Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([C:15]2[N:23](S(C3C=CC=CC=3)(=O)=O)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([C:15]2[NH:23][C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
A solution of 2-(1-(3-ethoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.2 g, 4.9 mmol) in ethanol (58.5 mL) and tetrahydrofuran (117 mL) was treated with an aqueous sodium hydroxide solution (10%, 22 mL). The reaction was stirred at 70° C. for 18 h. After cooling to 25° C., the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×150 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (50 g, ethyl acetate/petroleum ether 1:15) afforded 2-(1-(3-ethoxy-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 86%) as a yellow oil: 1H NMR (300 MHz, d6-DMSO) δ ppm 11.59 (s, 1H), 8.16 (d, 1H, J=4.5 Hz), 7.92 (d, 1H, J=7.5 Hz), 7.19 (t, 1H, J=7.8 Hz), 7.04 (q, 1H), 6.82 (t, 2H, J=2.1 Hz), 6.72 (s, 1H), 6.36 (d, 1H, J=1.8 Hz), 6.15 (d, 1H, J=9.9 Hz), 3.95 (q, 2H, J=13.8 Hz), 2.61-2.49 (m, 1H), 1.26 (t, 3H, J=6.9 Hz), 1.03 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.[CH3:20][CH:21]([CH3:25])[CH2:22][CH:23]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:1]1([CH:23]([NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH2:22][CH:21]([CH3:25])[CH3:20])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)CC=O
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)CC(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
Benzotriazole, 4-chlorobenzamide, 3-methylbutanal, and p-toluenesulfonic acid were processed as in Example 53A to provide the desired product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(C(F)(F)F)=O.N#N>CCO.C(Cl)(Cl)Cl>[C:15]1([CH:14]2[C:6]3[NH:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5]=3[CH2:4][CH2:3][NH:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.1 %

Procedure:
1-Phenyl-2,3,4,9-tetrahydro-1H-beta-carboline was prepared by the addition of tryptamine-HCl (500 mg, 2.54 mmol), CHCl3 (20 mL), absolute EtOH (16 mL), benzaldehyde (520 μL, 5.08 mmol), and TFA (1.9 mL, 25.4 mmol) to a N2 purged 50 mL flask. The reaction solution was allowed to stir at ambient temperature for 18 hours and then at 60° C. for 4 hours. The solution was concentrated under reduced pressure, and the crude material was chromatographed (SiO2, 100% hexane to 25% EtOAc) to yield 95 mg of 1-phenyl-2,3,4,9-tetrahydro-1H-beta-carboline; MS (ESI): 249 (MH+).
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[C:37]([OH:38])=[CH:36][CH:35]=[C:34]([CH3:39])[CH:33]=1.[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4OC5C=CC=C(C)C=5N=4)=[CH:52][CH:51]=3)[C:42]=12>>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[O:38][C:37]5[CH:36]=[CH:35][C:34]([CH3:39])=[CH:33][C:32]=5[N:31]=4)=[CH:52][CH:51]=3)[C:42]=12
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Reactant: Cc1ccc(O)c(N)c1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: Cc1ccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
Cis-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-methyl-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.057 g, 0.140 mmol) and 2-amino-p-cresol (0.017 g, 0.140 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-4-methyl-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.010 g, 13%): 1H NMR (DMSO-d6, 400 MHz) δ 10.81 (s, 1H), 8.23 (s, 1H), 7.93 (d, 2H), 7.66 (d, 2H), 7.38 (d, 1H), 7.30 (s, 1H), 6.96 (d, 1H), 4.80 (m, 1H), 2.60-2.07 (m, 12H), 2.39 (s, 3H), 2.15 (s, 3H), 1.71-1.59 (m, 5H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.48 min., 90%; m/z 538 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.CC([O-])=O.[K+].[CH3:15][NH2:16]>CN(C=O)C.[Cu]I>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH3:8])[NH:16][CH3:15]
Reactant: CN
Reactant: Cc1ccc(Br)cc1F
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1ccc(C)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a suspension of 4-bromo-2-fluoro-1-methylbenzene (1.0 g, 5.3 mmol), KOAc (1.3 g, 13.2 mmol), and CuI (1.2 g, 6.4 mmol) in DMF (20 mL) was added methylamine (26.5 mL, 2.0M in THF, 53.0 mmol) at r.t. under N2. The reaction was stirred at 100° C. overnight in a sealed tube. The reaction mixture was filtered, diluted with water (50 mL), and extracted with EtOAc (50 mL×3). The organic layers were washed with ammonium hydroxide (50 mL×3) and brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=20:1) to give 310 mg (42%) of the title compound as a yellow oil. [M+H] Calc'd for C8H10FN, 140. Found, 140.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:41]([O:45][C:46](=[O:71])[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][N:55]1[C:63]2[CH:62]=[C:61]3[NH:64][C:65]([NH2:67])=[N:66][C:60]3=[CH:59][C:58]=2[C:57]([CH3:69])([CH3:68])[C:56]1=[O:70])([CH3:44])([CH3:43])[CH3:42]>CN(C)C=O>[C:41]([O:45][C:46](=[O:71])[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][N:55]1[C:63]2[CH:62]=[C:61]3[NH:64][C:65]([NH:67][C:1]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:9])=[N:66][C:60]3=[CH:59][C:58]=2[C:57]([CH3:69])([CH3:68])[C:56]1=[O:70])([CH3:44])([CH3:42])[CH3:43]
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)C(C)(C)c2cc3nc(N)[nH]c3cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4cccnc4)[nH]c3cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of nicotinic acid (11.8 mg; 0.09 mmol), TBTU (28.1 mg; 0.09 mmol) and DIPEA (33 μl) in N,N-dimethylformamide (600 μl) is stirred at RT for 5 min. Afterwards D18 (26.5 mg) is added and the mixture is stirred at RT for 18 h. After evaporation of the solvent the crude material is used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+].C(OCC)(=O)C.Cl>O.CC(C)=O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C#Cc2ccc(O)c(C(=O)O)c2)cc1

Procedure:
Ethyl 2-hydroxy-5-[[4-[(3-methyl-2-pyridinylamino)sulfonyl]phenyl]ethynyl]benzoate (15.5 g, 35 mmol) was refluxed in potassium hydroxide (10 g, 0.15 mol) in water (100 ml) for 1 h. After cooling to ca 70° C., ethyl acetate (50 ml) was added and hydrochloric acid was added to reach pH 7-8. Cooling during stirring and then filration gave a solid that was disolved in acetone (100 ml) and water (100 ml). The solution was acidified at ca 50° C. and cooled, filtered and washed with water. Yield 8.0 g (56%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[C:37]2=[O:52].CCOC(C)=O>CN(C)C=O>[O:51]=[C:45]1[CH:44]([N:38]2[C:37](=[O:52])[C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:11][N:10]=4)=[O:14])[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)nc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A stirred mixture of 5-ethanesulfonyl-pyridine-2-carboxylic acid (0.34 g, 1.60 mmol) and CDI (0.27 g, 1.70 mmol) in N,N-dimethylformamide (15 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.61 g, 1.60 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×75 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient, product eluted at 80-90% EtOAc). The product fractions were combined and concentrated to give 5-ethanesulfonyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.25 g, 32% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.15 min (96.20%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 1.15 (t, J=7.4 Hz, 3H), 2.00-2.20 (m, 1H), 2.52-2.67 (m, 2H), 2.77-3.01 (m, 1H), 3.48 (q, J=7.4 Hz, 2H), 4.69 (d, J=6.2 Hz, 2H), 5.14 (dd, J=5.4, 12.7 Hz, 1H), 7.73-8.04 (m, 3H), 8.29 (d, J=8.3 Hz, 1H), 8.49 (dd, J=2.3, 8.1 Hz, 1H), 9.10 (d, J=1.7 Hz, 1H), 9.86 (t, J=6.3 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 6.83, 21.99, 30.93, 42.58, 49.01, 49.34, 122.17, 122.68, 123.54, 129.87, 131.59, 133.63, 137.04, 138.13, 147.09, 147.60, 153.38, 163.02, 166.97, 167.12, 169.80, 172.72; LCMS: MH=485; Anal Calcd for C22H20N4O7S: C, 54.54; H, 4.16; N, 11.56. Found: C, 54.82; H, 3.92; N, 11.57.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[CH2:19](O)[CH2:20][CH2:21][CH3:22].[C:24]1(C)[CH:29]=CC=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[C:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:29][CH2:24][CH2:25][CH3:26])=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:19][CH2:20][CH2:21][CH3:22])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Cc1ccccc1
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)c1ccc(-c2ccc(C(=O)OCCCC)cc2)cc1

Procedure:
A mixture of biphenyl-4,4′-dicarboxylic acid (15.2 g, 63 mmol), 100 mL of n-butanol, 200 mL of toluene, and a catalytic amount of p-toluenesulfonic acid was heated at reflux with continuous separation of evolved water (Dean-Stark trap) for 7 d. The reaction mixture was cooled to ambient, diluted with dichloromethane, filtered, washed with 10% aqueous NaHCO3 then with brine, dried (MgSO4), and concentrated. The crude product was purified by recrystallization from heptane to obtain 13.4 g (60% of theory) of colorless crystals. 1H NMR (CDCl3): δ 0.97 (t, 6H), 1.5 (m, 4H), 1.8 (m, 4H), 4.35 (q, 4H), 7.68 (d, 4H), 8.13 (d, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[C:8]=2[C:14]([F:17])([F:16])[F:15])[N:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([O:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)[C:8]=2[C:14]([F:17])([F:16])[F:15])[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(O)c1C
Product: CC(=O)Oc1c(C)c(C)nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c12
Temperature: 122.5 °C

Procedure:
A solution of 3.4 g of 4-(4-trifluoromethoxyphenoxy)-3-trifluoromethyl-aniline, 2.4 g of ethyl 2-methylacetoacetate, and 0.3 g of p-toluenesulfonic acid dissolved in 100 mL of xylene was heated under reflux for 36 hr. This reaction solution was cooled, and the precipitated crystals were collected by filtration to give 1.73 g of 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-7-trifluoromethyl-quinoline. The filtrate was concentrated under the reduced pressure to give 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline. Acetic anhydride (40 mL) was added to 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline obtained from the filtrate, and the mixture was heated at 120 to 125° C. for one hr. This reaction solution was concentrated under the reduced pressure, ethyl acetate was then added to the concentrate, and the mixture was washed with brine. Thereafter, the solvent was removed under the reduced pressure, and the crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 0.35 g of 4-acetoxy-2,3-dimethyl-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH:22]([F:24])[F:23])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH:22]([F:23])[F:24])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2C2=CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18.25 h

Procedure:
4-[5-(1-Cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Example 142) (0.31 g, 0.88 mmol) was dissolved in ethanol (15 mL), 10% palladium on charcoal was added, and the suspension was stirred at room temperature under hydrogen (36psi) for 18.25 hours. The reaction was filtered through celite, and the ethanol removed in vacuo to give a white solid, which was recrystallized from methylene chloride/isooctane (0.31 g, 99%): mp 199-203° C.; 1H NMR (acetone-d6) 300 MHz 8.05 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 6.69 (t, J=55.0 Hz 1 H), 6.47 (s, 1H), 5.02 (br s, 2H), 2.67 (m, 1H), 1.71-1.88(m, 5H), 1.24-1.43 (m, 5H); 19F NMR (acetone-d6) 300 MHz: −112.86 (d).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:26]=[CH:25][C:11]3[N:12]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.[C:27](O)(=O)[CH3:28].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH2:27]([N:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:26]=[CH:25][C:11]3[N:12]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:6])=[O:7])[CH2:2]1)[CH3:28]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CNC3)ccc21
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN1CC(S(=O)(=O)c2ccc3c(c2)nc(CC(C)(C)C)n3CCN(C)C)C1
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-(azetidin-3-ylsulfonyl)-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (STEP A, 25 mg, 0.066 mmol), acetic acid (11 microL, 0.20 mmol) and acetaldehyde (75 microL, 1.3 mmol) in dichloromethane (1 mL) and methanol (0.5 mL) was added sodium triacetoxyborohydride (28 mg, 0.13 mmol) at room temperature. After 1 h, the mixture was concentrated. The residue was diluted with methanol (4 mL). The solution was filtered through SCX column and the column was washed with 1 mol/L ammonia in methanol solution (2 mL×2) to wash out the desired compound. The filtrate was concentrated in vacuo. The residue was purified by prep-LC-MS (“process A”).
Reaction SMILES: C(O)(C)(C)C.C(NCC)C.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Br[CH2:22][C:23]([C:25]1[CH:26]=[N:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:24].OS(O)(=O)=O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][CH2:22][C:23]([C:25]2[CH:26]=[N:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:24])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: O=C(CBr)c1ccc(Cl)nc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCNCC
Solvent: CC(C)(C)O
Product: O=C(CCC(=O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
The zinc chloride (3.04 g, 22.82 mmol), tert-butyl alcohol (1.576 mL, 16.71 mmol) and diethylamine (1.731 mL, 16.71 mmol) were combined in benzene (12 mL). The resulting slurry was stirred at room temperature for 2 hours until all solid dissolved. To this slurry was added 1-(6-chloropyridin-3-yl)ethanone (2.60 g, 16.71 mmol; reference: Bioorganic & Medicinal Chemistry Letters, 1998, 8, 3087-3092), followed by 2-bromo-1-(6-chloropyridin-3-yl)ethanone (2.61 g, 11.14 mmol; reference: Bioorganic & Medicinal Chemistry Letters, 1998, 8, 3087-3092). The resulting clear yellow solution was stirred at room temperature for 88 hours. The thick reaction mixture was treated with 5% H2SO4 (10 mL), stirred for 30 minutes, filtered and dried to give the title compound (2.91 g, 85%) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[C:16]([CH2:27][O:28][CH3:29])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.Cl.C([O:35][C:36](=[O:40])[CH2:37][NH:38][CH3:39])(C)(C)C.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O>[CH3:29][O:28][CH2:27][C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:38]([CH3:39])[CH2:37][C:36]([OH:40])=[O:35])[CH:8]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]
Reactant: COCc1cc(-c2nc(-c3ccnc(CCl)c3)no2)ccc1-c1ccccc1C
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COCc1cc(-c2nc(-c3ccnc(CN(C)CC(=O)O)c3)no2)ccc1-c1ccccc1C
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of 3-(2-(chloromethyl)pyridin-4-yl)-5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazole (0.097 g; 0.24 mmol), sarcosine t-butyl ester hydrochloride (0.037 g; 0.27 mmol) and K2CO3 (0.043 g; 0.27 mmol) in dioxan (3 mL) was heated at 70° C. for 7 days. DCM and water were added to the reaction mixture. The mixture was poured through a hydrophobic frit. The solvent was evaporated in vacuo. The material was purified by SCX chromatography and the material treated with HCl solution in dioxan (5 M; 3 mL) and the reaction mixture stirred at 70° C. for 18 hours. The solvent was evaporated in vacuo and the residue purified by preparative HPLC, affording the title product as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.78 (1 H, d, J=5.1 Hz), 8.42 (1 H, s), 8.16 (1 H, dd, J=8.2, 2.0 Hz), 8.08 (1 H, s), 8.04 (1 H, dd, J=5.2, 1.5 Hz), 7.38-7.21 (4 H, m), 7.12 (1 H, d, J=7.4 Hz), 5.39 (1 H, br s), 4.23 (2 H, dd, J=17.0, 12.7 Hz), 4.17 (2 H, s), 3.54 (2 H, s), 3.34 (3 H, s), 2.66 (3 H, s), 2.08 (3 H, s). LC/MS: 388 (M+H)+. HPLC (Method B) Rt 2.97 min (Purity: 99.2
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH:19]1([OH:26])[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([O:25][CH:22]3[CH2:23][CH2:24][CH:19]([OH:26])[CH2:20][CH2:21]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: OC1CCC(O)CC1
Product: OC1CCC(Oc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, yellow solid, MS: m/e=295.3 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and cyclohexane-1,4-diol by using Cs2CO3 as base and dioxane as solvent for 16 hours at 100° C.
Reaction SMILES: C([O:5]O)(C)(C)C.C(CC(C)(C)C)(C)C.[CH2:15]([OH:29])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@@H:17]1[O:5][C@H:16]1[CH2:15][OH:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCC/C=C/CO
Reactant: CC(C)(C)OO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Solvent: O
Product: CCCCCCCCCCC[C@@H]1O[C@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 1.00 g of 4A powdered molecular sieves in 50 ml of dry CH2Cl2 was cooled to 0° C. under argon. To the cooled suspension was added 403 mg (1.42 mmole) of Ti(OiPr)4 and 463 mg (1.98 mmole) of L(+)diisopropyl tartrate via syringe. The mixture was stirred for 15 min and cooled to -20° C. A solution of tert-butylhydroperoxide in isooctane (3.8 M, 5.58 ml, 21.2 mmole) was added slowly to the mixture and the catalyst was allowed to "age" for 30 min at -20° C. A solution of 3.00 g (14.2 mmole) of E-2-tetradecen-1-ol in 10 ml of CH2Cl2 was dried over 3A molecular sieves for 15 min before being added to the mixture slowly, with stirring, at -20° C. The solution was then placed in the freezer (-30° C.) and allowed to stand of 24 H. The mixture was warmed to 0° C. and poured into a solution of 1.00 g of citric acid and 5.00 g of FeSO4 in 15 ml H2O. The organic layer was separated and the aqueous layer washed twice with 20 ml of CH2Cl2. The CH2Cl2 layers are combined, dried over MgSO4, filtered and evaporated to yield a sticky white solid. Recrystallization from Et2O:petroleum ether afforded 2.34 g of white solid, mp 68-70° C. 1H NMR δ 3.92 (ddd, 1, J=2.5, 6, 12 Hz), 3.63 (ddd, 1, J=4, 7, 12 Hz), 2.95 (m, 2), 1.64 (dd, 1, J=7, 5 Hz), 1.6-1.2 (m, 20), 0.88 (t, 3, J=5 Hz). Mass Spectra: M-31(--CH2OH)(1.0)197.2, M(100)55.1.