Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](I)[CH3:30]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]1[CH2:25][N:24]([CH2:29][CH3:30])[C:23](=[O:26])[CH2:22]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C1CNC(=O)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC([C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)CC1=O
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-pyrrolidon-4-yl)pyrrolidine (38.5 g, 0.1 mol, the compound of Reference Example 1-6) in tetrahydrofuran (200 ml) was added 60% sodium hydride in oil (4.2 g, 0.1 mol) under ice-cooling, and the mixture was stirred for 1 hour. To the mixture was added ethyl iodide (8 rag, 0.1 mol), and after stirring at room temperature overnight, the reaction mixture was concentrated. The residue was extracted with ethyl acetate (500 ml), and the mixture was washed with water (200 ml) followed by a saturated sodium chloride aqueous solution. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (Wakogel™ C-300, chloroform) to obtain (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-ethyl-2-pyrrolidon-4-yl)pyrrolidine (40.3 g, yield: 97.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH3:11].C([Li])CCC.[I:17]I>C1COCC1.C(OCC)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([I:17])=[C:4]([F:9])[C:3]=1[O:10][CH3:11]
Reactant: II
Reactant: COc1c(F)cc(F)cc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(Cl)cc(F)c(I)c1F
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-3,5-difluoro-2-methoxybenzene (2.0 g, 0.01 mol) in THF at −75° C. was added n-butyl lithium (2.5M in hexanes 6.7 mL) and the resulting solution was stirred at −75° C. for 1 hour. A solution of iodine (5.1 g, 0.02 mol) in THF (10 mL) was added and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with ethyl ether (50 mL) and aqueous sodium thiosulfate (10%, 50 mL) was added and stirred for 1 hour. After separating the phases, the organic phase was dried (Na2SO4) and concentrated to give 1-chloro-3,5-difluoro-4-iodo-2-methoxybenzene as a white solid: mp 62-64° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].[C:8](Cl)(=[O:10])[CH3:9].N1C=CC=CC=1.O1CCCC1>C(Cl)(Cl)Cl>[C:8]([N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: O=C1NCCCN1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCNC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of 10 parts by weight of 1,3-diaza-cyclohexan-2-one, 11.8 parts by weight of acetylchloride, 8.7 parts by weight of pyridine, 50 parts by volume of tetrahydrofurane and 50 parts by volume of chloroform was stirred for 24 hours at room temperature, filtered and washed out with tetrahydrofurane chloroform (1:1). The combined solutions were evaporated to dryness, recrystallized from acetone/ethanol; 50 parts by volume of NaHCO3 -solution were added, and the mixture was extracted 3 times with 50 parts by volume of ethylacetate at a time. The combined organic solutions were dried over MgSO4, evaporated to dryness, and the residue was recrystallized from acetone/petrol-ether.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14](=[O:16])[NH2:15])(=[O:3])[NH2:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[C:14]([CH2:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:1](=[O:3])[NH2:2])(=[O:16])[NH2:15].[C:14]([CH2:13][O:12][C:7]1[CH:8]=[C:9]([S:18]([Cl:17])(=[O:20])=[O:19])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:1](=[O:3])[NH2:2])(=[O:16])[NH2:15]
Reactant: O=S(=O)(O)Cl
Agent: NC(=O)COc1ccccc1OCC(N)=O
Solvent: ClC(Cl)Cl
Product: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Temperature: 60 °C

Procedure:
1,2-Bis(carbamoylmethoxy)benzene was prepared by a known method (H-S Kim. et al., (1998) J. Heterocyclic Chem., 35, 177-181). 1,2-Bis(carbamoylmethoxy)benzene (4.4 g) was added to chlorosulfonic acid (13 ml) at 0° C. with good stirring. Chloroform (4 ml) was added and warmed to about 60° C. for 2 hours. The reaction mixture was poured into chopped ice. The precipitates were collected, and washed with cold water. The solids were again washed with acetonitrile, and dried in vacuo to yield the title compound (4.9g).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39]>>[F:23][C:18]1[CH:17]=[C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:38])[C:26]=3[CH3:39])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)[CH:21]=[CH:20][C:19]=1[CH3:22]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: Cc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1F
Product: Cc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(3-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.29-7.42 (m, 3H), 6.98 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.09 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.32 (s, 3H), 2.24 (s, 3H), 2.03 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H21F4NO3S, 466.1 (M−H). found 466.1.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][N:11]([CH2:23][C:24]1([CH3:27])[CH2:26][O:25]1)[C:12](=[O:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:27][C:24]([OH:25])([CH3:26])[CH2:23][N:11]([CH3:10])[C:12](=[O:22])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CN(CC1(C)CO1)C(=O)OCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(CC(C)(O)Cn1cc([N+](=O)[O-])nc1Cl)C(=O)OCc1ccc(F)cc1
Yield: 65 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (0.953 g, 6.46 mmol) and 4-fluorobenzyl N-methyl-(2-methyloxiran-2-ylmethyl)carbamate (1.964 g, 7.75 mmol) were dissolved in ethanol (20 ml). To the solution, sodium acetate (0.583 g, 7.11 mmol) was added followed by stirring under reflux overnight. The reaction mixture was concentrated under reduced pressure. To the residue, ethyl acetate and water were added, and the solution was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford 4-fluorobenzyl [3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-N-methylcarbamate (1.683 g, yield 65%) as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]([CH2:34][CH2:35][CH3:36])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31]CC)=[O:30])=[CH:24][CH:23]=2)=[S:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1>O.C(O)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][C@@H:18]([CH2:34][CH2:35][CH3:36])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=2)=[S:20])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=S)Nc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of K2CO3 (962 mg) in water (15 ml) was added to a solution of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (1.23 g) in ethanol (50 ml). The whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove ethanol completely that a small amount of purified water was added to the residue, and then the mixture was concentrated under reduced pressure. The residue was dissolved in purified water and washed with ethyl acetate. The aqueous layer was acidified with 1N HCl, and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na2SO4. Then, the solvent was evaporated under reduced pressure and the crude product was recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-4-methylthiobutanamide (800 mg).
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]1[NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21].[OH-].[Ca+2].[OH-].[CH3:30]I>CC(C)=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]1[NH:19][C:20](=[N:22][C:23]([O:25][CH3:26])=[O:24])[S:21][CH3:30]
Reactant: CI
Reactant: CCCSC1=C(Cc2ccccc2)C(NC(=S)NC(=O)OC)C(=N)C=C1
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCSC1=C(Cc2ccccc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-iminophenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (3.88 g.; 0.01 mol) in acetone (40 ml.) and water (10 ml.) there is added calcium hydroxide (0.74 g.; 0.01 mol). The mixture is stirred at room temperature for 4 hours and then is added methyl iodide (1.42 g.; 0.01 mol). The mixture is stirred at room temperature for 4 hours and the precipitate collected and dried to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13](Br)[CH:14]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1B(O)O)(=[O:20])[CH3:19].C([O-])(=O)C.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1[C:13]1[CH:14]=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH2:1])[N:7]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cccc(N)n2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cccc(N)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 30.8 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 221a (354 mg, 1.2 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (1.20 g, 3.0 mmol), Pd(dppf)Cl2 (99 mg, 0.12 mmol), potassium acetate (235 mg, 2.4 mmol), K3PO4 (532 mg, 2.4 mmol), acetonitrile (12 mL), and water (10 drops). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 30:1 ethyl acetate/methanol to afford 221b (210 mg, 31%) as a yellow solid. MS-ESI: [M+H]+ 568.3
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].[SH2:9]>>[C:2]([SH:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:1])[CH3:3]
Reactant: C=C(C)CC(C)(C)C
Reactant: S
Product: CC(C)(C)CC(C)(C)S
Temperature: 45 °C

Procedure:
200 ml of dry sulphonated Amberlyst 15 resin are placed in a tubular reactor with a capacity of approximately 420 ml (length: 135 cm; bore: 20 mm). Liquid diisobutylene at a rate of 112 g/h (that is 1 mole/h) and 136 g/h of gaseous H2S (that is 4 moles of H2S per 1 of diisobutylene) are introduced continuously at the head of the reactor at a pressure of 10 bars. The reactants are mixed intimately before their entry into the reactor, where the reaction mixture is maintained at the temperature of 45° C. The liquid flowing continuously from the reactor is collected and the remaining hydrogen sulphide is degassed. Analyses are carried out both on the crude liquid reaction products and on the gaseous effluents from the reaction, with the aim of establishing the complete balance of the reaction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>C(OCC)(=O)C>[CH2:19]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[F:1])[CH3:20]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-5-nitro-benzoic acid (0.269 g, 1.45 mmol) in 3 mL ethanol, was added concentrated sulfuric acid (0.5 ml). The solution was refluxed under argon for 3 hours. The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo to give pure 2-fluoro-5-nitro-benzoic acid ethyl ester.
Reaction SMILES: [O-:1][P:2]([O:5]P([O-])([O-])=O)(=[O:4])[O-:3].[Ca+2:10].[Ca+2].C(=O)([O-])[O-].[Ca+2]>>[P:2]([O-:5])([O-:4])([O-:3])=[O:1].[Ca+2:10].[Ca+2:10].[Ca+2:10].[Ca+2:10]
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]

Procedure:
Calcium pyrophosphate was reacted with calcium carbonate by a conventional method, and calcined to obtain tetracalcium phosphate in powder form. 2 grams of this powder was mixed with 1 g of a setting solution prepared by dissolving 0.1 g of chitosan ("Flonac N" made by Kyowa Yushi Kogyo K.K.) and 3 g of saccharose in 10 g of an aqueous solution of 40% citric acid. A plastic gum-like composition was obtained and this composition set in about 5 minutes to produce a setting material having a high strength.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[C:19]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:18])([F:17])[F:1])=[CH:10][CH:11]=1)#[CH:19]
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a stirred suspension of the product of Example 36, Step A, (0.21 g, 1 mmol) and K2CO3 (0.166 g, 1.1 mmol) in anhydrous MeOH (5 mL) was added a solution of dimethyl 1-diazo-2-oxopropylphosphonate (0.212 g, 1.1 mmol) in anhydrous MeOH (1 ml) and the mixture was stirred overnight at room temperature. The solvent was evaporated to dryness and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4, and filtered. The filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the product (0.21 g, 85.4%), as creamy paste, which was used as such in next step. 1H-NMR (CDCl3) 3.11 (s, 1H); 7.25-7.31 (m, 3H); 7.44-7.55 (m, 4H); 7.73 (d, 1H, J=7.69 Hz).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[C:10](Cl)[CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1(B(O)O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[C:10]([C:26]4[C:27]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH:23]=[CH:24][CH:25]=4)[CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=C1c2c(Cl)cccc2CC1C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: O
Product: O=C1c2c(cccc2-c2cccc3ccccc23)CC1C1CCCCC1
Temperature: 125 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Using a method similar to Example 16d), 2.73 g (0.011 mol) of 2-cyclohexyl-7-chloro-1-indanone, 2.24 g (0.013 mol) of naphthylboronic acid and 2.6 g (24.6 mmol) of sodium carbonate were placed in 55 ml of ethylene glycol/5 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 18 mg (0.09 mmol) of palladium acetate and 0.15 g (0.27 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 60 ml of water, the aqueous phase was extracted 4 times with 60 ml each time of ether, the combined ether phases were washed with 60 ml of water and 60 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 3.0 g of 2-cyclohexyl-7-(1-naphthyl)1-indanone.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=1)[CH3:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>[Pd].C([O-])(=O)C.C(#N)C>[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:19][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=2)=[CH:16][CH:15]=1)[CH3:12]
Reactant: C=Cc1ccc(OCC)cc1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1ccc(C=Cc2cc(F)c(F)c(F)c2)cc1

Procedure:
A mixture of 10.5 g of 1-bromo-3,4,5-trifluorobenzene, 7.4 g of p-ethoxystyrene, 0.25 g of Pd acetate, 0.6 g of tri-o-tolylphosphine, 7 g of triethylamine and 125 ml of acetonitrile is heated at reflux until completion of the reaction. Customary working-up gives 1-(p-ethoxyphenyl)-2-(3,4,5-trifluorophenyl)ethene (C 76 I), which is hydrogenated on PD-C (5%) in THF to give 1-(p-ethoxyphenyl)-2-(3,4,5-trifluorophenyl)ethane, C 45 I.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrBr
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Temperature: 5 °C
Reaction time: 18 h
Yield: 42.1 %

Procedure:
A solution of 32.5 g (163 mmol) of tert-butyl 4-oxo-piperidine-1-carboxylate in 200 ml of chloroform was treated with 24.0 g (168 mmol) of disodium hydrogen phosphate and cooled to 5° C. A solution of 27.9 g (175 mmol) of bromine in 75 ml of chloroform was added dropwise during 1 hour, thereafter the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was worked-up by extraction with ice-water and methylene chloride, the organic phase was dried over magnesium sulphate, filtered and the solvent was distilled off in a water-jet vacuum. The crude product (38 g) was chromatographed on silica gel with methylene chloride and ethyl acetate as the eluent. The thus-obtained product was recrystallized from ethyl acetate and n-hexane. There were obtained 19.1 g (42% of theory) of tert-butyl 3-bromo-4-oxo-piperidine-1-carboxylate as a pale yellow solid; MS: 277, 279 (M)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.C(O[C:26]1(O[Si](C)(C)C)[CH2:28][CH2:27]1)C.[B-]C#N.[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[CH:26]1([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)[CH2:28][CH2:27]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CC(c2ccccc2N2CCN(C3CC3)CC2)CC(C)(C)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b) in methanol (3 mL) were added [(1-ethoxycyclopropyl)oxy]trimethylsilane (105 mg, 0.6 mmol), sodium cyanotrihydroborate (28.3 mg, 0.45 mmol), acetic acid (60.1 mg, 1 mmol) and molecular sieves 3A (50 mg) in that order, followed by stirring for 5 hours and 30 minutes at an external temperature of 80° C. Ethyl acetate was added to the reaction mixture, which was filtered through Celite, and the filtrate was concentrated. Water was then added to the residue, extraction was performed with ethyl acetate, and the organic layer was washed with 2N aqueous solution of sodium hydroxide and brine. The organic layer was dried over magnesium sulfate, the desiccant was filtered off, and then the filtrate was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-cyclopropyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a white solid. The obtained compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate (0.040 mL, 0.160 mmol) was added. The solution was concentrated, and hexane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant hexane solution was removed and the resulting solid residue was dried under reduced pressure to give 37.7 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][C:26]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:21]([Cl:40])=[CH:20][N:19]=1>>[Cl:40][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][C:26]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CN(C)c1ccc(Nc2nc(Cl)ncc2Cl)c(S(=O)(=O)N(C)C)c1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N(C)C)cc4S(=O)(=O)N(C)C)n3)cc2CC1

Procedure:
The title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-dimethylamino-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a yellow foam (0.053 g, 45%). MP: 72-82° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.75 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.04 (s, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.20 (dd, 1H, J=8.1 Hz and J=2.0 Hz, 1H), 7.15 (d, J=2.8 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 6.91 (dd, J=9.1 Hz and J=3.0 Hz, 1H), 6.88 (s, 1H), 3.53 (t, J=5.7 Hz, 2H), 3.36 (s, 3H), 3.02 (s, 6H), 2.91-2.80 (m, 4H), 2.76-2.66 (m, 12H). MS: 574.17 (MH)+.