Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][C:23](OC(C)C)=[O:24])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][CH2:23][OH:24])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CC(=O)OC(C)C)c12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CCO)c12
Yield: 62.3 %

Procedure:
To a solution of isopropyl [4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (453 mg, 0.920 mmol) in tetrahydrofuran (5 mL) was added lithium tetrahydroborate (60 mg, 2.76 mmol), and the mixture was refluxed for 2 hr. After cooling, the reaction mixture was quenched with water and extracted with ethyl acetate (×2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residual solid was recrystallized from ethyl acetate-n-hexane to give the title compound (250 mg, 0.573 mmol, 62.3%) as a colorless crystal. The filtrate was concentrated in vacuo, and the residual solid was recrystallized from ethyl acetate-n-hexane to give the title compound (91 mg, 0.209 mmol, 22.7%) as a colorless crystal. Total amount: 341 mg, 0.781 mmol, 85%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1[C:7]2[C:14](=O)[NH:13][CH:12]=[N:11][C:8]=2[NH:9][N:10]=1.CN(C)C1C=CC=CC=1>>[Cl:3][C:14]1[N:13]=[CH:12][N:11]=[C:8]2[NH:9][N:10]=[CH:6][C:7]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2[nH]ncc12
Solvent: CN(C)c1ccccc1
Product: Clc1ncnc2[nH]ncc12
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Phosphorus oxychloride (300 mL, 3.2 mol) was added to allopurinol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 20 g, 0.15 mol) and then N,N-dimethylaniline (30 mL, 0.24 mol) was added at room temperature. The resulting mixture was heated at reflux for 90 min and then cooled. The solvent was removed under vacuum. The residue was co-evaporated twice with toluene, and the resulting dark colored syrup was poured into a mixture of ice and water (500 mL). The mixture was stirred for 15 min, then transferred to a separatory funnel and extracted with ether (4×500 mL) and ethyl acetate (2×500 mL). The combined organic layers were washed twice with ice-water, dried (sodium sulfate), and concentrated to approximately 1.5 L. Charcoal was added to the slightly purple solution and the mixture was filtered through Celite. The Celite was washed with ethyl acetate and the combined filtrates were evaporated to dryness to give 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (13 g, 56%) as a pale green solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.81 (s, 1H), 14.50 (br s, 1H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:5][CH2:4]1)#[CH:2].[CH2:13]([Li])[CH2:14][CH2:15]C.CN(C)P(=O)(N(C)C)N(C)C.C(I)CC>O1CCCC1.CCCCCC.O>[CH2:11]1[CH2:10][O:9][C:6]2([CH2:5][CH2:4][CH:3]([C:1]#[C:2][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2)[O:12]1
Reactant: C#CC1CCC2(CC1)OCCO2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC#CC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of 6.5 g of 4-ethynyl-1,1-ethylenedioxycyclohexane in 40 ml of tetrahydrofuran was treated at -20° C. with 39.1 ml of a 1.4M solution of butyl lithium in hexane. Subsequently, the mixture was treated at 0° C. with 60 ml of hexamethylphosphoric acid triamide (brief temperature rise to 26° C.) and then dropwise with 6.5 ml of propyl iodide. The cooling bath was removed and the mixture was left to warm to room temperature. A white precipitate formed. After 30 minutes, the mixture was treated with 150 ml of water and extracted three times with hexane. The organic phases were washed three times with water and the wash-water was back-extracted with hexane. The organic phases were dried over magnesium sulphate, filtered and freed from solvent on a rotary evaporator. Low-pressure chromatography of the resulting, yellow liquid (9 g) on silica gel with ethyl acetate/petroleum ether (vol. 10:90) and treatment with active carbon gave 6.23 g (76.5%) of 1,1-ethylenedioxy- 4-(1-pentynyl)cyclohexane as a light pale yellow liquid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=3[CH2:35][OH:36])[CH:12]=2)[N:7]=1.C(OCC)(=O)C.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([O:36][CH2:35][C:28]1[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:27]=1[C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH2:5])[N:15]=[C:14]2[C:16]([N:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26]1)=[O:17])(=[O:3])[CH3:2]
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
27 μl of acetyl chloride are added to a solution of 150 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 5 ml of dimethylformamide, and the mixture is stirred at 80° C. for 16 h. 8 ml of ethyl acetate and 8 ml of water are added, the organic phase is separated off and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][NH:10][CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21].C(N(C(C)C)CC)(C)C.[Cl:32][CH2:33][C:34](Cl)=[O:35]>CN(C=O)C.C1COCC1>[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][N:10]([C:34](=[O:35])[CH2:33][Cl:32])[CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CNC3
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CN(C(=O)CCl)C3
Temperature: 25 °C

Procedure:
To 50 mg (0.158 mmol) of 3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide hydrochloride in 3.0 ml of DMF was added dropwise 0.32 ml of 1.0 M solution containing diisopropylethylamine (DIPEA) in THF and (0.16 mmol) of 2-chloroacetyl chloride in 1.0 ml of DMF, according to standard procedures. The resulting mixture was continuously stirred at room temperature for several hours, and the progress of the reaction was monitored by TLC. The solvent was removed under vacuum, and the residue was recrystallized from a polar solvent. Similar procedures were used for 3-amino-6-[2-(4-benzyl-cyclohexylamino)-acetyl]-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (103) and 3-amino-6-(6-morpholin-4-yl-pyridine-3-carbonyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (105). In some cases, if the product was not recrystallized from methanol or ethanol, the reaction mixture was purified by flash column chromatography or preparative HPLC. All products were verified by NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[NH:17][C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][CH2:33][CH3:34].O>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:28])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[N:17]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])[CH2:32][CH2:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: N#Cc1ccc(N)c(NC(=O)CCCCCNC(=O)OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)CCCCCNC(=O)OCc1ccccc1)c1cc(C#N)ccc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound (961 mg) obtained in Example 48-1 was dissolved in DMF (20 ml). After having been cooled to 0° C., the solution was added with 60% sodium hydride (72.9 mg) and warmed back to room temperature and the whole was stirred for 30 minutes. 1-Iodopropane (0.30 ml) was dropped to the solution and the whole was stirred for additional 3 hours. After having been cooled to 0° C., the solution was added with water to stop the reaction and concentrated. The residue was subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (317 mg) as a yellow oily substance.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]([CH3:10])[CH:8]=[N:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:10][N:7]1[C:6]2[CH:11]=[CH:12][C:3]([OH:2])=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: COc1ccc2c(c1)ncn2C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1cnc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.9 %

Procedure:
To a solution of 5-methoxy-1-methyl-1H-benzo[d]imidazole (500 mg, 3.08 mmol) in CH2Cl2 (6 ml) was added BBr3 (3.1 g, 12.33 mmol) dropwise at 0° C. After addition, the mixture was stirred for 2 h at 0° C. The mixture was then quenched by slow addition to ice water (50 mL). The resulting mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (100 mg, 21.9%) as a white solid which was used in next step without further purification. LCMS (m/z): 149.1 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCN2C(=NCCC2)CC1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[CH2:32]([O:19][C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Boc-4-iodophenylalanine was dissolved in acetonitrile and DBU (1 equivalent) was added followed by benzyl bromide (1 equivalent). The mixture was stirred for 2 h at room temperature. After removal of the solvent under reduced pressure, the residue was dissolved in EtOAc and the solution washed with 10% aqueous HCl and water. Drying (MgSO4) and concentration under reduced pressure gave a crude product that was purified by crystallization from hexane.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][C:18]3[O:19][C:20]([F:23])([F:22])[O:21][C:17]=3[CH:16]=2)(=[O:13])=[O:12])=[CH:7][C:6]=1[F:35])([CH3:4])([CH3:3])[CH3:2].C[O:37][C:38]([C:40]1[CH:41]=[CH:42][C:43](Br)=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)=[O:39].C([O-])([O-])=O.[K+].[K+].O[Li].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:25]([C:43]3[CH:42]=[CH:41][C:40]([C:38]([OH:39])=[O:37])=[C:49]4[C:44]=3[CH:45]=[CH:46][CH:47]=[N:48]4)=[CH:24][C:18]3[O:19][C:20]([F:22])([F:23])[O:21][C:17]=3[CH:16]=2)(=[O:12])=[O:13])=[CH:7][C:6]=1[F:35])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(Br)c2cccnc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc3c(cc2B2OC(C)(C)C(C)(C)O2)OC(F)(F)O3)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc3c(cc2-c2ccc(C(=O)O)c4ncccc24)OC(F)(F)O3)cc1F
Temperature: 95 °C
Yield: 50.4 %

Procedure:
A mixture of the 4-tert-butyl-N-[2,2-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzodioxol-5-yl]-3-fluorobenzenesulfonamide (3.2 g, 6.22 mmol), methyl-5-bromoquinoline-8-carboxylate (Example 1, step-b, 1.66 g, 6.22 mmol) and 2 M aq. K2CO3 (7.8 mL, 15.55 mmol) in 1,4-dioxane (50 mL) was purged with nitrogen for 5 minutes. Pd(PPh3)4 (360 mg, 0.31 mmol, 5 mol %) was added and the reaction mixture was heated at 95° C. for overnight. The reaction mixture was cooled to r.t. LiOH.H2O (2.6 g, 62.2 mmol) was added and heated at 80° C. for 1 hour. Cooled to r.t, pH of the reaction medium was adjusted to ˜6 with 2N aq.HCl, extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was triturated with methanol to get pure (>95%) title compound as an off-white solid (1.75 g, 50%). 1H NMR (400 MHz, CD3OD) δ 8.96-8.94 (m, 1H), 8.57 (d, J=7.4 Hz, 1H), 7.93-7.91 (m, 1H), 7.57-7.54 (m, 2H), 7.42-(t, J=7.8 Hz, 1H), 7.30-7.26 (m, 1H), 7.18-7.15 (m, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.88 (s, 1H), 6.56 (br, 1H), 1.43 (s, 9H); MS: (ES) m/z calculated for C27H21F3N2O6S.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:20]=[CH:19][C:13]([O:14][Si](C)(C)C)=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][CH:3]=1.Br[C:22]1C=CC(C(C2C=CC(O)=CC=2)=C)=CC=1.C[Si](C)(C)N[Si](C)(C)C.C(I)I>CCOCC.[Zn].Cl[Cu]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:10]3[CH:20]=[CH:19][C:13]([OH:14])=[CH:12][CH:11]=3)[CH2:22][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: C=C(c1ccc(Br)cc1)c1ccc(O[Si](C)(C)C)cc1
Agent: Cl[Cu]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Zn]
Solvent: CCOCC
Solvent: ICI
Product: Oc1ccc(C2(c3ccc(Br)cc3)CC2)cc1

Procedure:
Eg) A mixture of 457 mg of zinc dust and 692 mg of CuCl in 15 ml of ether is heated under reflux under argon. Subsequently, a solution of 934 mg of [4-[1-(4-bromo-phenyl)-vinyl]-phenoxy]-trimethyl-silane in 15 ml of ether, prepared from 748 mg of 4-[1-(4-bromo-phenyl)-vinyl]-phenol (Ex. Ef) and 14 ml of hexamethyldisilazane under reflux, is added dropwise and thereafter 0.56 ml of methylene iodide is added. The reaction mixture is heated under reflux and diluted with ether. The residue is washed with ether and the filtrate is washed with water, dried and concentrated. The crude product is purified over silica gel with ethyl acetate-hexane as the eluent. 4-(1-(4-Bromo-phenyl)-cyclopropyl)-phenol is obtained as a brown oil, MS: m/e 288 (M+H+, 1Br).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1([C:27]#[CH:28])[OH:26]>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1([CH:27]=[CH2:28])[OH:26]
Reactant: C#CC1(O)c2cc(OC)ccc2CC(N(C)S(=O)(=O)c2ccc(C)cc2)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C=CC1(O)c2cc(OC)ccc2CC(N(C)S(=O)(=O)c2ccc(C)cc2)C1(C)C
Yield: 95 %

Procedure:
A mixture of 205 g of 2,2-dimethyl-1-ethinyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4-tetrahydro-1-naphthol, 0.8 g of 0.5% palladium on calcium carbonate, 0.8 g 5% palladium on charcoal and 1000 ml of ethyl acetate is submitted to hydrogenation at atmospheric pressure and room temperature. After the absorption of 1200 ml of hydrogen the catalysts are removed by filtration. The solution is concentrated by evaporation in vacuo of most of the solvent, whereafter the product crystallizes as white crystals melting at 152°-154° C. Yield 95%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CCOC(C)=O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring mixture of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol), potassium carbonate (7.0 g, 50.4 mmol), in 65 ml of DMF add pyrrolidine (6.7 g, 95 mmol) and stir at room temperature for 72 h. Dilute reaction mixture with 100 ml EtOAc and wash 2 times with 100 ml saturated NaHCO3, and 2 times with 100 ml of brine. Dry organics over Na2SO4, and evaporate in vacuo to obtain 5-nitro-2-pyrrolidin-1-yl-pyridine. Mass spec.: m+1=194 (AP+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[S:20]([CH2:23][CH2:24][NH:25][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)N1CCC(N(Cc2nccs2)S(=O)(=O)CCN)CC1
Product: CC(C)N1CCC(N(Cc2nccs2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 5 iii) starting from 61 mg (1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 129 mg (0.37 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-sulfamoyl]-ethyl}-amide. The title compound was obtained as its formate in form of a light brown amorphous material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:7]=1.[Mn]([O-])(=O)(=O)=[O:30].[K+]>ClCCl.O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([OH:30])=[O:17])=[CH:14][CH:13]=2)[CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(C=O)cc1)C(F)(F)F
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
To a solution of 106 mg (0.266 mmol) 4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]benzaldehyde in 5 mL dichloromethane was added 42 mg (0.266 mmol) of potassium permanganate and the reaction stirred at room temperature. The reaction was monitored by TLC. After several hours, a few drops of water were added and the potassium permanganate dissolved. After 1 hour, a few drops of glacial acetic acid was added followed by 42 mg (0.226 mmol) of potassium permanganate. After 4 days, the reaction was filtered through diatomaceous earth. The pH of the filtrate was adjusted (pH 6) with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organics layers were washed with 1 N aqueous HCl, dried over magnesium sulfate, and concentrated to leave a light brown oil. The crude residue was concentrated from hexanes-diethyl ether to afford and off-white solid. Recrystallization from hexanes-diethyl ether gave 26 mg (24%) of the title compound, m.p. 174° C.-177° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[F-].[Cs+].C[Si](C)(C)[C:38]([F:41])([F:40])[F:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[CH2:25][CH2:24][C:23]([C:38]([F:41])([F:40])[F:39])([OH:26])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: O=C1CCC2(Cc3ccccn3)c3cn4nnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC1(C(F)(F)F)CCC2(Cc3ccccn3)c3cn4nnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
rac-(4aR,13bS)-9-(4-Fluorophenyl)-13 b-(pyridin-2-ylmethyl)-4,4a,5,6,7,13 b-hexahydro-1H-benzo[3,4]cyclohepta[1,2-d][1,2,3]triazolo[1,5-a]pyridin-3 (2H)-one (157, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.139 g, 0.316 mmol) was suspended in DME (3 mL) and CsF (0.029 g, 0.19 mmol) was added. The mixture was cooled to about −10° C. then trimethyl(trifluoromethyl)silane (0.093 mL, 0.63 mmol) was added. After stirring overnight, TBAF (1 M in THF) (0.316 mL, 0.316 mmol) was added and the mixture was allowed to warm to rt. The mixture was concentrated under reduced pressure then the residue was purified on silica gel (12 g) using a gradient of 10-85% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure and then triturated with EtOAc to provide rac-(3R,4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,7,13b-octahydro-1H-benzo[3,4]cyclohepta[1,2-d][1,2,3]triazolo[1,5-a]pyridin-3-ol (158, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl, R3=Trifluoromethyl) (0.031 g, 20%); LC/MS, method 2, Rt=2.45 min, MS m/z 511 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 8.34-8.29 (m, 1H), 8.11 (s, 1H), 8.08-8.02 (m, 2H), 7.40-7.30 (m, 3H), 7.06-7.00 (m, 1H), 6.52-6.47 (m, 1H), 5.97 (s, 1H), 3.67 (d, J=13.4 Hz, 1H), 3.56-3.42 (m, 1H), 3.27-3.15 (m, 2H), 2.22-2.07 (m, 2H), 2.07-1.67 (m, 7H), 1.55-1.38 (m, 1H), 1.30-1.20 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:38][CH2:39][C:40]2[S:44][CH:43]=[N:42][CH:41]=2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCc1cncs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C(=O)NCc2cncs2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, 5-(aminomethyl)thiazole (21.7 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.25-1.39 (m, 3H) 4.43-4.54 (m, 2H) 4.58-4.68 (m, 2H) 7.04-7.14 (m, 1H) 7.37-7.45 (m, 1H) 8.83-9.19 (m, 1H); MS (ESI) positive ion 304 (M+H).