Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@H:7]([O:8][C:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:29])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: O=C1CCC(=O)O1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](OC(=O)CCC(=O)O)O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Artemisinin (500 mg) and cation exchange resin (1 g) are stirred in tetrahydrofuran (10 ml) at room temperature for 5 minutes. Sodium borohydride (250 mg) is added slowly for 10 minutes and the reaction mixture is stirred for about 30 minutes at room temperature (20-35 degree C.). After completion of the reaction succinic anhydride (250 mg) and triethylamine (0.7 ml) are added at room temperature and the reaction mixture is stirred further for 1 hours at room temperature. The resin is filtered. After usual workup and column chromatography of the crude product (710 mg), 480 mg of pure artesunic acid (yield=96% w/w) is obtained.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:17]=2)[CH:13]=[CH:12][N:11]=1>CN(C=O)C>[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:17]=2)[C:13]([I:1])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2nc(N)ncc2I)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Temperature: 60 °C
Yield: 79.3 %

Procedure:
N-iodosuccinimide (356 mg, 1.58 mmol) was added to a solution of ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate (700 mg, 1.44 mmol) in DMF (15 mL). The reaction mixture was heated at 60° C. for 4 h, allowed to cool to room temperature, concentrated and then diluted with EtOAc (30 mL). The organic phase was washed with sodium sulfite, water, brine, dried over sodium sulphate, and evaporated to afford the title compound as yellow solid (0.70 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](Cl)=[N:6][OH:7].[CH3:12][O:13][C:14](=[O:19])[CH2:15][C:16]([CH3:18])=O.C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)=[N:6][O:7][C:16]=1[CH3:18])=[O:19]
Reactant: COC(=O)CC(C)=O
Reactant: ON=C(Cl)c1cccc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(F)c2)noc1C
Yield: 69.7 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 3-fluoro-N-hydroxybenzimidoyl chloride (8.00 g, 46.09 mmol), methylacetoacetate (10.07 g, 92.18 mmol) and sodium methoxide (7.47 g, 138.27 mmol), a white solid required compound (7.60 g, 32.14 mmol, 70%) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[O:12]=[C:9]1[CH2:8][O:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]=2[NH:10]1
Reactant: CCOC(=O)CBr
Reactant: O=C1COc2cccc(O)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1NC(=O)CO2
Temperature: 27 °C
Reaction time: 16 h

Procedure:
A solution of 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.604 mmol) and K2CO3 (167 mg, 1.21 mmol) in anhydrous DMF (5 mL) was stirred at 27° C. for 5 minutes, then ethyl 2-bromoacetate (121 mg, 0.727 mmol) was added. The reaction mixture was stirred at 27° C. for 16 h and concentrated. MS (ESI+) e/z: 238.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:41][S:38]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])=[O:31])=[CH:18][CH:19]=2)[N:3]=1
Reactant: NS(=O)(=O)c1cccnc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccnc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and pyridine-3-sulfonamide: 1H-NMR [CDCl3/CD3OD(10:1)] δ 9.10 (1H, d, J=2.2 Hz), 8.71-8.70 (1H, m), 8.24 (1H, d, J=8.3 Hz), 7.45-7.16 (1H, m), 6.26 (1H, br.s), 3.42-3.33 (2H, m), 2.80-2.73 (2H, m), 2.29 (3H, s), 2.20 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([OH:34])=O)=[N:10]2)=[CH:5][CH:4]=1.C([N:37](CC)CC)C.ClC(OCC(C)C)=O.[OH-].[NH4+]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:22][CH:23]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([NH2:37])=[O:34])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(=O)O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Method A. A suspension of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (61, 1.5 g, 3.3 mmol) in EtOAc (20 mL) was treated with triethylamine (TEA, 433 mg, 0.60 mL, 4.3 mmol, 1.3 equiv) at room temperature, and the resulting reaction mixture was treated dropwise with iso-butyl chloroformate (587 mg, 0.55 mL, 4.3 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for an additional 30 min. When TLC and HPLC showed the mixed anhydride formation reaction was complete, the reaction mixture was poured into a cold (0-5° C.) ammonium hydroxide solution (NH4OH, 28% aqueous solution, 25 mL) with good stirring. The resulting mixture was stirred at room temperature for an additional 4 h. The solids were collected by filtration, washed with a mixture of methanol and water (1:1 v/v, 2×20 mL), and dried in vacuo at 40-45° C. for 12 h to afford the crude desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (62, 1.06 g, 1.52 g theoretical, 70%) as off-white crystals. For 62, CIMS m/z 460 (M++H, C25H25N5O4).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])(=[O:4])=[O:3].[Cl-].[NH4+].O>C(O)C.[Fe]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]([F:15])([F:16])[F:17])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(N)cc1C(F)(F)F
Yield: 76.2 %

Procedure:
A mixture of 4-(methylsulfonyl)-3-(trifluoromethyl)nitrobenzene (1.55 g, 5.76 mmol), iron powder (1.61 g, 28.8 mmol), and ammonium chloride (0.031 g, 0.58 mmol) in ethanol (30 mL), and water (8 mL) was heated at reflux temperature for 1 hour. After cooling, insolubles were filtered off by Celite, and volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (50 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The residue was washed with hexane to give the subtitle compound (1.05 g, 76.2%, yield).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][N:24]=1>C1COCC1>[C:5]([O:4][C:3](=[O:9])[N:2]([CH:10]1[CH2:14][CH2:13][N:12]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=2)[CH2:11]1)[CH3:1])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(N)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.3 %

Procedure:
To a solution of commercially available tert-butyl methyl(pyrrolidin-3-yl)carbamate (1.0 g, 5.0 mmol) in THF (25 mL) was added triethylamine (0.70 mL, 5.0 mmol) and 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with a satd. aq. NaHCO3 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate/hexanes) to afford the desired product (1.0 g, quant.) as a yellow solid. The solid was dissolved in tetrahydrofuran (50 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.5 g) and the reaction mixture was placed under an atmosphere of hydrogen (1 atm) until the reduction was complete by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (940 mg, 100%) as a red oil. ESI MS m/z 293 [C15H24N4O2+H]+
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.[Br:14][C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1>CN(C)C=O.O>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:5][CH2:4][C:3]([OH:11])=[O:10])=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(Br)cc1
Reaction time: 0.08 h

Procedure:
A mixture of a 60% suspension of sodium hydride in mineral oil (4.8 g, 120 mmol) in N,N-dimethylformamide (50 mL) at about 5° C. was treated with diethyl malonate (36.4 mL, 240 mmol). The mixture was stirred for about 5 minutes, slowly treated with a solution of 4-bromobenzyl bromide (20.0 g, 80 mmol) in N,N-dimethylformamide (20 mL), stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated under high vacuum. The residue was dissolved in a mixture of acetic acid (46 mL), water (30 mL), and concentrated sulfuric acid (13 mL) and was heated to reflux for 18 hours. The reaction mixture was cooled, concentrated under high vacuum, and diluted with water. The formed crystalline solid was collected by filtration, washed with water and diethyl ether, and was dried under high vacuum to provide the desired product. MS (DCI-NH3): m/z 246, 248 (M+NH4)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:30](O)(=[O:32])[CH3:31]>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O
Reactant: NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
(R)-2-(3-(Aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 8; 0.034 g, 0.085 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.085 mmol) were placed in a THF-DCM solution (1:1, 3 ml) at 0° C. The resulting suspension was shaken vigorously at 0° C. for 45 min. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.018 g, 48%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.36 (m, 2H), 7.12 (d, J=9.6 Hz, 1H), 7.04-6.99 (m, 2H), 6.09 (br s, 1H), 5.19-5.02 (m, 1H), 4.36-4.17 (m, 2H), 3.83-3.71 (m, 2H), 1.99 (s, 3H), 1.88-1.83 (m, 1H), 0.98-0.87 (m, 2H), 0.72-0.66 (m, 2H). MS: Calcd.: 442. Found: [M+H]+ 443.
Reaction SMILES: NC(N)=O.[CH3:5][S:6][CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=1[OH:22])(=[O:13])=[O:12].[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[Cl:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:32]([NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=2[Cl:23])=[O:33])=[C:15]([OH:22])[C:14]=1[S:11]([NH:10][CH2:9][CH2:8][CH2:7][S:6][CH3:5])(=[O:13])=[O:12]
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 69.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-(3-methylthiopropyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (250 mg, 0.80 mmol) and 2,3dichlorophenylisocyanate (1 82 mg, 0.97 mmol) were coupled to form the desired urea (278 mg, 70%). 1H NMR (MeOD-d4): δ 8.29 (d, 1H), 8.06 (d, 1H), 7.24 (m, 2H), 7.05 (d, 1H), 3.07 (t, 2H), 2.48 (t, 2H), 1.98 (s, 3H) 1.74 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[N:8]([CH2:12][CH2:13][CH2:14]Br)[C:7](=[O:16])[C:6]=2[CH:17]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][N:8]2[C:7](=[O:16])[C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[S:9]2(=[O:11])=[O:10])[CH2:26][CH2:25]1
Reactant: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCN1CCN(c2ncccn2)CC1

Procedure:
0.03 mol of 5-fluoro-2-(3-bromopropyl)-1,2-benzisothiazol-3(2H)one 1,1-dioxide and 0.03 mol of 1-(2-pyrimidinyl)piperazine are stirred at 50° to 60° C. with 0.03 mol of K2CO3 in 100 ml of absolute DMF for 2 hours. The mixture is then evaporated, water is added to the residue and the base is extracted with methylene chloride. Purification is carried out by chromatography on silica gel; the eluting agent is CH2Cl2 /CH3OH (98:2), recrystallisation is on roluol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([SH:20])[CH2:17][CH2:18][CH3:19]>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:20][CH2:16][CH2:17][CH2:18][CH3:19])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCS
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Solvent: CCOCC
Product: CCCCSSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 92.1 %

Procedure:
61 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 800 ml of diethyl ether is reacted in a stirred apparatus with 18 g of 1-butylmercaptan for 6 hours at 25° C. The completion of the reaction is determined by gas chromatography. After removal of the solvent, there is obtained 66 g (92% of theory) of (4-nitro-2-trichloromethylphenyl)-n-butyl disulfide as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:12]([CH3:16])([CH2:13]2)[CH2:11][CH2:10][C:9](=[O:17])[CH:8]=3)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[Br:23]Br>C(Cl)Cl.CCOC(C)=O>[Br:23][C:8]1[C:9](=[O:17])[CH2:10][CH2:11][C:12]2([CH3:16])[C:7]=1[C:6]1[C:14](=[CH:15][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:13]2
Reactant: COc1ccc2c(c1)CC1(C)CCC(=O)C=C21
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CC1(C)CCC(=O)C(Br)=C21
Temperature: 25 °C
Reaction time: 22 h
Yield: 46.5 %

Procedure:
A mixture of 7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (32 mg, 0.14 mmol) and NaHCO3 (60 mg, 0.7 mmol) in CH2Cl2 (0.5 ml) was treated with bromine (0.008 mL, 0.154 mmol), and the resulting mixture was stirred at room temperature for 22 hours. The mixture was diluted with EtOAc (8 ml), washed with dilute aqueous Na2S2O3 (4 mL) and brine (4 ml), dried over MgSO4, filtered, and evaporated under vacuum to a yellow oil (43 mg). This material was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing twice with CH2Cl2, to afford 4-bromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (20 mg) as a gum. The product was contaminated with a trace of 4,6-dibromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:43][C:44]([F:56])([F:55])[O:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](O)=[O:50]>ClCCl.O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:49](=[O:50])[C:48]2[CH:52]=[CH:53][CH:54]=[C:46]([O:45][C:44]([F:43])([F:55])[F:56])[CH:47]=2)[N:13]=1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(OC(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 203 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 230 mg of 3-trifluoromethoxy benzoic acid is added and agitation is carried out for 4 hours and 30 minutes at ambient temperature. Water is added, followed by extracting with methylene chloride, drying, evaporating the solvents, recrystallizing from ether, separating, drying and 326 mg of expected product is collected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1>>[O:28]1[CH2:29][CH2:30][CH:26]([NH:25][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:27]1
Reactant: NC1CCOC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOC2)n(C)n1
Yield: 69 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using rac-3-aminotetrahydrofuran instead of 2-amino-2-methyl-1-propanol, to the title compound (84 mg, 69%) which was obtained as a light brown solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@:14]([F:22])([C:16]3[N:17]=[N:18][N:19]([CH3:21])[N:20]=3)[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.Cl>>[F:33][C:31]([F:32])([F:34])[C:29]1[CH:30]=[C:25]([CH2:24][O:23][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:15][C@@:14]3([F:22])[C:16]2[N:17]=[N:18][N:19]([CH3:21])[N:20]=2)[CH:26]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:28]=1
Reactant: Cn1nnc([C@]2(F)C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Agent: Cl
Product: Cn1nnc([C@]2(F)C[C@]3(c4ccccc4)N[C@H]2CC[C@H]3OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]-methoxy}-6-fluoro-6-(2-methyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 173b; 74 mg, 0.12 mmol) was treated with an etheral solution of hydrogen chloride and concentrated. The residue was dissolved in ethanol (20 ml) and 10% palladium on charcoal (109 mg) was added. The mixture was stirred under hydrogen atmosphere (1 atm) at +60° C. for 30 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and the residue was purified by chromatography on silica gel (dichloromethane:methanol:ammonia) to give the title compound (52 mg, 82%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][Cl:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Si:1]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][Cl:15])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCCC#CCCCl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC/C=C\CCCl
Yield: 70.6 %

Procedure:
5.2 g of 6-chlorohex-3-yn-1-ol t-butyldimethylsilyl ether in 50 ml of ethanol was hydrogenated under 1 atmosphere of hydrogen in the presence of 0.3 g of Lindlar catalyst wntil 370 ml of hydrogen had been absorbed. The catalyst was removed by filtration thru celite and the ethanol evaporated in vacuo. The crude product was chromatographed on 200 g of silica gel, eluting with 1 to 4% ether/hexane. Distillation of the appropriate fractions gave 3.7 g of 6-chlorohex-3Z-en-1-ol t-butyldimethylsilyl ether, bp 80°/0.5 mm.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.C(O)C.[NH2:15]OS(O)(=O)=O>O>[NH2:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nn1ncc2ccccc21
Temperature: 55 °C
Yield: 47.3 %

Procedure:
To a solution of 2.2 g(55 mmol) of sodium hydroxide in 30 ml of water was added 1.33 g(10 mmol) of 1H-indazole and ethanol was slowly added at 50° C. until the reaction mixture was dissolved thoroughly. The resulting mixture was heated to 55° C. and 2.83 g(25 mmol) of hydroxylamine-O-sulfonic acid was slowly added over 30 min with vigorous stirring followed by further stirring for 30 min. After completion of reaction, the resulting precipitate was filtered off, and the filtrate was extracted with dichloromethane(30 ml×2), dried over anhydrous magnesium sulfate and concetrated under the reduced pressure. The concentrate was chromatographed over silica gel using 10% ethyl acetate/dichloromethane as an eluent. The fractions containing the desired product were concentrated under the reduced pressure and crystallized from benzene/petroleum ether to give 0.63 g of the desired compound(47%).