Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:17][O:18][C:19]([C:21]1[S:22][C:23]([C:40]#[C:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:24][C:25]=1[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)=[O:20].CO>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:17][O:18][C:19]([C:21]1[S:22][C:23]([C:40]#[C:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:24][C:25]=1[N:26]([C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9])[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:29][CH2:28]1)=[O:20]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
trans-4-Methylcyclohexyl carboxylic acid chloride (23.88 mmol) and pyridine (2.89 mL, 35.82 mmol) are added to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-(N-tert-butoxycarbonyl-piperidin-4-yl)amino-thiophene-2-carboxylic acid methyl ester from step III (5.142 g) in dry toluene (50 mL). The mixture is refluxed for 24 h, then it is brought to room temperature, and additional amount of pyridine (1.0 mL) and MeOH (5 mL) are added. Then the mixture is diluted with CH2Cl2, washed with brine, organic fraction is separated, dried over Na2SO4, and concentrated to give 5.198 g of crude 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(N-tert-butoxycarbonyl-piperidin-4-yl)amino]-thiophene-2-carboxylic acid methyl ester containing variable amounts of 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].[CH3:29][N:30](CCN(C)C)C.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>CN(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]>[C:29]([C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15])#[N:30]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2Br)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2C#N)CC1
Temperature: 160 °C
Reaction time: 0.05 h

Procedure:
A mixture of tert-butyl 4-{[2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine-1-carboxylate (380 mg, 0.84 mmol), Zn(CN)2 (59 mg, 0.51 mmol), Pd2(dba)3 (7 mg, 0.0042 mmol), TMEDA (20 mg, 0.17 mmol), and xantphos (5 mg, 0.0084 mmol) in 3 mL of DMF was stirred under microwave irradiation for 3 min at 160° C. The solvent was removed in vacuum to afford the crude compound, which was purified via prep-TLC to afford tert-butyl 4-{[2-cyano-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine-1-carboxylate. 1H-NMR (400 MHz, MeOD) δ ppm 9.82 (s, 1H), 8.31 (d, J=1.6 Hz, 1H), 8.12˜8.16 (m, 1H), 7.68 (d, J=7.8 Hz, 1H), 4.14 (s, 2H), 3.43˜3.72 (m, 8H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28](O)=[O:29]>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:29]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1c(Cl)cccc1Cl)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2,6-dichlorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (d, J=7.9 Hz, 1H), 8.02-8.08 (m, 1H), 7.96-8.00 (m, 1H), 7.89-7.95 (m, 1H), 7.49-7.51 (m, 2H), 7.30-7.45 (m, 1H), 4.04 (s, 2H), 3.81-3.84 (m, 4H), 3.08-3.12 (m, 4H); MS (ESI+) M/Z 433 (M+H)+.
Reaction SMILES: C[O-].[Na+].[CH2:4]1[C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[CH2:5]1.[N+:13]([CH3:16])([O-:15])=[O:14]>CO>[N+:13]([CH2:16][C:9]1([OH:12])[CH2:10][CH2:11][C:6]2([CH2:5][CH2:4]2)[CH2:7][CH2:8]1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCC2(CC1)CC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])CC1(O)CCC2(CC1)CC2
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To 4M solution of sodium methoxide (14 mL) in methanol (10 mL) was added a solution of spiro[2.5]octan-6-one (4.6 g, 0.031 mol) and nitromethane (2.3 mL, 0.042 mol) in methanol (20 mL) at room temperature and stirred overnight. The reaction was quenched with acetic acid (4.5 mL) and water (50 mL) and the volatiles were removed under reduced pressure. The residue was extracted with dichloromethane (2×50 mL), and the combined extracts were dried, filtered and evaporated. The residue was purified by flash chromatography to afford the desired product (3.2 g, 52%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16](=[O:26])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[CH3:14][O:15][C:16](=[O:26])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])=[CH:21][CH:20]=1
Reactant: COC(=O)C=Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: COC(=O)C=Cc1ccc(NC(=O)c2ccc3ccccc3c2)cc1

Procedure:
Using an analogous method (H4), the title compound was prepared from 2-naphthalenecarbonyl chloride (0.557 g, 2.91 mmol) and 3-(4-amino-phenyl)-acrylic acid methyl ester (3) in a form of white solid (0.950 g, 75%). 1H NMR (DMSO-d6, HMDSO), δ: 3.65 (3H, s); 6.51 (1H, d, J=16.0 Hz); 7.47-8.25 (12H, m); 10.63 (1H, s).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([OH:28])=O)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH2:42])[CH2:37][CH2:36]1>>[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:32])[F:33])=[O:6])[CH:9]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)[CH:24]=2)[CH2:37][CH2:36]1
Reactant: CN1CCC(CN)CC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)O)c4)ccc32)c1
Product: CN1CCC(CNC(=O)c2cccc(-c3ccc4c(c3)ncn4-c3cccc(NC(=O)NCC(F)(F)F)c3)c2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 starting from 3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)-phenyl]-1H-benzimidazol-5-yl}benzoic acid and 1-(1-methylpiperidin-4-yl)methanamine (Matrix Sci., Cat. No. 016352). LCMS (M+H)+: m/z=565.3.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.COC1CCC(C(O)=O)CC1.NC1C=CC(C2[NH:26][C:27]3[CH:33]=[CH:32][C:31](N)=[CH:30][C:28]=3[N:29]=2)=CC=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[C:1](=[C:2]1[N:29]=[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]2=[N:26]1)=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Agent: COC1CCC(C(=O)O)CC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C=C1N=c2ccccc2=N1
Temperature: 60 °C

Procedure:
Bis-4-methoxyclohexyl carbonyl benzimidazole was synthesized as follows: Oxalyl chloride, (1.07. ml, 2 M in CH2Cl2) was added to 4-methoxy-cyclohexane carboxylic acid (0.338 g, 2.14 mmole) followed by one drop DMF. The mixture was allowed to react at RT for 1.0 hour. To the above solution was added 2-(4-aminophenyl)-6-amino-benzimidazole (0.200 g, 0.89 mmole) in pyridine (2 ml). The reaction was heated to 60° C. overnight. The reaction was cooled and the precipitate filtered and washed with NaHCO3 and hexanes.
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2.O>C1COCC1>[CH3:1][N:2](/[CH:4]=[C:13]1/[C:14](=[O:19])[NH:15][C:16]2[C:12]/1=[CH:11][C:10]([F:9])=[CH:18][CH:17]=2)[CH3:3]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(C)/C=C1/C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DMF-DMA (3.15 g, 26.4 mmol) was added into a solution of 5-fluoroindolin-2-one LXXXVIII (2.0 g, 13.2 mmol) in dry THF. The reaction mixture was stirred at rt for 4 hr before being poured into water and extracted by EtOAc. The organic layer was separated and dried by Na2SO4, and concentrated to give (E)-3-((dimethylamino)methylene)-5-fluoroindolin-2-one LXXXVIX.
Reaction SMILES: S(Br)([Br:3])=O.[F:5][C:6]1[N:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=1.CC(OO)=O>C(Cl)Cl>[Br:3][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([F:5])=[N:11][CH:10]=1)[CH3:13]
Reactant: CC(O)c1ccc(F)nc1
Reactant: O=S(Br)Br
Agent: CC(=O)OO
Solvent: ClCCl
Product: CC(Br)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
Thionyl bromide (11.60 mL, 149 mmol) was added (dropwise over 15 min; gas evolution) to a solution of 1-(6-fluoropyridin-3-yl)ethanol (10.55 g, 74.7 mmol) in DCM (300 mL) at 25° C., and the resulting orange solution was stirred at 25° C. for 3 h. Excess SOBr2 was then carefully quenched with water (150 mL) at 0° C. with vigorous stirring, and 5.0N aqueous NaOH (100 mL) was then carefully added at 0° C. (over about 10 min) to neutralize HBr and SO2. (Yellow mixture results; final pH about 9; adjust with saturated aqueous NaHCO3,to a pH of about 9 as necessary.) The resulting mixture was vigorously stirred at 0° C. for 5 min to ensure complete quench of acidic species, and the resulting mixture was then partitioned between DCM (200 mL) and half saturated aqueous NaHCO3 to a pH of about 9 (600 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (300 mL). The combined organic extracts were sequentially washed with saturated aqueous NaHCO3 (500 mL) and brine (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-(1-bromoethyl)-2-fluoropyridine (14.58 g, 96% yield) as a yellow oil (71% LCAP; m/z (ESI, +ve) 204.0 (M+H)+), which was used directly in Step 3.
Reaction SMILES: C(OC([N:8]([CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:17]([OH:19])=O)[CH2:9][CH2:10][CH2:11][CH3:12])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:67][C@@H:68]([CH2:82][C:83]1[CH:88]=[C:87]([F:89])[CH:86]=[C:85]([F:90])[CH:84]=1)[C@H:69]([OH:81])[CH2:70][NH:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[C:75]([CH2:79][CH3:80])[CH:74]=1.[ClH:91]>C(Cl)Cl.CO.C(OCC)C>[ClH:91].[ClH:91].[CH2:9]([NH:8][CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:17]([NH:67][C@@H:68]([CH2:82][C:83]1[CH:84]=[C:85]([F:90])[CH:86]=[C:87]([F:89])[CH:88]=1)[C@H:69]([OH:81])[CH2:70][NH:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[C:75]([CH2:79][CH3:80])[CH:74]=1)=[O:19])[CH2:10][CH2:11][CH3:12]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN(Cc1cc(C)cc(C(=O)O)c1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNCc1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-{[(tert -butoxycarbonyl)(butyl)amino]methyl}-5-methylbenzoic acid (90 mg, 0.28 mmol) in methylene chloride (3 mL) is added HBTU (160 Mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol), and N,N-diisopropylethylamine (0.142 mL, 0.84 mmol), followed by (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (114 mg, 0.28 mmol), and the reaction mixture is stirred for 12 h at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 10% methanol/chloroform) affords a clear oil, which is dissolved in methanol (2 mL). To this solution is added hydrochloric acid (5 mL, 4 N dioxane, 20 mmol), and the reaction mixture is stirred for 1 h at room temperature. The reaction mixture is then diluted with ethyl ether (10 mL). The precipitate that is formed is collected by filtration to provide the title compound. ESI MS m/z 538.5 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=1.O>CN(C)C=O>[CH3:37][C:32]1[C:31]([CH2:30][O:3][C:4]2[CH:28]=[CH:27][C:7]([CH2:8][N:9]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]3)=[CH:6][CH:5]=2)=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: Cc1ncccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Chloromethyl-2-methylpyridine (212 mg) was added to the mixture, which was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(2-methyl-3-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (581 mg, yield: 85%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:39])[N:25]([CH2:30][CH2:31][C:32](=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:34]([NH:33][C:32]([CH2:31][CH2:30][N:25]([CH:26]1[CH2:27][CH2:28][CH2:29]1)[C:24](=[O:39])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1)=[O:38])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCC1
Reaction time: 64 h

Procedure:
A solution of (2-{3-[(2-tert-butylcarbamoyl-ethyl)-cyclobutyl-carbamoyl]-5-chloro-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.021 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 64 h and then concentrated under reduced pressure to give the title compound (0.020 g) as a colourless gum.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH3:26])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:40][CH2:41][CH2:42][CH2:43][Cl:44]>O1CCCC1>[C:28]1([CH2:27][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH2:40][CH2:41][CH2:42][CH2:43][Cl:44])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCCCCBr
Reactant: CCOCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOCn1c(CCCCCCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of N,N-bis(phenylmethyl)-1-ethoxymethyl-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 3.43 mmole, Example 1 Part E) in tetrahydrofuran (30 mL) was cooled to -78° C. Butyllithium (1.4 mL of 2.5M in hexanes, 3.5 mmole) was added dropwise followed by the addition of 1-bromo-4-chlorobutane (4 mL, 34 mmole). The reaction mixture was allowed to warm to ambient temperature then it was quenched with diethyl ether and water. The ether layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel eluting with 10% ethyl acetate in hexanes v/v) to provide 1.5 g of N,N-bis(phenylmethyl)-2-(5-chloropentyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:10][N:11]([CH:12]3[CH2:17][CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)=[N:10][N:11]([CH:12]3[CH2:17][CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCOC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCCOC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 4-(4-methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (160 mg) in acetonitrile (15 mL) were added sodium iodide (124 mg) and chloro(trimethyl)silane (0.418 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (153 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=2)[CH:5]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(F)(F)F)c2)cn1
Yield: 30 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-(trifluoromethyl)phenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (55 mg, 30%) which was obtained as a white solid. MS (ESI): m/e=370.0 [M+H]+.
Reaction SMILES: [BH4-].[Li+].C([C@@H]1COC(=O)N1[C:16](=[O:24])[C@H:17]([CH3:23])[CH2:18][C:19]([F:22])([F:21])[F:20])C1C=CC=CC=1.O>C(OCC)C>[F:20][C:19]([F:22])([F:21])[CH2:18][C@@H:17]([CH3:23])[CH2:16][OH:24]
Reactant: C[C@H](CC(F)(F)F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C[C@@H](CO)CC(F)(F)F
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A solution of lithium borohydride (23 mL, 2.0 M in THF, 45 mmol) was added dropwise to a solution of (4R)-4-benzyl-3-[(2R)-4,4,4-trifluoro-2-methylbutanoyl]-1,3-oxazolidin-2-one (12.9 g, 40.9 mmol) and water (810 μL, 45.0 mmol) in diethyl ether (200 mL) at 0° C. The reaction mixture was allowed to warm to 25° C. and, after 1 h, was cooled to 0° C. and quenched with aqueous 1 N NaOH (124 mL). The mixture was warmed to 25° C. and stirred until both layers were homogeneous. The layers were separated and the organic extract was washed with brine, dried using MgSO4 and concentrated. Flash chromatography (eluent: 3:7 ether-petether) provided (2R)-4,4,4-trifluoro-2-methylbutan-1-ol (5.05 g, 87%) as a colorless oil. 1H NMR was identical to that which was found in the literature (J. Med. Chem. 37: 1282-1297 (1994)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[Si]([N-:18][Si](C)(C)C)(C)C.[Li+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][NH2:18])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=Cc1cc(Cl)cc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1cc(Cl)cc2ccccc12
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
The 3-chloro-1-naphthalenecarbaldehyde (2 g) dissolved in dry THF (12 mL) was added dropwise to lithium bis(trimethylsilyl)amide 1M in THF (11.5 mL) previously cooled at −40° C. The resulting yellow mixture was stirred from −40° C. to −20° C. over 1.5 h; then it was cooled down at −50° C. and lithium aluminium hydride 1M in Et2O (10.6 mL) was added; the mixture was stirred at −40° C. for 2 h then it was quenched with HCl 2N (10 mL) and allowed to reach room temperature. The reaction mixture was diluted with further aqueous HCl 2N solution (20 mL) and extracted with CH/Et2O 1/1 (50 mL). The acidic aqueous phase was basified at 0° C. with NaOH pellets until pH=14, then it was extracted with diethyl ether (2×150 mL). The organic phase was dried and concentrated in vacuo to give the title compound (1.78 g) as a white solid.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]([CH2:12]O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:29])=O.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]([CH2:12][Cl:29])=[N:10][N:11]=2)=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Fc1ccccc1-n1c(CCl)nnc1-c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
[5-Biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl]methanol (1.81 g) was suspended in toluene (25 ml), followed by addition of thionyl chloride (1.5 ml) and chloroform (25 ml), and stirred at 60° C. for 5 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting white solid was washed with a mixture solution of n-hexane and ethyl acetate, to afford the entitled compound as white solid (1.54 g, 81%). The physico-chemical values are as follows.