCMS (Method 3): Rt 5.48 min, m/z 923.7 [MH+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]2[O:18][C:19]3[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=3[CH2:21][N:22]([C:23]([NH:25][NH2:26])=[O:24])[C:16]=2[CH:15]=1>>[O:12]=[C:10]([NH:26][NH:25][C:23]([N:22]1[CH2:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][C:17]2[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][C:16]1=2)=[O:24])[CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCc1cccs1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCCCc1cccs1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-5-(2-thienyl)pentyl]hydrazide (59) was prepared in the manner described in Example 7 on a 7.6 mmol scale from 5-(2-thienyl)pentanoic acid (58), prepared as described above in Example 58, and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1. Analysis calculated for C23H22N3O3SCl (M.W. 455.95): C, 60.58; H, 4.86; N, 9.22; Cl, 7.78; S, 7.03. Found: C, 60.72; H, 4.94; N, 9.22; Cl, 7.97; S, 7.08.