Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)C1C=CC=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[CH:47]1([C:50]2[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:51]=2[C:52](O)=[O:53])[CH2:49][CH2:48]1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>>[CH:47]1([C:50]2[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:51]=2[C:52]([NH:44][C@H:40]2[CH2:41][CH2:42][CH2:43][C@@H:39]2[NH:38][C:35]2[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=2)=[O:53])[CH2:48][CH2:49]1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1c(F)cccc1C1CC1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1C(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(F)cccc1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared according to the procedure for 2-(difluoromethyl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 65) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 100 mg, 0.35 mmol) and 2-cyclopropyl-6-fluorobenzoic acid (CAS number 1603213-26-8; 64 mg, 0.35 mmol) except to this was added EDC (68 mg, 0.354 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (48 mg, 0.35 mmol) and triethylamine (0.1 ml, 0.71 mmol) and the reaction was stirred at room temperature for a further 1 hour. The reaction mixture was partitioned between DCM and water, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) and then triturated with heptane/diethyl ether to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.C(=O)(O)[O-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N)cc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Temperature: 0 °C
Yield: 91.2 %

Procedure:
To a solution of 1-(4-amino-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.5 g, 5.5 mmol), in 1:1 acetone:water (12 mL) was added sodium bicarbonate (1.2 g, 13.7 mmol). The resulting solution was cooled to 0° C. and benzyl chloroformate (2.8 mL, 8.2 mmol, 50% solution in toluene) was added dropwise. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5:5 EtOAc:Pet. ether) to provide the title compound (2.05 g, 92%) as off white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH:18]2[CH2:20][CH:10]([CH2:11][C:12]3[CH:13]=[C:14]([OH:21])[CH:15]=[CH:16][C:17]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH:23](Cl)([F:25])[F:24].[OH-].[K+]>O1CCOCC1>[CH2:1]([N:8]1[CH2:19][CH:18]2[CH2:20][CH:10]([CH2:11][C:12]3[CH:13]=[C:14]([O:21][CH:23]([F:25])[F:24])[CH:15]=[CH:16][C:17]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)CC1CC2CN(Cc2ccccc2)C1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)Oc1ccc2c(c1)CC1CC2CN(Cc2ccccc2)C1

Procedure:
11-Benzyl-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-5-ol (572 mg, 2.05 mmol) was stirred in dioxane (5 mL) and H2O (1 mL) at reflux under a balloon of freon (HCF2Cl). To this was added 3N KOH dropwise so as to maintain a pH˜12. The consumption of starting material was monitored by TLC for over 2 hours. The reaction was cooled, diluted with H2O (40 mL) and extracted with EtOAc. The organic layer was washed with a sat. aq. Na2CO3 soln. (25 mL) and brine (25 mL), dried (MgSO2), filtered and concentrated to an oil (620 mg, 92%). GCMS m/e 329 (M+).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1.[Cl:18][CH2:19][C:20](N(C)C)=[O:21].Cl>O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:15]([C:20](=[O:21])[CH2:19][Cl:18])=[CH:16][CH:17]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C(=O)CCl
Reactant: Fc1ccc(-c2ccco2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCl)c1ccc(-c2ccc(F)cc2)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.60 g (21.98 mmol) of n-butyllithium (2.5N in n-hexane) are added dropwise to 4.44 g (27.41 mmol) of 2-(4-fluorophenyl)furan in 40 ml of absolute tetrahydrofuran at -75° C. After stirring for 45 min, 5.21 g (42.86 mmol) of 2-chloro-N,N-dimethylacetamide in 20 ml of absolute tetrahydrofuran are added at -75° C. After 60 min, the mixture is poured into 200 ml of ice-water, neutralized at 0° C. with 2N hydrochloric acid and extracted 6× with 60 ml of ethyl acetate each time, the combined organic phases are washed 2× with 20 ml of water each time, dried over sodium sulphate and filtered, and the solvent is stripped off. The product is purified by column chromatography (280 g of silica gel 60; solvent: PE/EA 20:1), recrystallized from ethanol and digested with diisopropyl ether.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].[NH2:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]2[C:21]=1[CH2:22][O:23][C:24]2=[O:30]>C(#N)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[N:19]/[C:20]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]3[C:21]=2[CH2:22][O:23][C:24]3=[O:30])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(C=O)cc1
Reactant: Nc1cc(F)cc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CN(C)Cc1ccc(/C=N/c2cc(F)cc3c2COC3=O)cc1
Yield: 53.1 %

Procedure:
To a stirred mixture of 4-((dimethylamino)methyl)benzaldehyde (4 g, 24.5 mmol) and anhydrous magnesium sulfate (15.8 g, 111.5 mmol) in anhydrous acetonitrile (100 mL) was added 4-amino-6-fluoroisobenzofuran-1(3H)-one (4 g, 22.3 mmol) at 0° C. After the addition, the mixture was stirred at reflux for 3 days. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product, which was re-crystallized with isopropanol to give the title compound (3.7 g, yield 55%). LC-MS (ESI) m/z: 314 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:15][C:16]1[CH:17]=[C:18]([NH:24][C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:19]=[CH:20][C:21]=1[C:22]#[N:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:24][C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:17][C:16]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1ccc(C#N)c(N)c1
Reactant: Cc1cccc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cccc(Nc2cc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)ccc2C#N)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Dioxane (1.0 mL), 2-chloro-6-methylpyridine (0.035 mL, 0.32 mmol) and cesium carbonate (138 mg, 0.424 mmol) were added to tert-butyl rel-{(1R,2S)-2-[(3-amino-4-cyanophenyl)amino]cyclohexyl}carbamate (70 mg, 0.21 mmol). The reaction mixture was purged with argon, and then palladium (II) acetate (5 mg, 0.02 mmol) and Xantphos (18 mg, 0.032 mmol) were added. The reaction mixture was purged with argon, and then heated to 80° C. After 12 hours, the reaction mixture was cooled to room temperature, filtered through celite (washed with chloroform), and diluted with water. The organics were separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-50% acetone/hexanes, linear gradient) to afford tert-butyl rel-[(1R,2S)-2-({4-cyano-3-[(6-methylpyridin-2-yl)amino]phenyl}amino)cyclohexyl]carbamate. The solid was diluted with hydrochloric acid (4.0 M solution in dioxanes, 1.0 mL, 4.0 mmol). After 10 minutes, the mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (0.5 mL). To this solution were added hydrogen peroxide (30% solution in water, 0.020 mL, 0.20 mmol) and sodium hydroxide (4.0 N in water, 0.050 mL, 0.20 mmol). The reaction mixture was stirred until complete consumption of the intermediate nitrile was observed. The reaction mixture was purified directly by reverse phase HPLC (20-60% acetonitrile/water with 0.1% TFA, linear gradient) to afford rel-4-{[(1R,2S)-2-aminocyclohexyl]amino}-2-[(6-methylpyridin-2-yl)amino]benzamide TFA salt. MS ESI calc'd. for C19H26N5O [M+H]+ 340. Found 340. 1H NMR (500 MHz, CD3OD) δ 8.02-7.94 (m, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.02-6.95 (m, 2H), 6.65 (d, J=8.9 Hz, 1H), 3.97 (s, 1H), 3.56-3.47 (m, 1H), 2.58 (s, 3H), 1.92-1.82 (m, 3H), 1.82-1.73 (m, 1H), 1.73-1.60 (m, 2H), 1.60-1.45 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH2:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][C:13]=1[NH2:21]>>[NH2:21][C:13]1[CH:14]=[C:15]([C:16]2[O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[N:9]=2)[CH:19]=[CH:20][C:12]=1[O:11][CH3:10]
Reactant: Nc1cc(Cl)ccc1O
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(-c2nc3cc(Cl)ccc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 4-chloro-2-aminophenol (429 mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitle compound was obtained, 111 mg (10%). 1H NMR (CDCl3) δ 7.70(d, J=1.9 Hz, 1H), 7.65(dd, J=1.9, 8.3 Hz, 1H), 7.59(d, J=1.9 Hz, 1H), 7.46(d, J=8.3 Hz, 1H), 7.28(dd, J=1.9, 8.3 Hz, 1H), 6.90(d, J=8.3 Hz, 1H), 3.96(s, 3H). MS 275 m/z (M+H)+.
Reaction SMILES: [CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](=[O:22])[CH3:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:23]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=[C:5]12)([CH3:3])[CH3:2].[CH3:34][Mg+].[Br-]>C1COCC1>[CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[C:13]([C:20]([OH:22])([CH3:34])[CH3:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:23]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:27]=[CH:26][C:24]=3[N:25]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CC(=O)c1cnc(N2CCn3c(nc4ccc(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a solution of 1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (20 mg, 0.04 mmol, prepared according to example 1) in THF (5 mL) was added MeMgBr (0.6 mL, 0.20 mmol) dropwise at 0° C. under N2. The mixture was stirred at 0° C. for 2 h. The mixture was quenched with sat. aq. NH4Cl (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and then purified by preparative TLC to afford a racemic mixture of 2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (6.90 mg, 33% yield) as a white solid. LC-MS m/z 498.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.79 (s, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.90-7.81 (m, 2H), 6.08 (d, J=8.0 Hz, 1H), 5.35 (dd, J=4.4 and 14.0 Hz, 1H), 4.33-4.27 (m, 1H), 4.25-4.12 (m, 1H), 3.88-3.73 (m, 1H), 3.09 (s, 3H), 2.57-2.48 (m, 1H), 1.99 (s, 1H), 1.66 (s, 6H), 1.32 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H).
Reaction SMILES: [H-].[Na+].CO.[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C:20]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[CH:21]N(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(Cl)cc2Cl)cc1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a dried round bottom flask was added NaH (3.73 g in 60% disp.; 93.3 mmol), DMF (100 mL), and methanol (3.78 mL; 93.3 mmol) under a nitrogen atmosphere. To this suspension was added a solution of 2-cyanoacetamide (3.92 g; 46.6 mmol) in DMF (30 mL) via syringe. Then a solution of the crude product of Step B (42.4 mmol) in DMF (30 mL) was added via syringe. The resulting reaction mixture was heated to 95° C. and stirred for 3 hours. The reaction was quenched with saturated aq. NaHSO4 solution and extracted with methylene chloride (3×). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by trituration in ethanol. The precipitate was collected and washed with cold ethanol to afford the desired product: m/e=355 (M+1) Rt=3.3 min on LCMS.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[OH-].[Na+].Br[CH2:16][C:17]1[C:18]([F:30])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1[F:23].N12CCN(CC1)CC2>CCCCCCC.O.C(#N)C>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH2:16][C:17]2[C:18]([F:30])=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: Fc1ccc(-c2ccccc2)c(F)c1CBr
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: O
Solvent: CC#N
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1c(F)ccc(-c2ccccc2)c1F

Procedure:
To a mixture of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (2.2 g, 0.11 mole) in 75 ml of heptane was added sodium hydroxide (0.42 g, 0.011 mole) in 5 ml of water. The mixture was shaken until the acid dissolved. The water was then removed by distillation, the volume of the reaction mixture being reduced to 50 ml. To the reaction mixture was added 3-bromomethyl-2,4-difluoro[1,1'-biphenyl] (3.0 g, 0.011 mole) and 0.1 gram of 1,4-diazabicyclo[2.2.2]octane in 35 ml of acetonitrile. The mixture was heated under reflux for 3 hours. The solvent was then removed by evaporation under reduced pressure, and the residue was partitioned between water and diethyl ether. The ether phase was washed with two portions of aqueous 2% hydrochloric acid, two portions of water, two portions of aqueous 10% sodium carbonate, two portions of water and one portion of aqueous saturated sodium chloride solution in that order. The washed ethereal solution was dried over magnesium sulfate, and the ether was evaporated under reduced pressure. The oily residue was purified by column chromatography on silical gel, elution with hexane. This afforded (2,4-difluoro-[1,1'-biphenyl]-3-yl)methyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (1.8 g), Example XIV in Table 1.
Reaction SMILES: N1([CH2:10][NH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)C2C=CC=CC=2N=N1.[Cl:17][C:18]([Cl:27])=[C:19]([O:25][CH3:26])[O:20][Si](C)(C)C.B(F)(F)F.CCOCC>ClCCl>[CH3:26][O:25][C:19](=[O:20])[C:18]([Cl:27])([Cl:17])[CH2:10][NH:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: c1ccc2c(c1)nnn2CNC1CCCC1
Reactant: COC(O[Si](C)(C)C)=C(Cl)Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(Cl)(Cl)CNC1CCCC1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 4.3 g (0.02 mole) of benzotriazol-1-ylmethyl-cyclopentyl-amine and 6.4 g (0.030 mole) of (2,2-dichloro-1-methoxy-vinyloxy)-trimethyl-silane in 140 ml of anhydrous dichloromethane was added dropwise 3.7 ml (0.030 mole) of boron trifluride diethyl etherate at 0 degrees. The reaction was stirred at 0 degrees for 1 hour and then at room temperature for 24 hours. The reaction was quenched by the addition of 10% aqueous sodium carbonate and extracted with dichloromethane. The organic layer was washed with saturated sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-85:15) gave 2.4 g of 2,2-dichloro-3-cyclopentylamino-propionic acid methyl ester as a colorless oil.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH:4]=1.CN(C)C=O.P(Cl)(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc(Nc2ncc(C#N)s2)cc1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnc(Nc2ncc(C#N)s2)cc1CCl

Procedure:
2-(4-Hydroxymethyl-5-methyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (9-8, 0.400 g, 1.62 mmol) was stirred in 5 mL of anhydrous dichloromethane. N,N-Dimethylformamide (0.125 mL, 1.62 mmol) was added followed by the addition of phosphorous oxychloride (0.151 mL, 1.62 mmol). After 2 hours the reaction was concentrated in vacuo. Half-saturated NaHCO3 (aq) was added and the resulting precipitate was filtered and washed with water. Air drying provided the titled product, 9-9 contaminated with BINAP oxide. 1H NMR (DMSO-d6) δ 8.24 (s, 1H), 8.22 (s, 1H), 7.17 (s, 1H), 4.80 (s, 2H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]3[NH:21][C:22]([C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28](Br)[CH:27]=4)=[O:25])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][N:34]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]3[NH:21][C:22]([C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:36]5[C:37]6[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH:33]=[N:34][CH:35]=5)[CH:27]=4)=[O:25])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc3nc(C(=O)c4ccnc(Br)c4)[nH]c3n2)CC1
Reactant: OB(O)N1C=Cc2ccccc2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3nc(C(=O)c4ccnc(-c5cncc6ccccc56)c4)[nH]c3n2)CC1
Temperature: 120 °C
Yield: 34.1 %

Procedure:
The mixture of [4-[2-(2-bromo-pyridine-4-carbonyl)-3H-imidazo[4,5-b]pyridine-5-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (40 mg, 0.08 mmole), 2-isoquinoline boronic acid (13.8 mg, 0.08 mmole), Pd(Ph3)4 (27.6 mg, 0.24 mmole), 2 molar of K3PO4 aqueous (0.08 ml, 0.16 mmole), and dioxane (3.0 ml) was degassed and heated to 120° C. for 20 minutes in microwave. Reaction solution was diluted with water and extracted with EtOAc. EtOAc layer was concentrated. Residue was purified by using silica gel chromatography, eluting with 50% to 100% of EtOAc in CH2Cl2 to afford [4-[2-(2-isoquinolin-4-yl-pyridine-4-carbonyl)-3H-imidazo[4.5-b]pyridine-5-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (15 mg, 34%). 1H NMR (400 MHz, CD2Cl2) δ 1.27 (d, 9H), 1.89 (m, 2H), 325 (m, 2H), 3.51 (m, 2H), 3.66 (m, 2H), 3.78 (m, 2H), 6.65 (d, J=9.03 Hz, 1H), 7.61 (t, J=7.53 Hz, J=7.53 Hz, 1H), 7.69 (t, J=7.53 Hz, J=7.53 Hz, 1H), 7.84 (d, J=9.03 Hz, 1H), 8.03 (d, J=8.03 Hz, 1H), 8.27 (d, J=8.03 Hz, 1H), 8.39 (d, J=4.52 Hz, 1H), 8.66 (s, 1H), 8.71 (s, 1H), 8.95 (d, J=5.02 Hz, 1H), 9.28 (s, 1H). HR-MS m/z 550.2570 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([CH:9]=[CH:10][C@H:11]([CH3:14])[CH2:12][CH3:13])=[C:6]([F:8])[CH:7]=1>CCCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][CH2:10][C@H:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([F:15])[CH:3]=1
Reactant: CC[C@@H](C)C=Cc1c(F)cc(Br)cc1F
Solvent: CCCCCCC
Product: CC[C@@H](C)CCc1c(F)cc(Br)cc1F
Reaction time: 20 h

Procedure:
0.4 g of 5% PVC (dry) is added to a solution of 1.8 g (5.9 mmol) of 2 in 0.50 ml of heptane, and the mixture is hydrogenated at atmospheric pressure for 20 hours. The solvent is removed under reduced pressure, and the entire amount is converted into 4,
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C([N-]C(C)C)(C)C.[Li+].[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.C([O:32]C)(C)(C)C>O1CCCC1>[C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:15]12([C:25]([OH:26])=[O:32])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2
Reactant: COC(C)(C)C
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: C=C(C)C(N)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C12CC3CC(CC(C3)C1)C2
Reaction time: 0.17 h

Procedure:
90.0 g of methacrylamide was dissolved in 1,350 g of tetrahydrofuran (THF), and 944 mL of a 1.12 mol/L lithium diisopropylamide (LiDA) solution was dropwise added thereto at 5° C., followed by stirring for 10 minutes. Subsequently, 900 g of THF having 231.1 g of 1-adamantanecarbonyl chloride dissolved therein was added thereto, followed by stirring at 5° C. for 18 hours. After completion of the reaction, THF and t-butylmethylether (TBME) were added thereto, followed by washing with a 1 wt % aqueous hydrochloric acid solution and pure water, and concentration under reduced pressure. n-hexane was added to the obtained solution, and crystallization was conducted at 5° C., followed by filtration. The obtained solid was dried under reduced pressure, thereby obtaining 194.4 g of 1-adamantanecarboxylic acid methacrylamide (compound (51)).
Reaction SMILES: [CH3:1][CH2:2][CH3:3].[F:4][C:5]([F:12])([F:11])[C:6]([F:10])=[C:7]([F:9])[F:8]>>[F:4][C:5]([F:12])([F:11])[CH:6]([F:10])[C:7]([F:9])([F:8])[CH:2]([CH3:3])[CH3:1]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CCC
Product: CC(C)C(F)(F)C(F)C(F)(F)F

Procedure:
n-Propane-(1.50 g., 34.2 mmole) and hexafluoropropene (1.71 g., 11.4 mmole) were heated together at 295° for 4 days in a 300 ml. Pyrex ampoule to give: (i) hexafluoropropene (0.55 g., 3.68 mmole; 32% recovery); (ii) n-propane (1.13 g., 25.5 mmole; 75% recovery); (iii) 1,1,1,2,3,3,-hexafluoro-4-methylpentane (CH3)2CH.CF2. CHF CF3 (1.20 g., 6.1 mmole; 80% based on C3F6 consumed) (Found: C, 37.4; H, 4.4; F, 58.1%; M, 194. C6H8F6 requires C, 37.2; H, 4.2; F, 58.6%; M, 194) b.p. 79.8° C. Reaction carried out at 330° C between n-propane and hexafluoropropene and on the same scale as above gave a lower yield (62% based on C3F6 consumed) of 1,1,1,2,3,3-hexafluoro-4-methylpentane.