Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12](=[O:16])[C:13](Cl)=[O:14])[CH3:10].[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:4]1[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=1)=[O:14])[CH3:10]
Reactant: CSc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
37.5 g (0.3 mol) of Thioanisol and 41.4 g (0.3 mol) of chloro-oxo-acetic acid ethyl ester dissolved in 200 ml of dichloromethane are added dropwise to a suspension of 60 g (0.45 mol) of aluminum trichloride in 350 ml of dichloromethane at 0° C. The solution is stirred overnight at room temperature and then heated to reflux for two hours. After cooling to room temperature, the reaction mixture is poured on a mixture of 100 ml conc. HCl and ice/water. After extraction with dichloromethane, the organic phase is washed with water and sodium bicarbonate and dried over magnesium sulfate. The salt is filtered off and the solvent distilled to give 52.3 g (78%) of (4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester as a yellow oil. This oil is used for the next step without further purification. The structure is confirmed by the 1H-NMR spectrum (in CDCl3). δ[ppm]: 7.87 (d,2H), 7.24 (d,2H), 4.39 (q,2H), 2.48 (s,2H), 1.37 (t,3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[CH:9]=[C:8]([OH:11])[CH:7]=[CH:6][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: BrBr
Reactant: CCCCc1ccc(O)cc1
Solvent: CC(=O)O
Product: CCCCc1ccc(O)cc1Br
Temperature: 40 °C
Reaction time: 4 h

Procedure:
22.5 g (0.15 mol) of commercially available p-n-butylphenol was dissolved in 100 ml glacial acetic acid and was slowly heated to 40° C. 24.5 g (0.153 mol) of bromine was added and the solution was stirred for four hours at 60° C. The glacial acetic acid in the reaction solution was removed by distillation and 31.7 g of 3-bromo-4-n-butylphenol was obtained from the residue by vacuum distillation (85° C./1 mmHg). The yield of 3-bromo-4-n-butylphenol was calculated to be 92.1%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][O:15][CH2:16][C:17]([NH:7][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:18]
Reactant: COCC(=O)Cl
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Solvent: c1ccncc1
Product: COCC(=O)Nc1c(C)n[nH]c1-c1ccccc1
Reaction time: 2 h

Procedure:
To a RT solution of 416 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 4.6 mL pyridine was added 242 μL of methoxyacetyl chloride. After 2 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with 0.5 N hydrochloric acid and saturated aqueous sodium carbonate and brine. The organic portion was dried with sodium sulfate and concentrated under reduced pressure. The residue contained the title compound as a tan, amorphous solid and was used without further purification.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=O)C.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(O)(=O)C>O1CCOCC1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:6]([C:8]3[CH:13]=[N:12][CH:11]=[CH:10][N:9]=3)=[N:5][CH:4]=[N:2]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=NC(=O)c1cnccn1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-n2ncnc2-c2cnccn2)cc1
Temperature: 90 °C

Procedure:
10.0 g. of portion of N-(dimethylaminomethylene)-pyrazine carboxamide is added to a mixture of 10.3 g. of 4-nitrophenylhydrazine, 200 ml. of acetic acid and 50 ml. of p-dioxane. The mixture is heated at 90° C. for 5 hours and evaporated to dryness in vacuo. The residue is recrystallized from ethanol giving 9.0 g. of the desired product as tan crystals, mp. 188°-189° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[C:25]([CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[O:26])=[CH:11][CH:10]=1>CCOCC>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1

Procedure:
With stirring, trifluoroacetic acid (10 ml) was added to 4-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2yl]carbonyl-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1.65 g, 3.77×10-3 mole). After 30 minutes the reaction was cooled in an ice bath and ether (150 ml) was added. The flask was stoppered and placed in the refrigerator. After several hours, the solid was collected by filtration, washed with EtzO, and dried by suction. Crystallization from ethanol/ether afforded [1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-4-piperidinylmethanone, mono (trifluoroacetate) as colorless needles: 1.45 g (84%), m.p. 213°-215° C. (decomp).
Reaction SMILES: C(N1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)CC1)(C)C.[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH2:7]([O:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][N:23]([CH2:29][CH2:28][O:27][CH3:26])[C:24](=[O:25])[C:15]3=[CH:14][C:13]=2[CH:12]=1)[C:8]1[CH:9]=[CH:13][CH:12]=[CH:11][CH:19]=1
Reactant: COCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCCn2c(cc3cc(OCc4ccccc4)ccc32)C1=O

Procedure:
The title compound was synthesized in analogy to example 17, from 9-benzyloxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 15, intermediate b)), 2-bromoethyl methyl ether and sodium hydride, to give the compound as a white solid (77%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:18]([C:10]1([CH2:15][CH2:16][CH3:17])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH2:19][CH3:20]
Reactant: CCCC1(CCC)CN(Cc2ccccc2)CCC1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC1(CCC)CNCCC1O

Procedure:
A mixture of 1-benzyl-3,3-di-n-propyl-4-hydroxypiperidine (0.9 g, 3.27 mmole) and 20% palladium hydroxide (0.2 g) in methanol (20 ml) was stirred at ambient temperature in hydrogen atmosphere (1 atm.) for 8 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-di-n-propyl-4-hydroxypiperidine as oil. Yield 0.5 g (84%), C12H23NO, m/z 186 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:11][C:12]1(O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH3:11][C:12]1([C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[C:8]([C:4]3([CH3:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[C:7]=2[OH:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC1(O)CCCCC1
Reactant: CC(C)c1ccc(O)cc1
Product: CC(C)c1cc(C2(C)CCCCC2)c(O)c(C2(C)CCCCC2)c1

Procedure:
38 parts of para-isopropylphenol and 96 grams 1-methylcyclohexanol were reacted as described in Example 15 to give 2,6-bis (1-methyl-cyclohexyl)-4-isopropylphenol, γmax 3620 cm-1 (--OH).
Reaction SMILES: C(C1(C)[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5]C1)#N.[OH-].[Na+].O1CCCC1.C(O)(=O)[CH2:36][C:37]([CH2:42]C(O)=O)([C:39]([OH:41])=[O:40])O>C(O)C>[CH3:42][C:37]1([C:39]([OH:41])=[O:40])[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:36]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CN(c1cccc2cc(C3=NCC(C)(C#N)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cccc2cc(C3=NCC(C)(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 69 %

Procedure:
A mixture of N-[2-(5-cyano-5-methyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.15 g), 2N aqueous sodium hydroxide solution (0.36 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was heated under reflux for 4 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.11 g, yield 69%) as yellow crystals from a fraction eluted with tetrahydrofuran. melting point >232° C. (decomposition).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:15]>CN(C=O)C>[Br:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2nccc(O)c2c1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: COc1ccc2nccc(Br)c2c1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-hydroxy-6-methoxyquinoline (1.20 g, 70.5 mmole) in DMF (60 mL) at RT was added PBr3 (8.0 mL, 84.6 mmole) dropwise. After 2 h, the reaction contents were poured onto H2O (300 mL) and the product filtered and washed with H2O to give, after drying under high vacuum, the title compound (14.3 g, 87%) as a light yellow solid: LC-MS (ES) m/e 233 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5]Br.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[CH3:1][O:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: CON(C)C(=O)CBr
Solvent: C1CCOC1
Product: CON(C)C(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The above amide (1 equiv) is dissolved in THF. Piperidine (1.1 equiv) is added and the reaction solution is stirred at ambient temperature for 48 h. The reaction mixture is concentrated and the product is purified by flash chromatography on silica using MeOH/CH2Cl2 as the mobile phase to yield N-methoxy-N-methyl-2-(piperid-1-yl)-ethanamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH:27][CH:28]([CH3:30])[CH3:29])[N:21]=3)[N:16]=2)[CH:6]=[C:7]([CH3:14])[C:8]=1[O:9][CH2:10][C@@H:11]1[CH2:13][O:12]1)[CH3:2].[NH3:31]>CO>[NH2:31][CH2:13][CH:11]([OH:12])[CH2:10][O:9][C:8]1[C:7]([CH3:14])=[CH:6][C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH:27][CH:28]([CH3:29])[CH3:30])[N:21]=3)[N:16]=2)=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(-c2nc(-c3cc(C)nc(NC(C)C)n3)no2)cc(C)c1OC[C@@H]1CO1
Reactant: N
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)nc(NC(C)C)n3)no2)cc(C)c1OCC(O)CN

Procedure:
A solution of (S)-{4-[5-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methyl-pyrimidin-2-yl}-iso-propyl-amine (48 mg, 0.12 mmol) in 7M NH3 in MeOH (5 mL) is stirred at 65° C. for 24 h. Volatiles are removed in vacuo to give the crude 1-amino-3-{2-ethyl-4-[3-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenoxy}-propan-2-ol as a yellow oil (43 mg); LC-MS: tR=0.76 min; [M+H]+=426.80.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:24]([O:26]C)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1C(=O)O
Yield: 85.9 %

Procedure:
To a stirred solution of methyl (2S, 4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl carboxylate (5.37 g) in THF (116 ml) was added 0.25 N NaOH (116 ml, 29.0 mmol) at room temperature. The resulting mixture was stirred over night. After removal of the solvent, the mixture was acidified by the addition of 1 N HCl and extracted with CHCl3. The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was recrystallized with n-hexane-CHCl3, to give (2S, 4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid [4.44 g, 85%(2 steps)] as a white powder. 1H-NMR (DMSO-d6) δ 1.37 and 1.41 (s, 9H, amide isomers), 2.26 (d, J=13.9 Hz, 1H), 2.65 (m, 1H), 3.47 (d, J=11.5 Hz, 1H), 3.81 (m, 1H), 4.30 (m, 1H), 5.14 (m, 1H), 7.02–7.86 (m, 7H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2].CI.[C:25](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH3:25])[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCCCc1c(C(=O)OCC)cc(O)c2ccc(OC)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCCc1c(C(=O)OCC)cc(OC)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 64 h
Yield: 78.7 %

Procedure:
A solution of 1-butyl-4-hydroxy-7-methoxy-2-naphthalenecarboxylic acid ethyl ester (6.5 g) and methyl iodide (7 mL) in acetone (65 mL) containing potassium carbonate (5 g) was stirred at room temperature for 64 hours. After the reaction mixture was filtered, the filtrate was concentrated to dryness and the residue was partitioned between dichloromethane (150 mL) and water (100 mL). The dried (MgSO4) organic layer was evaporated and the residual material crystallized from 2-propanol to yield 5.35 g of 1-butyl-4,7-dimethoxy-2-naphthalenecarboxylic acid ethyl ester, mp 44°-45° C. Anal. Calcd for C19H24O3 : C, 72.13; H, 7.64 Found: C, 72.03; H, 7.78
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C@H:33]([OH:40])[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:32][C@H:33]([OH:40])[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([O:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)COc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 36 h
Yield: 99.2 %

Procedure:
To a solution of methyl 4′-[2-[[tert-butoxycarbonyl]-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isobutoxy-4-biphenylcarboxylate (511 mg) in methanol (5.11 ml) and tetrahydrofuran (1.53 ml) was added 1N sodium hydroxide (2.79 ml) and the mixture was stirred at room temperature for 36 hours. Methanol and tetrahydrofuran were removed by evaporation under reduced pressure and the pH was adjusted to 5.9 with 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate (twice) and the extract was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave 4′-[2-[[tert-butoxycarbonyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isobutoxy-4-biphenylcarboxylic acid (494 mg) as a brown solid (foam).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[C:11]([Cl:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[CH3:14][C:15]([CH3:24])([CH3:23])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][NH:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].ClCCl>CS(C)=O>[ClH:12].[Cl:12][C:11]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:21]([CH2:20]/[CH:19]=[CH:18]/[C:17]#[C:16][C:15]([CH3:24])([CH3:23])[CH3:14])[CH3:22])[C:8]=2[S:9][CH:10]=1
Reactant: Clc1csc2c(CBr)cccc12
Reactant: CNC/C=C/C#CC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2c(Cl)csc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 77 %

Procedure:
To a solution of 0.34 g (1.3 mmol) of 7-bromomethyl-3-chlorobenzo[b]thiophene in 3 ml of dimethyl sulfoxide were added 0.246 g (1.31 mmol) of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine hydrochloride, and 0.27 g (1.95 mmol) of potassium carbonate -under ice cooling. The mixture was stirred for 19 hours at room temperature, poured into 40 ml of dichloromethane, washed with 30 ml×2 of water, and adjusted to pH 2 with 25 ml of water and 2N hydrochloric acid. The organic layer was separated, washed with 20 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and cooled to crystallize. The crystals were suspended in isopropylalcohol, filtered, washed with isopropyl alcohol and dried to obtain 0.37 g (yield: 77%) of the above identified compound as white crystalline powder. Melting point, IR and NMR data of the isolated compound agreed with those of Example 23 compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[NH:14][C@@H:15]([CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][C:17](O)=[O:18])([O-:3])=[O:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[O:31]1[CH2:32][CH2:33][N:28]([C:17](=[O:18])[CH2:16][C@@H:15]([NH:14][C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:20][S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a mixture of Example 10D (0.75 g) and morpholine (0.318 g) in N,N-dimethylformamide (5 mL) were added N,N-dimethylpyridin-4-amine (0.445 g) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.699 g). The mixture was stirred overnight, diluted with ethyl acetate and washed with 5% aqueous HCl and water. The organic layer was dried over Na2SO4 and concentrated to give the title compound.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH:7]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2([Br:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: BrBr
Reactant: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C2CCCCC2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C2(Br)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
A solution of 7.32 g (44.5 mmol) of bromine in 10 ml of methylene chloride is added dropwise at room temperature to a mixture of 10.18 g (37.10 mmol) of methyl3-phenyl-3-[4-(cyclohexylcarbonyl)phenyl]propionate in 250 ml of methylene chloride. The mixture is stirred for 16 hours at room temperature after which the reaction mixture is poured into a 5% aqueous sodium thiosulfate solution and stirred for 10 minutes. The organic layer is washed twice with 5% aqueous sodium thiosulfate solution, once with 10% sodium bicarbonate solution, dried over sodium sulfate, and concentrated to give 8.19.0 g (62.5%) of methyl3-phenyl-3-[4-((1-bromocyclohexyl)carbonyl)phenyl]propionate. Mass spectrum: m/z 429.1 (M+H)+.
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[C:10]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[NH:23])[CH2:21][Cl:22])[CH2:16][CH2:15]1)(=[O:12])[NH2:11].Cl>O>[ClH:22].[C:10]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[NH:23])[CH2:21][SH:5])[CH2:16][CH2:15]1)(=[O:12])[NH2:11]
Reactant: [O-]P([O-])([O-])=S
Reactant: N=C(CCl)N1CCC(OC(N)=O)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)N1CCC(OC(N)=O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.8 %

Procedure:
4.95 g of trisodium phosphorothioate were added to an ice-cooled solution of 6.40 g of 2-(4-carbamoyloxypiperidin-1-yl)-2-iminoethylchloride hydrochloride in 32 ml of water, and the mixture was stirred at room temperature for 2.5 hours. 28 ml of 1N hydrochloric acid were then added, and the mixture was heated at 60° C. for 30 minutes. The reaction mixture was worked up in the same manner as in Example 1(2), giving 6.20 g of 2-(4-carbamoyloxypiperidin-1-yl)-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(CCBr)cc1
Product: Cc1ccc(CCN(N=C(c2ccccc2)c2ccccc2)c2ccc(F)cc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-(4-fluorophenyl)-hydrazine (200 mg, 0.689 mmol; Example 84A) and 4-methylphenethylbromide (274 mg, 1.37 mmol; Aldrich) to the title compound: MS (DCI/NH3) 409 m/z (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[Cl:20][C:21]1[C:22]([CH:29]=O)=[N:23][N:24]([CH:26]([F:28])[F:27])[CH:25]=1>>[Cl:20][C:21]1[C:22]([CH2:29][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]3([CH3:18])[C:14]([F:15])([F:16])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]3)[CH:7]=2)=[N:23][N:24]([CH:26]([F:28])[F:27])[CH:25]=1
Reactant: O=Cc1nn(C(F)F)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Product: C[C@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)N=C(N)COCC1(F)F
Yield: 11.4 %

Procedure:
In an analogous manner as described for example 2 the reductive amination of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) (27.3 mg, 100 μmol) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (19.9 mg, 110 μmol) yielded the title compound (5 mg, 11.4%) as a colorless oil. MS (ISP): m/z=438.2 [M+H]+and 440.1 [(M+2+H)+].
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25](I)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>>[ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:31]5[O:30][CH:34]=[CH:33][CH:32]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Ic1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1
Agent: Cl
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cc(-c6ccco6)ccc45)ccc32)cc1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine hydrochloride and (furan-2-yl)-tri-n-butylstannane; δH [2H6]DMSO 9.94(1H, bs), 8.61 (1H, d), 8.55(1H, s), 8.21 (2H, d), 8.00(3H, m), 7.73(2H, s), 7.30(6H, s), 6.74(1H, s), 5.72(2H, s); m/z (M+1+) 418.