Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]3[N:21]([CH2:24][C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[N:22]=[N:23][C:18]3=[N:17][CH:16]=2)[CH2:11]1)C(=O)OC(C)(C)C.Cl>ClCCl>[CH3:1][NH:2][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]3[N:21]([CH2:24][C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[N:22]=[N:23][C:18]3=[N:17][CH:16]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Agent: Cl
Solvent: ClCCl
Product: CN[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of tert-butyl methyl{(3R)-1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-yl}carbamate (101 mg, 0.219 mmol) in dichloromethane (2.2 mL) was added hydrochloric acid (4 N in dioxane, 1.10 mL, 4.39 mmol). The reaction mixture was allowed to warm to room temperature as the ice bath melted, stirred for 3 hrs, then diluted with dichloromethane (20 mL). The organic solution was washed with saturated sodium bicarbonate (5 mL) and separated. The aqueous solution was extracted with dichloromethane (3×20 mL) and the organics were combined and concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 12M column eluting with chloroform/7 N ammonia in methanol (0.1-3.5%) to afford the title compound as the free base which was converted to the dihydrochloric acid salt (56 mg, 63%)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)cc1
Yield: 89 %

Procedure:
First, 25.2 g (75 mmol) of MQ obtained in section (L) mentioned above was suspended to 500 ml of methylene chloride in an 1-liter three-necked flask. To this suspension, 50 ml of a methylene chloride solution containing 19.0 g (75 mmol) of boron tribromide was added dropwise over a period of about 30 minutes with stirring under a nitrogen atmosphere. Then, the reaction mixture was refluxed for 10 hours with stirring under the nitrogen atmosphere. After the reaction was completed, the flask was cooled, and the solids that precipitated were obtained by filtration. The solids were washed with methylene chloride and dried. Then the solid was recrystallized with dimethylsulfoxide. In this way, 21.6 g (yield, 89%) of 4-hydroxy-p-quaterphenyl (HQ) was obtained as a white solid. The liquid-crystal transition temperature of HQ was 352° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]([CH3:20])[CH3:19])=[C:16]([S:21]([C:23]([F:26])([F:25])[F:24])=[O:22])[C:15]([C:27](=[N:29][OH:30])[NH2:28])=[N:14]1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([N:18]([CH3:20])[CH3:19])=[C:16]([S:21]([C:23]([F:25])([F:26])[F:24])=[O:22])[C:15]([C:27]2[N:28]=[CH:32][O:30][N:29]=2)=[N:14]1
Reactant: CN(C)c1c(S(=O)C(F)(F)F)c(C(N)=NO)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Product: CN(C)c1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 4375 %

Procedure:
1-(2,6-dichloro-4-trifluoromethylphenyl)-5-dimethylamino-4-trifluoromethylsulfinyl-3-pyrazolecarboxamide oxime 0.59 g (1.18 mmol) was dissolved in 5 ml of trimethyl orthoformate, and then 5 mg of p-toluenesulfonic acid monohydrate was added. After the mixture was was stirred at room temperature for 3 hrs, trimethyl orthoformate was distilled off in vacuo, and then added 40 ml of ethyl acetate. The ethyl acetate solution was washed twice with 15 ml of aqueous saturated sodium hydrogencarbonate solution, and then once with 15 ml of aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 583 mg (1.15 mmol) of the title compound as a colorless crystal. Yield 97%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.CCCCCC.O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1ccc(CBr)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
In 840 ml of carbon tetrachloride were suspended 100 g of 5-methyl-2-thiophenecarboxylic acid, 125.2 g of N-bromosuccinimide and 7 g of benzoyl peroxide. The suspension was heated to 90° C. with vigorous agitation. After the reaction started, the reaction temperature was raised to 100° C. and agitation was continued for 2 hours at the same temperature. The reaction mixture was cooled to 0° C., and 500 ml of n-hexane was added thereto. Precipitated crystals were collected by filtration and washed with 100 ml of n-hexane. The obtained crude crystals were suspended in 2 of water and the suspension was stirred at room temperature for 10 minutes. The suspended crystals were collected again by filtration and washed with 200 ml of water. The obtained crystals were recrystallized from ethanol-water to give 84 g of the desired 5-bromomethyl-2-thiophenecarboxylic acid as colorless crystals.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C2=CCCCCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C2CCCCCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 73 %

Procedure:
(2-Cyclohept-1-enyl-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (Example 75) ) is hydrogenated in MeOH in presence of 10% Pd/C under a hydrogen pressure of 100 bar at 100° C. for 18 h. Filtration, evaporation of the solvent and purification of the residue by preparative HPLC on a C-18 column with a H2O/MeCN gradient provided (2-Cycloheptyl-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone in 73% yield as colourless gum (M+H+: 509.6.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:14]([OH:17])([CH3:16])[CH3:15])[C:11]([OH:13])=O)=[C:5]([CH3:18])[C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:14]([OH:17])([CH3:15])[CH3:16])[C:11]([NH:31][NH:30][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([F:23])=[CH:33][CH:32]=2)=[O:13])=[C:5]([CH3:18])[C:4]=1[C:19]([F:20])([F:21])[F:22])#[N:2]
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 92.3 %

Procedure:
(R)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxy-3-methylbutanoic acid (500 mg, 1.58 mmol) and 4-fluorobenzohydrazide (244 mg, 1.58 mmol) were mixed together in THF (20 mL) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (214 mg, 1.58 mmol), TEA (0.33 mL, 2.37 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (454 mg, 2.37 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete, ethyl acetate (50 mL) was added and the solution was washed with 5% citric acid (2×40 mL), 5% NaHCO3 (2×40 mL) followed by water (40 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (660 mg, 92%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.81 (br s, 1H), 8.02-7.95 (m, 2H), 7.69-7.63 (m, 1H), 7.27-7.21 (m, 2H), 7.01-6.95 (m, 1H), 5.54 (d, J=7 Hz, 1H), 4.14 (d, J=8 Hz, 1H), 2.38 (s, 3H), 1.47 (s, 3H) and 1.43 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:16]#[N:17])=[CH:5][C:6]([CH2:10][CH2:11][O:12]C(=O)C)=[CH:7]OC.[BrH:19].CC(O)=O>C(O)(=O)C>[Br:19][C:16]1[C:4]([C:3]([O:2][CH3:1])=[O:18])=[CH:5][C:6]([CH2:10][CH2:11][OH:12])=[CH:7][N:17]=1
Reactant: COC=C(C=C(C#N)C(=O)OC)CCOC(C)=O
Reactant: Br
Solvent: CC(=O)O
Product: COC(=O)c1cc(CCO)cnc1Br
Temperature: 35 °C

Procedure:
Into a 1L three-neck round-bottom flask with a stirrer bar, nitrogen inlet and condenser were added 20 g (78.974 mmol) of methyl-4-(2-acetyloxyethyl)-2-cyano-5-methoxypenta-2,4-dienoate, which was dissolved in 55 ml acetic acid and heated to 35° C. The solution was slowly treated over a period of ½ h with 85.21 g (237 mmol) HBr/HOAc at 35-40° C. with occasional cooling. After the addition was completed the solvents were evaporated at 40° C. and 30 mm Hg and the residue was charged while stirring with a mixture of 60 ml water and 15 ml methanol. The reaction mixture was treated with 3.3 g charcoal and heated for ½ h at 40° C. The charcoal was filtered off and the methanol was distilled off under reduced pressure. The reaction mixture was evaporated and the residue was chromatographed at 100 g silica gel using a solvent mixture of Heptane:Ethyl acetate (2:1 v/v).
Reaction SMILES: O1CCOCC1.[OH-].[K+].C(N(CC)[C:12](=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([N:24]1[C:28]([I:29])=[CH:27][N:26]=[CH:25]1)[C:20]([OH:23])([CH3:22])[CH3:21])C.Cl>C(OCC)(=O)C>[I:29][C:28]1[N:24]([CH:19]2[C:14]3[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:30])[O:23][C:20]2([CH3:22])[CH3:21])[CH:25]=[N:26][CH:27]=1
Reactant: CCN(CC)C(=O)c1ccccc1C(n1cncc1I)C(C)(C)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1I
Temperature: 60 °C
Reaction time: 13.5 h

Procedure:
Dioxane (22 mL) and 1M aqueous KOH (22 mL, 22 mmol) are added to N,N-diethyl-2-[2-hydroxy-1-(5-iodo-imidazol-1-yl)-2-methyl-propyl]-benzamide (1.65 g) and the mixture is heated to 60° C. After 13.5 h, the mixture is cooled to 0° C. and acidified to pH=1 with conc. HCl. The mixture is heated to 60° C. After 24 h, the mixture is diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and filtered through a cotton plug. Concentration in vacuo gave an orange solid, which is purified by silica gel flash chromatography (methylene chloride-methanol, 49:1) to give a crystalline yellow solid; MS (ESI) m/z 369.0 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (s, 3 H), 1.57 (s, 3 H), 5.39 (s, 1 H), 7.19 (s, 1 H), 7.28 (br. d, J=7.6 Hz, 1 H), 7.39 (s, 1 H), 7.59 (td, J=7.6, 1.3 Hz, 1 H), 7.66 (td, J=7.6, 1.3 Hz, 1H), 8.27 (dd, J=7.6, 1.4 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Si:18]([O:17][C@H:8]([CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][O:6][C:5]1[CH:25]=[CH:26][C:2]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:3][C:4]=1[C:27]([F:30])([F:29])[F:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(Br)cc1C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(-c2ccccc2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 108 %

Procedure:
Prepared according to the method as described in Example 33a) from (2R)-1-(4-bromo-2-trifluoromethylphenoxy)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)butane (1.0 g, ~67% pure), benzeneboronic acid (0.18 g), tetrakis(triphenylphosphine)palladium(0) (0.035 g), toluene (10 ml), ethanol (2 ml) and aqueous sodium carbonate (2 M, 1.45 ml) with heating at 120° C. for 1 hour. After work up the residue was purified by chromatography over silica eluting with ethyl acetate:hexane (1:9) to give an impure sample of the sub-title compound as a light brown oil (0.80 g, ~67% pure).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=2)=[CH:14][C:13]=1[C:29]1[CH:38]=[CH:37][C:36]2[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=2[CH:30]=1)[CH2:4][CH2:5][CH3:6]>O1CCCC1>[CH2:3]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][C:13]=1[C:29]1[CH:38]=[CH:37][C:36]2[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:41])([CH3:42])[C:31]=2[CH:30]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCNCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 19.5 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 410 mg (10 mmol) of sodium hydroxide with 360 mg (0.7 mmol) of ethyl 4′-(3-butylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 5a) in 30 ml of tetrahydrofuran. 70 mg of 4′-(3-butylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=238° C., yield=20%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 4 & 5, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) was heated at reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and the residue triturated with petroleum ether. The crude product was collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether afforded the desired product as a yellow solid in 80% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH:18]([CH3:20])[CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH:18]([CH3:20])[CH3:19])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:21]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CC(C)C1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CC(C)C1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5-isopropyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.02 (s, 1H), 7.83 (dd, J=7.1, 2.2 Hz, 1H), 7.67 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (m, 2H), 7.53 (m, 1H), 7.52 (m, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.05 (dd, J=3.6, 1.3 Hz, 1H), 7.02 (dd, J=5.0, 3.7 Hz, 1H), 4.21 (d, J=14.4 Hz, 1H), 3.90 (d, J=14.4 Hz, 1H), 2.81 (m, 1H), 0.91 (m, 6H); Anal. Calc. for C22H19ClFNO2S: C, 63.53, H, 4.60; N, 3.37. Found: C, 63.34, H, 4.92; N, 2.97.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH3:18][C:19]([CH3:23])=[CH:20][CH2:21]Br.[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:19]([CH3:23])([CH3:18])[CH:20]=[CH2:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: CC(C)=CCBr
Agent: Cl
Agent: [In]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(C)(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.31 g; 1.09 mmol), 3,3-dimethylallyl bromide (90%; 1.40 mL; 10.8 mmol) and indium (1.26 g; 11.0 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) and stirred vigorously over 18 hours. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude oil. The crude oil was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH3:17][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(N)ccc2C)nc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask containing 5-amino-2-methyl-phenylboronic acid pinacol ester (348 mg, 1.5 mmol), 2-chloro-5-methylpyridine (381 mg, 3 mmol), Pd(PPh3)4(192 mg, 0.15 mmol) is added toluene (12 ml), EtOH (3 ml) and 2M aqueous Na2CO3 solution (3 ml). The flask is purged with argon and sealed. The mixture is stirred at 90° C. for 18 hours, cooled to room temperature and then water (20 ml) and ethyl acetate (20 ml) are added. The organic layer is separated, washed with brine, dried over MgSO4 and concentrated. The residue is purified by silica gel flash chromatography, eluted with 2% methanol in dichloromethane to afford 4-Methyl-3-(5-methylpyridin-2-yl)aniline as a brown oil. LC-MS m/z: 199.1 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH:6]([CH:9]=[CH:10][C:11]#[N:12])[CH2:5][CH2:4]1.[BH4-].[Na+].[H][H].Cl>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:12][CH2:11][CH2:10][CH2:9][CH:6]1[CH2:5][CH2:4][C:3]([N:2]([CH3:19])[CH3:1])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: CN(C)C1(c2ccccc2)CCC(C=CC#N)CC1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(CCCN)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(4-Dimethylamino-4-phenyl-cyclohexyl)-acrylonitrile (400 mg, 1.57 mmole) was dissolved in methanol (25 ml). Nickel(II) chloride hexahydrate (747.6 mg, 3.14 mmole) was added to the solution. NaBH4 (594 mg, 15.7 mmole) was then added in portions with ice water cooling. A black precipitate was formed accompanied by evolution of hydrogen. Once addition was complete, stirring was continued at 20° C. for 1 h. Working up was performed by combining the reaction mixture with 1M hydrochloric acid (15 ml). The black precipitate was filtered out on Celite and thoroughly washed with 1M hydrochloric acid (3×7 ml). The hydrochloric, aqueous-methanolic solution was reduced to half its volume in order to remove the methanol. The remaining aqueous phase was extracted with ether (3×15 ml) to remove neutral substances. The batch was then alkalised (pH 11) by addition of 2M NaOH, resulting in the formation of a bulky precipitate which did not dissolve even on addition of EE. The precipitate was filtered out and washed with water (1×3 ml) and EE (3×5 ml). The two phases of the clear mother liquor were separated. The aqueous phase was extracted with EE (3×15 ml). The combined extracts were washed with NaCl-solution (2×10 ml), dried over sodium sulfate and the solvent removed by distillation. The resultant residue was the mixture of the diastereoisomers of [4-(3-aminopropyl)-1-phenylcyclohexyl]dimethylamine (203 mg, light yellow oil, 50%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].[Zn].O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:20]#[N:21])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Cl)cc2)CCC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#N)cc2)CCC1
Temperature: 25 °C

Procedure:
A mixture of [1-(4-Chloro-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester 1-1 (prepared according to WO2008/070016; 1.57 g, 5.6 mmol), Zn(CN)2 (395 mg, 3.37 mmol), Pd2(dba)3 (257 mg, 0.28 mmol), dppf (311 mg, 0.56 mmol), Zinc powder (219 mg, 3.37 mmol) and 20 mL of DMF was heated to 100.deg.C for 2 hrs under nitrogen atmosphere. After cooling to room temperature, the mixture was poured into water and extracted with EA for three times. The combined EA layer was washed with water, brine and concentrated to give a residue, which was purified by silica gel chromatography eluting with EA/PE (3/1) to give 1.23 g of compound 1-2. MS (ESI) m/e (M+H+): observed=273.2, calculated=273.2.