Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]2[CH:16]=[CH:15][S:14][C:10]=2[N:11]=[CH:12][N:13]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH2:6]([NH:7][C:8]1[C:9]2[CH:16]=[CH:15][S:14][C:10]=2[N:11]=[CH:12][N:13]=1)[CH2:5][C:4]#[CH:3]
Reactant: C[Si](C)(C)C#CCCNc1ncnc2sccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCCNc1ncnc2sccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
16 ml of tetrahydrofuran, 0.37 g of the 4-(4-trimethylsilanyl-3-butynylamino)thieno[2,3-d]pyrimidine obtained in (1) above, and 2.1 ml of a 1 M tetrabutylammonium fluoride tetrahydrofuran solution were added to a nitrogen-substituted flask, and the obtained mixture was then stirred at a room temperature for 5 hours. After completion of the stirring, 50 ml of a saturated ammonium chloride aqueous solution was added to the reaction solution, and the thus obtained solution was then extracted with 30 ml of dichloromethane twice. The organic layer was washed with 30 ml of a saturated brine, and it was then dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. Thereafter, the residue was then purified by column chromatography (Wako Gel C-200; toluene:ethyl acetate=4:1), so as to obtain 0.20 g of 4-(3-butynylamino)thieno[2,3-d]pyrimidine.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]([Si:13]([CH3:33])([CH3:32])[O:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21]2)([CH3:12])[CH3:11]>CN(C=O)C>[Br:8][C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([O:17][CH2:16][CH2:15][O:14][Si:13]([C:10]([CH3:11])([CH3:9])[CH3:12])([CH3:33])[CH3:32])[CH:19]=2)[NH:23][C:22]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1cc2cc(OCCO[Si](C)(C)C(C)(C)C)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
NBS (0.137 g, 0.771 mmol) was added to ethyl 5-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1H-indole-2-carboxylate (0.255 g, 0.701 mmol) dissolved in DMF (2 mL) and the resulting mixture was stirred overnight at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4, filtered and the solvent evaporated. Purification was accomplished by silica gel column chromatography (0 to 50% EtOAc/hexanes) to afford the title compound (0.121 g, 39%) as an oily solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.90 (br. s., 1H), 7.27 (d, 1H), 7.02-7.07 (m, 1H), 7.01 (s, 1H), 4.43 (q, 2H), 4.11 (t, 2H), 4.00 (t, 2H), 1.43 (t, 3H), 0.91 (s, 9H), 0.11 (d, 6H). LC-MS (ES+) m/z 442.2 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>O>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:5](=[O:8])[N:6]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:44])[F:45])=[CH:43][CH:42]=2)[N:7]=1
Reactant: Oc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c(Cl)nn1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added 6-chloro-4,5-bis(4-chlorophenyl)pyridazin-3-ol (1.5 gm, 4.26 mmol), DMF (15 ml) and K2CO3 (1.17 gm, 8.52 mmol). The reaction was stirred at rt for 30 min. After this time, 4-trifluoromethylbenzyl bromide (1.2 gm, 5.19 mmol) was added to the reaction and the reaction was stirred at rt for an additional 8 hrs. The reaction mixture was then diluted with water (40 ml). The reaction mixture was poured into a separatory funnel and extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (4×30 ml) and saturated aqueous NaCl (30 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give product 6-chloro-4,5-bis(4-chlorophenyl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one as off white solid (1.5 gm, 65.1% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][NH:18][C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])=[O:20]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([C:19]([NH:18][CH3:17])=[O:20])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CNC(=O)c1cccc(N)c1
Product: CNC(=O)c1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-methylamino)carbonyl]aniline were reacted to provide 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.01 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz), 7.68-7.61 (m, 2H), 7.45 (t, 1H, J=8.4 Hz), 7.16-7.03 (m, 3H), 6.68 (td, 1H, J=1.2 and 8.7 Hz), 2.90 (s, 3H); LCMS: purity: 95%; MS (m/e): 354(MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=1)[CH2:15]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Reactant: C#CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.033 mL, 0.33 mmol), 5-bromo-7-methyl-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.102 g, 0.25 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-methyl-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.05 g, 43%).
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(Br)cc1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc(Br)cc1)Oc1ccc2c(c1)CCCN2

Procedure:
Nitrogen flushed mixture of 4-bromo-phenyl-carbamic acid 1-benzyl-1,2,3,4-tetrahydro-quinolin-6-yl ester (0.655 g., 1.5 mmol) and 5% Pd—C (0.06 g.) in absolute ethanol (20 ml) was shaken in a par apparatus at room temperature (40° C.) under 50 psi pressure of hydrogen for 5 hours. Then Pd—C was discarded through filtration. The reaction mixture was concentrated under reduced pressure and the residue was washed with dichloromethane (2×3ml) to give 2f; yield: 0.48 g. (92.3%), m.p: 198° C., C16H15BrN2O2; 1H NMR δ ppm (DMSO): 1.82-2.00 (bs, 2H), 2.76 (t, 2H), 3.27 (t, 2H), 7.01-7.08 (m, 3H), 7.25-7.39 (m, 4H), 10.14 (s, 1H), IR vmax (KBr) (cm−1): 506, 608, 690, 749, 814, 884, 927, 1005, 1211, 1265, 1319, 1354, 1401, 1440, 1501, 1550, 1601, 1748, 1938, 2370, 2779, 2725, 2767, 2823, 2922, 3262, 3420, 3774.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([F:20])[C:14]=2[Cl:21])[C:6]=1[F:22])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Br:19][C:17]1[CH:16]=[C:15]([F:20])[C:14]([Cl:21])=[C:13]([O:12][C:7]2[C:6]([F:22])=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][C:8]=2[Cl:11])[CH:18]=1
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Yield: 73.7 %

Procedure:
1-(azidomethyl)-3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorobenzene (8.3 g, 20.29 mmol) dissolved in THF (100 mL) was treated successively with triphenylphosphine (7.98 g, 30.4 mmol) and water (1.828 g, 101 mmol) at 25° C. for 2 days with stirring. The reaction mixture was concentrated to dryness and purified on 330 g silica gel eluted successively with EtOAc (to remove triphenylphosphine oxide) followed by 0 to 10% CH3OH/DCM to give ({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (5.73 g, 14.96 mmol, 73.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.48-7.63 (m, 3H), 6.71 (s, 1H), 3.77 (s, 2H), 1.90 (s, 2H). LC-MS (ES−) m/z 380.00, 381.97, 384.06 [M−1]. LC-MS (ES+) m/z 381.84, 383.83, 385.87 [M+H].
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH:31](O)(C)[CH3:32]>[Ni]>[Cl:18][C:14]1[C:15]([Cl:17])=[CH:16][C:11]2[N:10]([C@@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]3)[C:31]([CH3:32])=[N:19][C:12]=2[CH:13]=1
Reactant: CC(C)O
Reactant: CC(=O)OC[C@@H]1C[C@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ni]
Product: Cc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
(±)-(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (1.00 g, 2.16 mmol), Raney nickel (Aldrich, slurry in water, 100 mg wet), and isopropanol (200 mL) were shaken under hydrogen (50 psi) for 1.25 hours. Catalyst was filtered off with Celite and the filtrate-wash evaporated to dryness. The residual yellow oil was dissolved in triethylorthoaceate (20 mL) with 1 drop of methanesulfonic acid and the solution stirred at ambient temperature for 18 hours. Volatiles were removed in vacuo and the residue stirred in dioxane (20 mL)-1N sodium hydroxide (10 mL) for 5 hours at ambient temperature. The pH was then adjusted to 1 with concentrated hydrochloric acid and stirring continued for 15 minutes, at which point TLC (silica gel, developed with 20 % methanol-chloroform) showed one UV-absorbing spot at Rf 0.25. The solution was neutralized with sodium hydroxide and volatiles evaporated in vacuo. The residue was chromatograped on a silica gel column and title compound eluted with 10-15% methanol-chloroform. Crystallization from ethanol-methanol-water gave (±)-(1R*,2S*,3S*,5S*)-5-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as fine white crystals (0.482 g, 67%), m.p. 222°-226° C.; 1H-NMR(DMSO-d 6) δ: 8.30 and 7.72 (both s, 2,2 aromatic CH), 5.0-4.8 (m, 3,2 OH and NCH), 4.56 (t, J=5.1 Hz, 1, CH2OH), 4.2-4.1 (m, 2,2 OCH), 3.8-3.5 (m, 2, CH2O ), 2.58 (s, 3, CH3), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m, 2, CH2); mass spectrum (CI): 332 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([NH2:18])=[C:12]3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1.[C:22]([CH2:24][CH:25]([CH2:33][CH2:34]OS(C)(=O)=O)[CH2:26][CH2:27]OS(C)(=O)=O)#[N:23].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN1CCCC1=O.O.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH3:21])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([N:18]4[CH2:34][CH2:33][CH:25]([CH2:24][C:22]#[N:23])[CH2:26][CH2:27]4)=[C:12]3[C:11]([CH3:20])=[CH:10]2)=[C:6]([CH3:8])[CH:7]=1
Reactant: CS(=O)(=O)OCCC(CC#N)CCOS(C)(=O)=O
Reactant: Cc1cc(N)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(N2CCC(CC#N)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 135 °C
Yield: 65.7 %

Procedure:
A mixture of 1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ylamine (10.0 g), methanesulfonic acid 3-cyanomethyl-5-methanesulfonyloxy-pentyl ester (11.3 g) and N,N-diisopropylethylamine (8.25 g) in N-methylpyrrolidone (10 mL) was heated at 135° C. for 4 hours. Methanesulfonic acid 3-cyanomethyl-5-methanesulfonyloxy-pentyl ester (2.60 g) was added to the reaction mixture and the mixture was heated at 135° C. for 4.5 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of ethyl acetate, hexane and water (10/1/3), and separated. The aqueous phase was extracted with a mixture of ethyl acetate and hexane (10/1). The combined organic phase was washed with brine, dried over MgSO4, and filtered, and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate:CHCl3=4/1/0.5) to obtain a solid. The solid was crystallized from diisopropylether to obtain {1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile (8.61 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[CH2:14][CH2:15]2)[S:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(NC2CCN(C3CCCCC3=O)CC2)c1
Product: COc1ccc(S(=O)(=O)N(c2cccc(OC)c2)C2CCN(C3CCCCC3=O)CC2)cc1

Procedure:
The title compound, MS (ISP): m/e=551.4 (M+H+), was prepared as for example 99, steps (A) to (F). Step (B) was performed using 3-methoxy-aniline, and yielded (+/−)-trans-2-[4-(3-methoxy-phenylamino)-piperidin-1-yl]-cyclohexanol, which was oxidized to (+/−)-2-[4-(3-methoxy-phenylamino)-piperidin-1-yl]-cyclohexanone in step (C). This was then reacted with 4-methoxy-benzensulfonyl chloride in step (D), yielding (+/−)-N-(3-methoxy-phenyl)-4-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide. The final step (F) was performed with bromobenzene.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]([CH2:24][O:25][CH3:26])[CH2:21][C@H:20]1[C:27]([OH:29])=[O:28])=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>CC#N.CCOC(C)=O>[CH3:26][O:25][CH2:24][CH:22]1[CH2:23][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:18])[C@H:20]([C:27]([O:29][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[O:4])=[O:28])[CH2:21]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COCC1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC1C[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Yield: 86.7 %

Procedure:
To a solution of 2-bromo-1-(4-bromophenyl)ethanone (2.3 g, 8.39 mmol) and (S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (2.61 g, 10.06 mmol) in MeCN (100 mL) was added Et3N (1.26 mL, 9.24 mmol). After stirring over night, the solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (3.32 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:13]([O:30][CH:31]([CH3:33])[CH3:32])[CH:12]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:39]>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N+:16]([O-:39])=[C:15]([CH3:17])[C:14]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:27])[CH3:28])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:13]([O:30][CH:31]([CH3:33])[CH3:32])[CH:12]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cccc(CC)c1-c1cc(OC(C)C)c(COc2cc(C(C)C)ccc2C)c(C)n1
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc(OC(C)C)c(COc2cc(C(C)C)ccc2C)c(C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine (250 mg, 0.56 mmol) and 3-chloroperoxy-benzoic acid (77%, 150 mg, 0.67 mmol) in CH2Cl2 (10 mL) is stirred at room temperature for 2 hours. The mixture is diluted with CH2Cl2 (20 mL) and washed with saturated Na2CO3, brine dried over sodium sulfate, and concentrated in vacuo. The residue is purified on PTLC (1:1 hexane EtOAc) to give 6-(2,6-diethyl-phenyl)-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine 1-oxide. 1H NMR (CDCl3) 7.90 (m, 1H), 7.50-7.04 (m, 3H), 6.90-6.71 (m, 3H), 5.18 (m, 2H), 4.55 (m, 1H), 3.95 (m, 1H), 2.78 (s, 3H), 2.52-2.20 (m, 4H), 2.20 (s, 3H), 1.35 (d, 6H), 1.25 (d, 6H), 1.08 (t, 6H).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22](C#N)[CH2:21][CH2:20]3)=[N:11]2)(=O)=O)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:19]1([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: N#CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reaction time: 6 h
Yield: 418 %

Procedure:
To a stirred mixture of 4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperazine-carbonitrile (163 g, 0.44 mol) in tetrahydrofuran (2.01) was added, dropwise, lithium aluminum hydride (880 ml; 0.88 mol of a 1M lithium aluminum hydride solution in tetrahydrofuran). After complete addition, the reaction was heated to reflux and stirred for 6 hours, stirred at ambient temperature for one hour and allowed to sit at room temperature overnight. The reaction was quenched by the careful dropwise addition of water. After no more hydrogen could be observed to evolve, the reaction was filtered and the lithium salt filter cake was washed well with tetrahydrofuran. The filtrate was combined with the filtrate of another run (all together the starting material totaled 300 g, i.e. 820 mmol) and the combined filtrates were concentrated to afford 372 g of a yellow solid suspended in water. An attempt was made to partition the product between water and dichloromethane, but the product proved to be only slightly soluble in dichloromethane. Therefore, the biphasic product suspension was filtered through a course sintered funnel and the white product which was collected was dried to afford 121 g. The two phases of the filtrate were separated and the water was extracted again with dichloromethane. All of the dichloromethane phases were combined, washed twice with water, dried with magnesium sulfate, and concentrated to afford 41 g of a brown residue. The residue was triturated with diethyl ether and filtered to afford 10 g of a beige solid, m.p.=139°-150° C. The NMR and MS spectra were consistent with the structure. Recrystallization of 10 g from toluene afforded 7.5 g of 3-(1-piperazinyl-1H-indazole, m.p. 153°≥155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[CH2:11][OH:12]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[CH:11]=[O:12]
Reactant: OCCc1ccc(Cl)c(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc(CCO)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Manganese (IV) dioxide (1.00 g) was added to a solution of 2-(4-chloro-3-(hydroxymethyl)phenyl)ethanol (example 61, step b) (0.200 g) in DCM (5 mL), and the resulting suspension was stirred at room temperature overnight. The mixture was then filtered through Celite, washing the residue well with DCM. The filtrate and washings were concentrated in vacuo to afford the subtitled compound as a colourless oil. Yield 0.197 g.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CN(C)C=O.[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[NH:35][CH:34]=[CH:33]4)[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:22])[CH3:21]>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[NH:35][CH:34]=[C:33]4[CH:2]=[O:3])[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (1.1 mL) in dichloromethane (60 mL) at 0° C. was added a solution of N,N-dimethylformamide (1.16 mL) in dichloromethane (30 mL) dropwise during 30 mins. The reaction mixture was stirred at this temperature for 15 minutes. A solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (3.5 g) in dichloromethane (60 mL) was added in one portion. The mixture was warmed to room temperature slowly. After stirred at room temperature for 5 hours, dichloromethane was evaporated off. Ethyl acetate (300 mL), water (100 mL) and concentrated HCl solution (5 mL) was added to the residue. The obtained mixture was stirred for 30 minutes. KOH was added to basify the solution to pH value about 8. The organic layer was separated, washed with water and brine, dried over MgSO4. Filtration and evaporation afforded the product 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (4.0 g). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 4.87-4.93 (1H, m), 7.43-7.47 (2H, m), 8.07 (1H, dd), 8.21 (1H, dd), 8.37 (1H, d), 8.40-8.41 (2H, m), 10.06 (1H, s), 11.98 (1H, br s). MS (ES): C20H16ClN3O3 requires 381; found 382.1 (M+H+).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([NH2:16])[S:13][N:12]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C@@H:18]1[CH2:20][C@H:19]1[C:21](OCC1C=CC=CC=1)=[O:22].CC(C)([O-])C.[K+]>C([O-])(O)=O.[Na+]>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([NH:16][C:21]([C@@H:19]3[CH2:20][C@H:18]3[CH3:17])=[O:22])[S:13][N:12]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1ccc(-c2cc(N)sn2)cc1
Reactant: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Product: C[C@@H]1C[C@H]1C(=O)Nc1cc(-c2ccc(C(C)(F)F)cc2)ns1
Yield: 50.3 %

Procedure:
Mix 3-[4-(1,1-difluoroethyl)phenyl]isothiazol-5-ylamine (0.200 g, 0.833 mmol), benzyl (R,R)-2-methylcyclopropanecarboxylate (0.238 g, 1.250 mmol) and potassium t-butoxide (0.190 g, 1.667 mmol) for 1 h. Dilute with satd NaHCO3 and extract with EtOAc. Wash the organic phase with brine, dry (MgSO4) and evaporate. Chromatography on silica gel, eluting with 10% EtOAc in CHCl3, affords (R,R)—N-[3-[4-(1,1-difluoroethyl)phenyl]isothiazol-5-yl]-2-methylcyclopropane-carboxamide. Yield: 50.3%. ES-MS: m/e 323.3 (m+1).