Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[Li]CCCC.CN([CH:31]=[O:32])C.Cl>C1COCC1>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([CH:31]=[O:32])[CH:11]=[CH:10]3)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (2.249 g, 6.25 mmol, 1.0 eq.) was dissolved in THF (10 mL) under nitrogen atmosphere. Then the mixture was cooled down to −78° C. and a solution of n-BuLi in THF (2.5 M, 7.5 mL, 18.8 mmol, 3.0 eq.) was added to the mixture dropwise. The mixture was stirred at −78° C. for 15 min. then DMF (2.4 mL, 31.2 mmol, 5.0 eq.) was added to the mixture and stirred at −78° C. for 1 h. When the reaction completed, 1 M HCl was added to adjust the pH to 6. The mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using petroleum ether/ethyl acetate (10/1) as eluent to give 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde as a white solid (1.16 g, 60%). EDI-MS: 311.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.24 (s, 1H), 7.92-7.87 (m, 2H), 7.77 (d, 1H), 7.22-7.19 (m, 2H), 4.42-4.30 (m, 1H), 2.30-2.28 (m, 2), 1.93-1.90 (m, 2H), 1.48-1.11 (m, 5H), 0.82 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15](O)=[O:16])=[C:13]([CH3:18])[N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1.C[CH2:21][N:22](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.CN>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([NH:22][CH3:21])=[O:16])=[C:13]([CH3:18])[N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1
Reactant: Cc1nccc(-c2cc(F)c(Cl)cc2F)c1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2cc(F)c(Cl)cc2F)ccnc1C
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
To the stirred solution of 4-(4-chloro-2,5-difluorophenyl)-2-methylnicotinic acid (1.7 g, 4.02 mmol) in DMF (0.5 mL) was added DIEA (2.81 mL, 16.06 mmol), HOBT (1.230 g, 8.03 mmol), EDC (1.155 g, 6.02 mmol) at 0° C. followed by addition of methylamine hydrochloride (0.488 g, 7.23 mmol). After stirring for 10 min, the ice bath was removed and the reaction mixture was allowed to stir overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (10 mL) and washed with water (10 mL) followed by brine (10 mL). The organic layer was separated and dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford 4-(4-chloro-2,5-difluorophenyl)-N,2-dimethylnicotinamide (1 g, 2.123 mmol, 53% crude yield) as a brown solid which was taken to the next step without purification. LC/MS (ESI) m/e 297.3 [(M+H)+, calcd for C14H12ClF2N2O 297.1]; LC/MS retention time (method B): tR=0.76 min.
Reaction SMILES: C([C:4]1[S:8][C:7]2[S:9][C:10]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[CH:5]=1)(O)=O.C>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.[Cu]>[S:9]1[C:7]2[S:8][CH:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[C:12]([C:14]1[CH:15]=[C:16]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Agent: [Cu]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 250 °C
Yield: 61 %

Procedure:
2-{3-(5-Carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (14 g), copper powder (1.5 g) and copper turnings (1.5 g) are suspended in diphenyl ether (60 cc) and heated at 250° C. for 30 minutes. After cooling, the reaction mixture is diluted with methylene chloride (100 cc), decolourizing charcoal (1 g) is added and the mixture is filtered. The filtrate is extracted three times with a 10% (w/v) aqueous solution of sodium carbonate (total 150 cc), and then washed twice with distilled water (total 100 cc). The combined aqueous phases are acidified to pH 1 by the addition of 12N concentrated hydrochloric acid and extracted four times with methylene chloride (total 200 cc). The combined methylene chloride solutions are washed three times with distilled water (total 90 cc), dried over anhydrous sodium sulphate and evaporated. Crude 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (7.5 g) in the form of an oil is thus obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10](Br)[CH:11]=[CH2:12].[Cl:14][C:15]1[CH:16]=[C:17]2[NH:24][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[N:22][C:18]2=[N:19][C:20]=1[I:21]>C1COCC1>[CH2:10]([N:24]1[C:17]2[C:18](=[N:19][C:20]([I:21])=[C:15]([Cl:14])[CH:16]=2)[N:22]=[C:23]1[S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=[CH2:12]
Reactant: C=CCBr
Reactant: CS(=O)(=O)c1nc2nc(I)c(Cl)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCn1c(S(C)(=O)=O)nc2nc(I)c(Cl)cc21
Temperature: 60 °C

Procedure:
N,N-diisopropylethylamine (0.69 ml, 3.95 mmol) and allyl bromide (0.32 ml, 3.70 mmol) were added to a stirred suspension of 6-chloro-5-iodo-2-methylsulfonyl-1H-imidazo[4,5-b]pyridine (1.0824 g, 3.03 mmol) in THF (12.0 ml). The reaction mixture was heated to 60° C. for 18 h, then cooled to room temperature. The reaction mixture was partitioned between EtOAc (50 ml) and brine (50 ml). The organic layer was washed with brine (1×50 ml). The combined aqueous layers were extracted with EtOAc (1×50 ml). The organic layers were combined, dried over Na2SO4, filtered, and evaporated under reduced pressure to give the title compound as a yellow foam. This material was a mixture of the allyl regioisomers and was used without further purification. LC-MS: calculated for C10H9ClIN3O2S 396.91 observed m/e: 397.89 (M+H)+ (Rt 1.12 and 1.17/2 min).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5](=[O:35])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1.[C:36]([Cu])#[N:37]>CN(C=O)C>[C:36]([C:2]1[CH:3]=[CH:4][C:5](=[O:35])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1)#[N:37]
Reactant: N#C[Cu]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(I)ccc3=O)CC2)C1
Solvent: CN(C)C=O
Product: N#Cc1ccc(=O)n(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
A solution of N-({1-[4-(5-iodo-2-oxo-2H-pyridin-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 8, Step C, 300 mg, 0.5 mmol), CuCN (Aldrich, 1 mmol), DMF (4 mL) in a sealed tube was irradiated under microwave at 180° C. for 30 min. The solid was filtered off and the residue was partitioned between water and a chloroform/IPA “cocktail” (˜3:1, v/v). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as yellow solid.
Reaction SMILES: [CH2:1]([O:5][N:6]1[C:15]([C:16](O)=[O:17])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:25])[CH:12]=2)[C:7]1=[O:26])[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:30])=O>C1COCC1.CN(C=O)C>[CH2:1]([O:5][N:6]1[C:15]([C:16]([Cl:30])=[O:17])=[C:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:25])[CH:12]=2)[C:7]1=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCOn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOn1c(C(=O)Cl)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
2-Butoxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (370 mg) was dissolved in THF(6.0 ml), and oxalyl chloride (170 μl) and DMF (1 drop) were added at 0° C. with stirring. The mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times to give 2-butoxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl.[NH2:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[Cl:28])[CH3:18]>>[CH2:1]([O:8][C:9]([NH:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[Cl:28])[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](N)c1ccc(C(=O)O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1Cl
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Benzyloxycarbonyl chloride (750 mg) was dropwise added to an aqueous solution (10 ml) of (R)-4-(1-aminoethyl)-3-chlorobenzoic acid hydrochloride (690 mg) and sodium hydroxide (410 mg) at room temperature, and the mixture was stirred for 3 hours. After the reaction, conc. hydrochloric acid was added to the reaction mixture to make the same acidic, and the mixture was extracted with chloroform. The extract was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 680 mg of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzoic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][C@H:4]([NH:21][S@](C(C)(C)C)=O)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.[ClH:29].CCOCC>CO>[ClH:29].[CH3:1][CH:2]([CH3:28])[CH2:3][C@H:4]([NH2:21])[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1
Reactant: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)C[C@H](N)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
(S)-2-methyl-propane-2-sulfinic acid {(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butyl}-amide (38.83 g, 93.90 mmol) was dissolved in methanol and transferred to a 3-necked 1 L flask with overhead stirring and internal temperature. A total of 210 mL methanol was added to give a yellow solution. This was placed in an ice bath and at an internal temperature of 8° C., HCl in ether (188 mL, 2.0 M, 376 mmol) was added over 2 min. The temperature went up to 14° C. The ice bath was removed and the reaction stirred for ˜5 min as a yellow solution than as a white slurry. At 30 min, the reaction was rotovapped to dryness and the solid slurried in diethylether (200 mL) for 1 h. The solid was collected by Buchner filtration, washing with additional diethylether. This was suction dried for ˜1 h and then placed on the vacuum pump to give (S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamine hydrochloride (31.58 g, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6, δ): 9.19 (s, 2H) 8.78 (br. s., 3H) 8.61 (d, J=8.2 Hz, 2H) 7.93 (d, J=8.4 Hz, 2H) 4.47 (br. s., 1H) 1.84-2.03 (m, 2H) 1.41 (m, 1H) 0.83-0.96 (m, 6H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[Si:36]([O:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>O1CCCC1>[Si:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([O:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]4[N:33]=[CH:34][N:35]=[C:9]34)[CH2:4][CH2:3]2)=[CH:48][CH:49]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 45 h

Procedure:
4′-{[4-(trans-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.46 g), 4-{[tert-butyl(dimethyl)silyl]oxy}phenol (0.49 g) and triphenylphosphine (0.29 g) were dissolved in tetrahydrofuran (2 mL), a solution of diisopropyl azodicarboxylate (0.58 mL, 1.9 M toluene solution) in tetrahydrofuran (1 mL) was added dropwise at 0° C., and the mixture was stirred at room temperature for 45 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as an oily compound (0.31 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][OH:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.CCOC(C)=O.C1(C)C=CC=CC=1>CCOC(C)=O.O=[Mn]=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH:29]=[O:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCc1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To a solution of the benzylic alcohol of Step 5 (2.899 g, 6.20 mmol) in EtOAc (120 mL) was added portionwise activated MnO2 (10.15 g, 114 mmol) and the reaction was followed by TLC (EtOAc:toluene 7.5:92.5). When the reaction was completed (approximately 2 h), the mixture was filtered through silica, concentrated, and the title product was purified by flash chromatography on silica using EtOAc:toluene 2.5:97.5. Yield 2.18 g, 85%.
Reaction SMILES: O.[OH-].[Li+].O.[CH3:5][C:6]1[CH:15]=[C:14]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[C:18]([C:25]([O:27]C)=[O:26])=[CH:17]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1>O1CCCC1>[CH3:5][C:6]1[CH:15]=[C:14]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[C:18]([C:25]([OH:27])=[O:26])=[CH:17]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: COC(=O)c1cn(-c2cc(C)nc3ccccc23)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-n2cc(C(=O)O)c3cccnc32)c2ccccc2n1
Yield: 72.5 %

Procedure:
0.62 g (15 mmol) of lithium hydroxide monohydrate and 18 cm3 of water were added, at a temperature in the region of 20° C., to 1.6 g (5.0 mmol) of methyl 1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate in solution in 18 cm3 of tetrahydrofuran. After stirring at reflux of the solvent for 4 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was taken up in 80 cm3 of water. The mixture was extracted with 30 cm3 of ethyl acetate and then the pH was adjusted to 3 by addition of 14 cm3 of a 1N hydrochloric acid solution. The precipitate obtained was filtered off, washed twice with 10 cm3 of water, pulled dry and then dried in a desiccator under reduced pressure at a temperature in the region of 20° C. for 4 days and under reduced pressure (2.7 kPa) at a temperature in the region of 50° C. for 12 h. 1.1 g of 1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid were thus obtained in the form of a yellow crystalline powder melting at a temperature of greater than 260° C. used directly in the following stage.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]1[S:12](=[O:14])(=[O:13])[C:11]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH:9]([NH:22][C:23](=O)[CH2:24][CH3:25])[CH2:8]1.CSC.B>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]1[S:12](=[O:13])(=[O:14])[C:11]2[S:15][C:16]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:17][C:10]=2[CH:9]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:8]1
Reactant: CCC(=O)NC1CC(COCCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCCNC1CC(COCCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 60 °C

Procedure:
To a solution of 11 (39.9 g, 0.021 mol) in THF (400 ml) under N2 was added dropwise 10M borane dimethylsulfide (42.5 ml, 0.42 mol). After addition, the reaction which was fitted with a short-path distillation head was heated to 60° C. for 3 h while collecting distilled dimethylsulfide and THF. The solution was then concentrated to dryness and then 6N HCl was carefully added dropwise. After addition the reaction was heated at reflux for 1/2 h, the solution was concentrated, flushed with EtOH (2×) and the residue was then carefully treated with saturated NaHCO3. The aqueous layer was extracted with EtOAc (4×) and the organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column (120 mm) packed with silica gel and eluted with 20:1 CHCl3 --CH3OH to yield 15.4 g (40%) of trans -12 and then 4.7 g (12%) of cis-13.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12]([OH:14])=[N:11][CH:10]=[N:9][C:8]=2[S:7]/[C:6]/1=[N:15]\[C:16](=[O:28])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1F)[CH2:2][CH2:3][CH3:4].[CH2:29]([OH:33])[C@@H:30]([OH:32])[CH3:31].CC(C)([O-])C.[K+].C1COCC1>C(O)(=O)C>[CH2:1]([N:5]1[C:13]2[C:12]([OH:14])=[N:11][CH:10]=[N:9][C:8]=2[S:7]/[C:6]/1=[N:15]\[C:16](=[O:28])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:33][CH2:29][C@@H:30]([OH:32])[CH3:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ncnc(O)c21
Reactant: C[C@H](O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)O)sc2ncnc(O)c21
Yield: 66.4 %

Procedure:
A mixture of Example 1B (65 mg, 0.16 mmol), (S)-propane-1,2-diol (28 mg, 0.36 mmol) and 1N solution of potassium tert-butoxide in THF (0.33 mL, 0.33 mmol) was heated at 45° C. for 18 hours. The mixture was acidified to pH 5 with acetic acid then concentrated under reduced pressure. The residue was stirred with saturated aqueous NaHCO3, extracted with EtOAc, concentrated, and the residue was purified by chromatography (EtOAc-EtOH 19:1) to afford 50 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90-0.96 (m, 3H) 1.19 (d, J=5.76 Hz, 3H) 1.30-1.41 (m, 2H) 1.77-1.86 (m, 2H) 3.93-4.08 (m, 3H) 4.66-4.76 (m, 2H) 4.87 (d, J=4.07 Hz, 1H) 7.36 (d, J=8.82 Hz, 1H) 7.82 (dd, J=8.82, 2.03 Hz, 1H) 8.22 (s, 2H) 13.12 (s, 1H). MS (ESI) m/z 471 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:9]1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:42])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:30])([F:31])[F:29])=[N:9]1
Reactant: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
To a mixture of 1-(2-chloro-phenyl)-5-[2-(4-methylsulfanyl-phenyl)-pyridin-6-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (9.0 mg, 0.02 mmol) prepared in Example 153 in dichloromethane (1.0 mL), was slowly added meta-chloroperbenzoic acid (77%, 2.0 mg, 0.01 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/1) to give 2.0 mg of the titled compound as a white solid.
Reaction SMILES: Cl.[S:2]([N:12]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]1=2)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:24](OCCC(C)C)=[O:25]>C(OCC)C>[OH:25][N:24]=[C:16]1[CH2:17][CH2:18][N:12]([S:2]([C:5]2[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=2)(=[O:3])=[O:4])[C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[C:15]1=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CCC(=NO)C(=O)c3ccccc32)cc1
Yield: 61.2 %

Procedure:
Hydrochloric acid gas was bubbled through a cooled suspension of 1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one (30 g, 0.1 mol) in a dry diethyl ether (500 mL) at 0-5° C. Isoamyl nitrite (26.41 mL, 0.24 mol) was added drop wise and hydrochloric acid gas was continuously passed for 6-7 h after the addition. The precipitate that formed was filtered washed with diethyl ether and dried under reduced pressure to afford 4-(hydroxyimino)-1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5 (2H)-one (21.09 g). 1H NMR: 400 MHz, CDCl3) δ: 7.79 (1H, d, J=7.6 Hz), 7.2 (1H, t, J=7.6 Hz), 7.62 (1H, d, J=8.0 Hz), 7.55 (1H, t, J=7.2 Hz), 7.39 (2H, d, J=8.4 Hz), 7.16 (2H, d, J=8.4 Hz), 4.07 (2H, t, J=6.8 Hz), 2.88 (2H, t, J=6.8 Hz), 2.342 (3H, s), 1.98 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:25])([CH3:24])[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.Cl[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:25])([CH3:24])[CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[CH:15][CH:14]=2)[C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:5][CH:4]=1
Reactant: Clc1ncccn1
Reactant: COc1ccc(C(C)(C)CNCc2ccc(OC(F)(F)F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)(C)CN(Cc2ccc(OC(F)(F)F)cc2)c2ncccn2)cc1
Yield: 88.1 %

Procedure:
Condensation N-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethoxy)benzyl]amine (250 mg; 0.71 mmol) with 2-chloro-pyrimidine (85 mg; 0.74 mmol) as per general procedure E (2 eq DIEA, 210C, 14 hr) afforded N-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine (270 mg; 88% yield). MS: m/z 432 (M+1).