Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[NH:29][C:28]([C:38]3[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=3[O:48][CH2:49][CH3:50])=[N:27]2)=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH:30]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[N:29]([C:7]([C:6]3[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=3)=[O:8])[C:28]([C:38]3[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=[CH:40][C:39]=3[O:48][CH2:49][CH3:50])=[N:27]2)=[CH:24][CH:25]=1
Reactant: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
4-Chloromethylbenzoyl chloride (140 mg, 0.74 mmol) was added to a cooled solution of triethylamine (0.20 mL, 1.44 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-1H-imidazole (300 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with methylene chloride and washed with water and brine, and dried over anhydrous sodium sulfate. The solvents were removed under reduced pressure and flash chromatography of the residue over silica gel using 10-25% ethyl acetate in hexanes gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-chloromethyl-phenyl)-methanone (330 mg, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:15][O:16][CH2:17][C:18]3([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8]2)=[N:3]1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:15][O:16][CH2:17][C:18]3([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:19][CH2:20][N:21]([CH3:30])[CH2:22][CH2:23]3)=[CH:6][C:7]([C:11]([F:13])([F:12])[F:14])=[CH:8]2)=[N:3]1
Reactant: Cn1cc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)c2n1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cn(C)nc23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-methyl-7-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-2H-indazole (58 mg, 0.144 mmol) and sodium cyanoborohydride (18 mg, 0.288 mmol) in acetonitrile (1 mL) at room temperature was added formalin (50 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 15 mg (25%). 1H-NMR (CDCl3, 500 MHz) δ 7.97 (s, 1H), 7.85 (s, 1H), 7.41 (m, 2H), 7.34 (m, 2H), 7.22 (m, 1H), 4.82 (s, 2H), 4.21 (s, 3H), 3.58 (s, 2H), 2.60 (m, 2H), 2.20-2.33 (m, 4H), 2.22 (s, 3H), 2.06 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 147.6, 135.1, 129.3, 128.3, 127.4, 126.1, 125.5, 124.9 (q, J=272 Hz), 124.2 (q, J=32 Hz), 120.7, 118.7, 117.5 (q, J=4.8 Hz), 79.9, 68.7, 52.1, 46.2, 40.9, 40.7, 32.4. Mass spec.: 418.15 (MH)+. Accurate mass spec.: m/z 418.2019 [MH]+, Δ=0.7 ppm.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[N:3]=[N:2]1.S(Cl)([Cl:13])=O>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([Cl:13])=[O:10])[N:3]=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1c[nH]nn1
Solvent: ClCCl
Product: O=C(Cl)CCc1c[nH]nn1
Reaction time: 2 h

Procedure:
To a solution of 3-(1H-1,2,3-triazol-4-yl)propanoic acid (Example 19, step 2) (100 mg, 0.709 mmol) in DCM (5 mL) at RT under nitrogen was added thionyl chloride (0.621 mL, 8.50 mmol) and the reaction mixture stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:10]=[CH:9][S:8]1)=[O:5])[CH3:2].[I:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([I:22])[S:8]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)N=c1sccn1-c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N=c1sc(I)cn1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazoline (0.5 g) and N-iodosuccinimide (0.4 g) in chloroform (30 ml) was refluxed for 20 hours. After cooling, the reaction mixture was washed with an aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.1 of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-iodothiazoline (Compound No. 42).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]([CH3:38])([OH:37])[CH3:36])=[N:31][CH:32]=2)=[CH:23][CH:22]=1.[N:39]1([CH2:44][C:45]2[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]([CH3:38])([O:37][C:48]3[CH:47]=[CH:46][C:45]([CH2:44][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:50][CH:49]=3)[CH3:36])=[N:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Oc1ccc(CN2CCCC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C#Cc1ccc(-c2ccc(Cl)cc2)cn1)Oc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
131 mg (0.5 mmol) triphenylphosphane are added to a solution of 136 mg (0.5 mmol) 4-[5-(4-chloro-phenyl)-pyridin-2-yl]-2-methyl-but-3-yn-2-ol and 88 mg (0.5 mmol) 4-pyrrolidin-1-ylmethyl-phenol in 20 ml THF. Then 0.1 mL (0.5 mmol) diisopropyl azo-dicarboxylate is slowly added dropwise and the reaction mixture is stirred for 24 h at RT. The mixture is evaporated down i.vac., the residue is taken up in water, extracted exhaustively with EtOAc, the organic phase is washed with saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by HPLC.
Reaction SMILES: [CH2:1]([C:4]1([CH2:10][O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:19].[OH-].[Na+].OO>O1CCCC1>[CH2:13]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:11][CH2:10][C:4]1([CH2:1][CH2:2][CH2:3][OH:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH3:14]
Reactant: C=CCC1(CO[Si](CC)(CC)CC)CCCCC1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OCC1(CCCO)CCCCC1
Reaction time: 2 h

Procedure:
To a solution of [1-(allylcyclohexyl)methoxy]triethylsilane (1.70 g) in tetrahydrofuran (35 mL) were added a 2M borane-methyl sulfide complex solution in tetrahydrofuran (6.48 mL, 12.96 mmol) under ice cooling. The solution was stirred under ice cooling for 2 hours. To this were then added water, a 3N aqueous sodium hydroxide solution (6.5 mL) and 30% hydrogen peroxide (6.5 mL). The solution was stirred at room temperature for 16 hours. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=7:3) to give the title compound (810 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH3:5].CS(O[CH2:11][CH2:12][S:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]2[CH2:22][C@@H:17]1[C:18]2([CH3:24])[CH3:23])(=O)=O.O>ClCCl>[CH3:23][C:18]1([CH3:24])[C@H:17]2[CH2:22][C@@H:19]1[CH2:20][CH2:21][C@H:16]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11][N:4]([CH2:3][CH2:2][OH:1])[CH3:5]
Reactant: CC1(C)[C@H]2CC[C@@H](CCSCCOS(C)(=O)=O)[C@@H]1C2
Reactant: CNCCO
Solvent: O
Solvent: ClCCl
Product: CN(CCO)CCSCC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
10 ml of N-(2-hydroxyethyl)-N-methylamine were added to the solution of 2-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethylthio]ethyl methanesulfonate in dichloromethane obtained above. The dichloromethane was then distilled off under reduced pressure, and the remaining reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was worked up by adding 30 ml of water and extracting the mixture with ethyl acetate. The organic phase was separated and concentrated. The remaining residue was purified by chromatography on silica gel using n-hexane/dichloromethane/methanol as the eluent. 2.6 g of N-(2-[2((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethy lthio]ethyl]-N-(2-hydroxyethyl)-N-methylamine were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH3:22])[C:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.O>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:10]2[N:9]([CH3:22])[C:8]3[CH:23]=[CH:24][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[CH:15][CH:16]=1)#[N:21]
Reactant: COC(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)ccc21

Procedure:
5.0 g of 2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acid-methyl ester (15.7 mmol) are dissolved in 50 ml of methanol, treated with 20 ml of an aqueous sodium hydroxide solution(1 N) and boiled under reflux for 0.5 hours. It is then treated with 20 ml of an aqueous solution of hydrochloric acid (1 N) and diluted with water. The precipitated crystals are filtered off, and washed with water, acetone and ether. The raw product obtained is re-crystallized from dimethyl formamide. Yield: 4.5 g (94%); MPt.: >220° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([S:20][CH3:21])[NH:16][C:15]=3[CH:14]=[C:13]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([S:20]([CH3:21])=[O:44])[NH:16][C:15]=3[CH:14]=[C:13]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])=[O:24])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(S(C)=O)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a solution of N-(3-chloro-2-methylphenyl)-2-(methylsulfanyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (26 mg) in THF (3 mL), was added an aqueous solution of m-chloroperbenzoic acid (75%, 12 mg) (1 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to yield the titled compound (10 mg) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][C:62]=1[F:63])[N:59]=[C:58]([NH:64][CH2:65][CH2:66][NH:67][CH3:68])[CH:57]=[N:56]2>CN(C=O)C>[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][C:62]=1[F:63])[N:59]=[C:58]([NH:64][CH2:65][CH2:66][N:67]([CH3:68])[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16])[CH:57]=[N:56]2
Reactant: CNCCNc1cnc2cc(F)c(F)cc2n1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N(C)CCNc2cnc3cc(F)c(F)cc3n2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (50 mg, 0.21 mmol) in DMF (3 ml) was treated sequentially with N,N-diisopropylethylamine (0.20 ml, excess), HATU (79 mg, 0.21 mmol) then after 15 min. N-(6,7-difluoro-quinoxalin-2-yl)-N′-methyl-ethane-1,2-diamine.dihydrochloride, D2 (65 mg, 0.21 mmol). The reaction mixture was stirred at room temperature, under argon for 72 h then partitioned between diethyl ether and water. The organic phase was washed with water (3×), brine, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with pentane to afford the title compound as a pale yellow powder (38 mg, 40%).
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:23]1[N:24]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[O:26][CH:27]=1)[C:10]([C:12]1[N:13]=[CH:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:34]=[C:32]([CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][C:25]1[O:26][CH:27]=[C:23]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[N:24]=1
Reactant: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncoc2-c2ccccc2)co1
Agent: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CCCCc1nc(NC(=O)c2ncoc2-c2ccccc2)co1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-(5-phenyl-oxazole-4-carbonyl)-carbamic acid tert-butyl ester (31 mg, 0.06 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.05 mL, 0.64 mmol). After stirring at rt for 16 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a light brown solid. TLC: rf (1:1 hept-EA)=0.35. LC-MS-conditions 02: tR=1.02 min, [M+H]+=354.25.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([S:23](=[O:34])(=[O:33])[N:24]([CH2:29][CH2:30][O:31][CH3:32])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=4)[N:11]=3)=[CH:8][N:7]=[C:6]2[CH3:35])[CH2:3][CH2:2]1.C([Li])CCC.[CH3:41][C:42]([CH3:44])=[O:43].O>C1COCC1>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([S:23](=[O:33])(=[O:34])[N:24]([CH2:29][CH2:30][O:31][CH3:32])[C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:21][CH:22]=4)[N:11]=3)=[CH:8][N:7]=[C:6]2[CH2:35][C:42]([OH:43])([CH3:44])[CH3:41])[CH2:3][CH2:2]1
Reactant: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3CC3CC3)n2)cc1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(CC(C)(C)O)n3CC3CC3)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
4-(1-Cyclopropylmethyl-2-methylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(t-butyl)sulphamoyl]anilino}pyrimidine (Method 78; 1.15 g, 2.31 mmol) was dissolved in anhydrous THF (80 ml), under nitrogen. The solution was cooled to −78° C. and n-butyl lithium (2.88 ml of a 1.6 N solution in hexanes, 4.62 mmol), was added slowly, maintaining the temperature at less than −65° C. The reaction mixture was then stirred at −78° C. for 30 minutes, then acetone (1187 μl, 2.54 mmol) was added and mixture allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was then poured into water (100 ml), and extracted with EtOAc (2×50 ml). The organic extracts were combined, washed with water (50 ml), brine (50 ml), and dried. The volatiles were removed and the residue was purified by chromatography on silica gel eluting with EtOAc to give the title compound (465 mg, 36%) as a yellow solid. NMR: 0.10 (m, 2H) 0.18 (m, 2H) 0.89 (m, H) 1.07 (s, 6H) 1.12 (s, 9H) 2.75 (s, 2H) 3.15 (s, 3H) 3.38 (m, 4H) 4.54 (d, 2H) 7.11 (d, H) 7.58 (m, 3H) 7.75 (d, 2H) 8.34 (d, H) 9.8 (s, H); m/z 557.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCCCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 8.8 g. of p-n-pentylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 13.9 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-pentylbenzyliden)amino]benzonitrile which is obtained has a melting point of 45.6°-46.4° C. and a clearing point of 75.0° C. UV (ethanol): ε279 = 24400 (shoulder at 314 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[I:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C>>[I:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=2[C:5]#[N:6])[CH2:14][CH2:15]1)=[O:24]
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Reactant: O=C(Cl)c1cccc(I)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2cccc(I)c2)CC1
Yield: 95 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (200 mg; 0.7 mmol) (Example 123, Step 3) was stirred at room temperature with 3-iodobenzoyl chloride (187 mg; 0.7 mmol) and triethylamine (0.3 mL; 2.1 mmol) for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude solid was obtained as 2-[1-(3-iodo-benzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile. (310 mg; 95% yield).
Reaction SMILES: [CH2:1](I)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:10]1([CH2:13][O:14][C:15]2[C:16]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:36])[N:28]([CH3:37])[CH:27]=3)=[N:17][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:19][CH:20]=2)[CH2:12][CH2:11]1>CC#N>[CH:10]1([CH2:13][O:14][C:15]2[C:16]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:36])[N:28]([CH3:37])[CH:27]=3)=[N:17][C:18]([N:21]([CH2:1][CH3:2])[S:22]([CH3:25])(=[O:24])=[O:23])=[N:19][CH:20]=2)[CH2:12][CH2:11]1
Reactant: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(c1ncc(OCC2CC2)c(-c2cn(C)c(=O)c3ccccc23)n1)S(C)(=O)=O
Yield: 15.7 %

Procedure:
Ethyl iodide (95 mg, 0.6 mmol) and K2CO3 (55 mg, 0.4 mmol) were added to a solution of the title compound of Example 152 (80 mg, 0.2 mmol) in MeCN (5 mL). After refluxing 1 h, the mixture was cooled, concentrated under vacuum and subjected to CH2Cl2 extractive work up. HPLC purification gave the title compound (13.42 mg, yield: 15.2%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 4.02 (q, J=6.8 Hz, 2H), 3.97 (d, J=7.2 Hz, 1H), 3.60 (s, 3H), 3.43 (s, 3H), 1.25 (t, J=6.8 Hz, 1H), 1.10-1.07 (m, 1H), 0.46-0.42 (m, 2H), 0.24-0.20 (m, 2H). LCMS: 429.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([C:8]([CH3:13])([CH3:12])[C:9]([N:29]2[CH2:30][CH2:31][CH2:32][C:33]3[N:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)[N:26]=[CH:27][C:28]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)(C)C(=O)O
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)(C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 68 %

Procedure:
The title compound was from prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The organic layer was concentrated and the residue was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 80 mg (68%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.44 (m, 2H), 7.16 (m, 2H), 3.08 (m, 2H), 2.74 (t, J=6.6 Hz, 2H), 2.21 (s, 3H), 1.91 (s, 6H), 1.76 (ddd, J=5.8, 6.2, 10.5 Hz, 2H); MS: (ES) m/z calculated for C21H21ClF4N5O [M+H]+ 470.1, found 470.1.