Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[O:19][CH3:20])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.CCCCCC.S(Cl)([Cl:35])=O>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:35])=[O:15])=[CH:12][C:11]=2[O:19][CH3:20])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)c1ccccc1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: COc1cc(C(=O)Cl)ccc1NC(=O)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.69 g of 4-[([1,1'-biphenyl]-2-carbonyl]amino]-3-methoxy benzoic acid in 5 ml of thionyl chloride is heated on a steam bath for 1 hour under Argon. The volatiles are removed in vacuo to give a residue which is stirred with hexane to give 2.58 g of crystalline solid, m.p. 121°-123° C. M+ =361.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:8][NH:7][CH2:6]1)(=[O:4])=[O:3].F[C:10]1[C:11]([CH3:30])=[N:12][C:13]2[C:18]([N:19]=1)=[C:17]([C:20]1[NH:28][C:27]3[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=3[CH:21]=1)[CH:16]=[CH:15][CH:14]=2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:30][C:11]1[C:10]([N:7]2[CH2:8][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]2[NH:28][C:27]3[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=3[CH:21]=2)[N:12]=1
Reactant: CS(=O)(=O)C1CNC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N1CC(S(C)(=O)=O)C1
Yield: 48.6 %

Procedure:
A solution of 3-methanesulfonyl-azetidine (10.95 mg, 0.08 mmol) (Pharmablock Co. Ltd, cat# PBJH0053), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (24 mg, 0.081 mmol) and DIEA (15.50 μL, 0.09 mmol) in 0.5 mL of NMP was heated in a microwave at 125° C. for 30 min. Purification of the crude reaction mixture on a silica gel column (1-6% MeOH in DCM) gave 2-(2-methyl-3-(3-(methylsulfonyl)azetidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16 mg, 48% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br.), 7.93 (1H, m, 7.65 (1H, m), 7.44 (1H, m), 7.14 (1H, s), 6.99 (1H, br.), 4.72 (2H, m), 4.60 (2H, m), 4.48 (1H, m), 3.43 (2H, m), 3.15 (3H, s), 2.89 (2H, m), 2.63 (3H, s). m/z (ESI, +ve) 12.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[N:14][CH:15]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.CCOC(C)=O>[CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][N:5]([C:10]2[CH:15]=[N:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC1(O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1(O)CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
4-Methylpiperidin-4-ol (2.72 g, 23.6 mmol), 5-bromo-2-nitropyridine (3.2 g, 15.8 mmol), and tetrabutylammonium iodide (72 mg, 195 umol) in DMSO (20 ml) was heated to 120° C. for 18 hr. After cooling to room temperature, the reaction mixture was then diluted with EtOAc and washed with water (3×20 mL). The organic phase was then concentrated and triturated with ether to give 4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-ol as a yellow solid (2.55 g, 68.2%). (M+H)+=327.9 m/e.
Reaction SMILES: [C-]#N.[K+].[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[CH2:13]([OH:15])[CH3:14]>O>[OH:15][CH:13]([C:14]1[CH:11]=[CH:10][CH:9]=[CH:6][C:5]=1[F:4])[C:7]([C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[F:4])=[O:8]
Reactant: O=Cc1ccccc1F
Reactant: CCO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: O=C(c1ccccc1F)C(O)c1ccccc1F
Reaction time: 2 h

Procedure:
A mixture of potassium cyanide (2.0 g, 31 mmol), 2-fluorobenzaldehyde (26 g, 21 mmol), ethanol (30 ml) and water (30 ml) was heated at reflux for 1.5 h and then kept at -15° C. for 2 h. The precipitated compound was collected to give 20 g of 2-hydroxy-1,2-bis(2-fluorophenyl)ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[CH2:24][CH2:25]1)=[O:4]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1

Procedure:
To a solution of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (140 mg, 0.37 mmol) in DCM (4 mL) p-toluenesulfonic acid monohydrate (6 mg) and 3,4-dihydro-2H-pyran (38 μl, 0.42 mmol) were added at room temperature. After stirring for 1 h and 10 min saturated NaHCO3 was added. It was extracted with DCM, washed with brine, dried (MgSO4) and evaporated. The crude material was chromatographed over silica gel (prewashed with Et3N) (hexane:EtOAc—9:1 as eluent) yielding pure 3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (83 mg, 48%).
Reaction SMILES: OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[CH2:30][CH:29](C)[CH2:28][C:27](C)([CH3:32])[CH2:26]2)=[CH:21][CH:20]=1>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2([C:34]3[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=3)[CH2:30][CH2:29][CH2:28][CH:27]([CH3:32])[CH2:26]2)=[CH:23][CH:24]=1
Reactant: CC1CC(C)(C)CC(c2ccc(O)cc2)(c2ccc(O)cc2)C1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CC1CCCC(c2ccc(O)cc2)(c2ccc(O)cc2)C1

Procedure:
2,2-bis-(4-hydroxyphenyl)-propane and 1,1-bis-(4-hydroxyphenyl)-3,3,5-trimethyl-cyclohexane are particularly preferred.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.Cl.[NH:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH3:34].C(N(CC)CC)C.O>C1COCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[N:3]=[C:2]([N:33]([CH3:34])[CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:7]([C:8]#[N:9])=[C:6]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[C:5]=3[C:16]#[N:17])[N:21]=2)=[CH:30][CH:29]=1
Reactant: CNCC(=O)OC
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(N2CCCCC2)c1C#N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
100 mg (0.21 mmol) of the compound from Example 46A were dissolved in 2 ml of dry THF. 57 mg (0.41 mmol) of methyl sarcosinate hydrochloride and 86 μl (0.62 mmol) of triethylamine were then added in succession. The reaction mixture was stirred at RT for 10 h. 1 ml of water was added, and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were washed once with 3 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.I[CH:35]([CH3:37])[CH3:36]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:35]([CH3:37])[CH3:36])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)I
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(O)cc32)cc1
Product: CC(C)Oc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and 2-iodopropane (0.17 mL) as starting materials, N-[(4-dimethylaminophenyl)methyl]-7-isopropoxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (35 mg) was obtained.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][C:18](C)(C)C)=[O:16])[CH:9]=[CH:10][C:11]=1[Cl:12].O>CO.ClCCl>[NH2:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: CC(C)(C)OC(=O)CCc1ccc(Cl)c(N)c1
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCc1ccc(Cl)c(N)c1

Procedure:
Under reflux, 0.86 ml (11.7 mmol) of thionyl chloride was added dropwise to a solution of 1.0 g (3.91 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)propanoate in 20 ml of methanol. The mixture was stirred under reflux for 1.5 h and then, after cooling, diluted with dichloromethane. The solution was added to water, and after phase separation the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was dried under high vacuum. This gave 745 mg (90.3% of theory) of the target compound.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:21])[C:18](N)=[O:19].C(O)(=[O:24])C.Cl>O>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:21])[C:18]([OH:24])=[O:19]
Reactant: CC(=O)O
Reactant: CC(C(N)=O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: Cl
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 90 %

Procedure:
3.0 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionamide is refluxed in a mixture of 20 ml. of acetic acid and 30 ml. of concentrated hydrochloric acid for 3 hours. The solution is cooled and poured into water. The mixture is extracted with ethyl acetate and the extract is washed, dried and evaporated to yield 90% of 2-(5H-dibenzo[a,d] cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH:29](O)=[O:30]>C1(C)C=CC=CC=1>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH:29]=[O:30])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: O=CO
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Solvent: Cc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2NC=O)c1C
Reaction time: 9 h
Yield: 59.4 %

Procedure:
To a solution of the compound of Example 32 (0.20 g, 0.5 mmol) in toluene (2 mL), formic acid (0.21 g, 4.5 mmol) was added. The mixture was heated at reflux for 3 hours, additional formic acid (0.23 g, 5 mmol) was added and heating was continued for 9 hours. The mixture was concentrated and the residue was chromatographed on silica gel to provide the title compound (127 mg, 59%) as an off-white solid, m.p. 87-95° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[Cl:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([C@H:29]([NH2:32])[CH2:30][CH3:31])=[CH:24][C:23]=1[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C(O)(C)(C)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([NH:32][C@@H:29]([C:25]3[CH:24]=[C:23]([CH3:33])[C:22]([Cl:21])=[C:27]([CH3:28])[CH:26]=3)[CH2:30][CH3:31])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H](N)c1cc(C)c(Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2cc(Br)ccc2Cl)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC[C@@H](Nc1ccc(Cl)c(CN2CC(C(=O)OC(C)(C)C)C2)c1)c1cc(C)c(Cl)c(C)c1
Temperature: 100 °C

Procedure:
A mixture of INT 57 (250 mg, 0.693 mmol), amine INT 38 (137 mg, 0.693 mmol) and cesium carbonate (678 mg, 2.079 mmol) in toluene (4.5 mL) and tert-butanol (1.8 mL) was purged with argon for 10 minutes. Then, XPhos (66.1 mg, 0.139 mmol) and palladium acetate (15.56 mg, 0.069 mmol) were added, the vial was closed and heated at 100° C. for 3 hours. The reaction mixture was then diluted with EtOAc (35 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:32][O:33][CH:34]1[CH:39]([O:40][CH3:41])[CH:38]([O:42][CH3:43])[CH:37]([CH3:44])[O:36][CH:35]1[O:45][C:46](=O)[O:47]C1C=CC([N+]([O-])=O)=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH3:32][O:33][C@@H:34]1[C@H:39]([O:40][CH3:41])[C@@H:38]([O:42][CH3:43])[C@H:37]([CH3:44])[O:36][C@H:35]1[O:45][C:46](=[O:47])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2nccc(-c3ccc(N)cc3)n2)cc1
Reactant: COC1C(C)OC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)C1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nccc(-c3ccc(NC(=O)O[C@@H]4O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]4OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a mixture cooled in an ice bath of 112 mg (0.404 mmol) of 4-[2-(4-methoxyphenyl)-pyrimidin-4-yl]-phenylamine in 1.5 mL of dry THF was added dropwise via syringe 0.81 mL (0.40 mmol) of a 0.5 M solution of potassium hexamethyldisilazide in toluene over a 10-15 minute period. This solution was then added dropwise via syringe to a solution cooled in an ice bath of 126 mg (0.386 mmol) of carbonic acid 4-nitrophenyl ester 3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl ester in 2 mL of THF. The contents were allowed to gradually warm to room temperature and stir overnight and were added to cold saturated sodium bicarbonate. The mixture was extracted two times with ethyl ether and the combined extracts were dried (MgSO4). Concentration gave a red oil which was purified by chromatography on silica gel using 1:1 hexanes/EtOAc to afford 16 mg (8%) of Compound 234. 1H NMR (300 MHz, CDCl3) δ 8.79 (d, J=5.2 Hz, 1H), 8.55 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.53 (d, J=5.5 Hz, 1H), 7.05 (d, J=9.0 Hz, 2H), 6.84 (br s, 1H), 6.26 (d, J=1.7 Hz, 1H), 3.92 (s, 3H), 3.71-3.69 (m, 2H), 3.61 (s, 3H), 3.60 (s, 3H), 3.57 (s, 3H), 3.55-3.47 (m, 1H), 3.24 (t, J=9.4 Hz, 1H), 1.36 (d, J=6.1 Hz, 3H); MS (API-ES+) 510 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH2:8][NH:9]C(=O)C(F)(F)F)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[ClH:26]>CO.O.CCOCC>[ClH:26].[CH2:1]([S:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH2:8][NH2:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccccc1CNC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCS(=O)(=O)c1ccccc1CN
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(ethylsulfonyl)benzyltrifluoroacetamide (88 mg, 0.30 mmol) in methanol (11 mL) and water (0.74 mL) was added potassium carbonate (124 mg, 0.90 mmol). The mixture was heated to 65° C. and stirred under Ar overnight. The mixture was then concentrated to a colorless oil which was taken up in EtOAc and washed with a small amount of brine. The aqueous layer was extracted twice with CHCl3 and was then saturated with sodium chloride and further extracted with THF. The combined organic extracts were dried over MgSO4 and concentrated at reduced pressure. The residue was treated with 2 equivalents of 1.0 M HCl in ether. The resulting precipitate was collected by filtration and was dried on a high vacuum line to give the title compound as an off-white solid:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(O)[CH2:4]1.S(=O)(=O)(O)O.[OH-].[NH4+].[Cl-].[Na+]>O1CCOCC1>[CH3:1][N:2]([CH3:21])[CH:3]1[CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][CH2:9]1
Reactant: CN(C)C1CCc2ccccc2C(O)(c2ccccc2)C1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CN(C)C1C=C(c2ccccc2)c2ccccc2CC1
Reaction time: 0.05 h
Yield: 74.2 %

Procedure:
A mixture of 29.1 g of 7-dimethylamino-5-phenyl-5-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene and 290 ml of dioxane was refluxed under an inert gas and then 60 ml of 18 N sulfuric acid were added thereto. The mixture was stirred for 3 minutes and after cooling, was poured over ice. The pH was adjusted above 10 by addition of concentrated ammonium hydroxide and the mixture was saturated with sodium chloride and was extracted with ethyl acetate. The organic extracts were washed with aqueous sodium chloride solution, were dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 10-1 benzene-triethylamine mixture to obtain 20.2 g of 7-dimethylamino-9-phenyl-6,7-dihydro [5H] benzocycloheptene.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[BrH:38].C(O)(=O)C>C(OCC)C>[BrH:38].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CCCCCCCCCI
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodononane as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C.C(O)(=O)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][C:33]=1[S:40]([N:43]=[CH:44][N:45]([CH3:47])[CH3:46])(=[O:42])=[O:41].C([BH3-])#N.[Na+]>CO>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:19][C@H:16]2[CH2:15][CH2:14][C@@H:13]([O:12][C:11]3[C:2]([Cl:1])=[C:3]4[C:8](=[CH:9][CH:10]=3)[CH:7]=[N:6][CH:5]=[CH:4]4)[CH2:18][CH2:17]2)=[CH:34][C:33]=1[S:40]([N:43]=[CH:44][N:45]([CH3:46])[CH3:47])(=[O:42])=[O:41]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3cnccc3c2Cl)CC1
Reactant: CN(C)C=NS(=O)(=O)c1cc(C=O)ccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CN(C)C=NS(=O)(=O)c1cc(CN[C@H]2CC[C@@H](Oc3ccc4cnccc4c3Cl)CC2)ccc1Cl
Reaction time: 0.5 h
Yield: 90 %

Procedure:
34 mg (0.11 mmol) cis-4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexylamine (13) were dissolved in 5 ml MeOH and 22 mg (0.22 mmol) triethylamine were added. After the reaction was stirred 30 min, 65 mg (1.1 mmol) acetic acid, 60 mg (0.22 mmol) 2-chloro-N-dimethylaminomethylene-5-formyl-benzenesulfonamide (73) and freshly dried molecular sieves were added and the mixture was stirred for 30 minutes at room temperature. A solution of 20.5 mg (0.33 mmol) sodium cyanoborohydride in 1 ml methanol was added and the mixture was allowed to stand at room temperature overnight. The solvent was removed i. vac. The residue was dissolved in dichloromethane, washed with 1N NaOH and brine, dried over MgSO4 and evaporated. 53 mg of the title compound were isolated as crude product and used without further purification. Rt=0.87 min (Method #4). Detected mass: 535.2/537.1 (M+H+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:13][CH:12]=1
Reactant: Oc1ccc(CN2CCCCC2)nc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc(CN2CCCCC2)nc1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A solution of 6-piperidin-1-ylmethyl-pyridin-3-ol (0.225 g, 1.17 mmol), 1-bromo-3-chloro propane (0.23 mL, 2.34 mmol), and K2CO3 (0.483 g, 3.50 mmol) in acetone (10 mL) was heated to reflux temperature. After 10 h the reaction mixture was cooled to rt, diluted with acetone (50 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated, giving the crude title compound as an oil (0.250 g, 80%).
Reaction SMILES: [OH-].[K+].[CH2:3](Cl)/[CH:4]=[CH:5]/[CH2:6]Cl.[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]>[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>[CH:4]([CH:5]1[CH2:6][C:10]1([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH2:3]
Reactant: CCCCOC(=O)CC(=O)OCCCC
Reactant: ClC/C=C/CCl
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: C=CC1CC1(C(=O)OCCCC)C(=O)OCCCC
Yield: 34.1 %

Procedure:
Employing a reaction similar to that described in Example 1 except that a hydrocarbon solvent is included in the reaction mixture, 152 g 50% aqueous potassium hydroxide solution was added dropwise to a vigorously stirred solution of 64.5 g (0.52 mol) trans 1,4-dichlorobutene-2,112.5 g (0.52 mol) di-n-butyl malonate, 4.0 g tricaprylylmethylammonium chloride and 200 cc petroleum ether. Upon workup and distillation, 47.6 g (37.1% yield) of di-n-butyl 2-vinylcyclopropane-1,1-dicarboxylate (bp 101°-104° C. (0.30 mm)); nD24° 1.4556) was obtained. Infrared and proton nmr spectra were consistent with th desired vinylcyclopropane product. Attempts to carry out the reaction in the absence of the onium compound were unsuccessful.