Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C:9]([CH:11]=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S([CH2:32][N+:33]#[C-:34])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([C:8]2[C:9]([C:11]3[O:12][CH:34]=[N:33][CH:32]=3)=[CH:10][N:6]3[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ncnn2cc(C=O)c(-c3ccc([N+](=O)[O-])cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1ncnn2cc(-c3cnco3)c(-c3ccc([N+](=O)[O-])cc3)c12
Yield: 39.4 %

Procedure:
To a solution of 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (Intermediate H, Step 2) (692 mg, 2.44 mmol) was added tosylmethyl isocyanide (477 mg, 2.44 mmol) and potassium carbonate (338 mg, 2.44 mmol) in MeOH. The solution was allowed to stir at reflux overnight. The solution was dried and diluted with EtOAc (50 mL) and THF (50 mL). Water (50 mL) was added to the reaction mixture. The solution was transferred to a separatory funnel, and the organic layer was isolated and washed with brine (50 mL). The aqueous layers were back extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried (Na2SO4), concentrated onto silica gel, and purified by column chromatography (100% CH2Cl2 ramping to 95:5 v/v CH2Cl2-EtOAc) to afford 310 mg of the above compound as an yellow solid (yield 39%). 1H-NMR (DMSO-d6) δ 11.70 (s, 1H), 8.31 (d, J=8.5 Hz, 2H), 8.28 (s, 1H), 8.17 (s, 1H), 7.66 (d, J=7.1 Hz, 2H), 6.75 (s, 1H); MS [M+H]+=323.2; LCMS RT=2.57 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[O:8]1[CH2:11][CH2:10][C:9]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:8]1[CH2:11][CH:10]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH2:9]1
Reactant: OC1CCNCC1
Reactant: O=C1CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: OC1CCN(C2COC2)CC1
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a suspension of piperidin-4-ol (364 mg, 3.6 mmol) in DCE (30 mL) was added oxetanone (216 mg, 3.0 mmol). After 2 hours, sodium triacetoxyborohydride (1.02 g, 4.8 mmol) was added in one portion. After 20 hours at ambient temperature, the reaction mixture was loaded directly onto a 20 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo followed by flash chromatography of the resultant residue (silica, 10 g column, Si-SPE, 0-10% methanol in dichloromethane) afforded the title compound as a colourless oil (285 mg, 52%). 1H NMR (300 MHz, CDCl3): 4.64-4.63 (m, 4H), 3.77-3.77 (m, 1H), 3.49-3.47 (m, 1H), 2.65-2.55 (m, 2H), 2.04 (t, J=10.5 Hz, 2H), 1.94-1.93 (m, 2H), 1.62-1.61 (m, 2H), 1.47 (d, J=4.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[C:36]([CH2:38]O)[N:35]=[CH:34][N:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH:22]1([CH:25]([C:32]2[CH:37]=[C:36]([CH2:38][O:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[N:35]=[CH:34][N:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(c1cc(CO)ncn1)C1CC1
Reactant: COc1ccc(F)c(-c2ncc(O)cc2CC(C)(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)ncn1)C1CC1
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of 6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-ol (300 mg) and ethyl 3-cyclopropyl-3-(6-(hydroxymethyl)pyrimidin-4-yl)propanoate (259 mg) in THF (8.0 mL) were added 1,1′-(azodicarbonyl)dipiperidine (419 mg) and tributylphosphine (409 μL) at room temperature, and the mixture was stirred for 2 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (362 mg) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26]C1C=CC([N+]([O-])=O)=CC=1)=O.Cl.[NH2:37][C@H:38]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41]>CN(C)C=O>[Cl:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[O:26]
Reactant: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl)C(=O)N[C@@H](CO)C(=O)O

Procedure:
1.5 ml of triethylamine are added to a solution of 4.2 g of 4-nitrophenyl 2-(2,6-dichlorophenyl-amino)-phenyl-acetate and 3.6 g of the hydrochloride of the methyl ester of L-leucyl-L-serine in 30 ml of dimethylformamide and the mixture is allowed to react for one hour at room temperature. It is then acidified to pH 5 with 1 N hydrochloric acid and partitioned between chloroform and water. After washing with water, the organic phase is dried and evaporated. The residue is ground with diethyl ether. After recrystallising from a mixture of ethyl acetate and petroleum ether, the methyl ester of N-{[2-(2,6-dichlorophenyl-amino)-phenyl]-acetyl}-L-leucyl-L-serine is obtained as colourless crystals; melting point 216°-218°: [α]D =-30° (c=0.635 in chloroform).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[Cl:7][C:8](=[CH2:11])[CH2:9][OH:10].Cl>>[Cl:7][C:8](=[CH2:11])[CH2:9][O:10][C:1](=[O:5])[C:2]([Cl:4])=[O:3].[Cl:7][C:8](=[CH2:11])[CH2:9][O:10][C:1](=[O:5])[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(Cl)CO
Agent: Cl
Product: C=C(Cl)COC(=O)C(=O)Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Oxalyl chloride (130 ml, 1.49 mol) was placed in a dry 3-neck flask under N2 and cooled to 0° C. With stirring, 2-chloroallyl alcohol (138 g, 1.49 mol) was added dropwise in a manner which maintained the temperature at 0°-2° C. and controlled the vigorous evolution of HCl, then allowed to warm to room temperature and held 16 hours and distilled to yield title product, 214 g, b.p. 82°-84° C./23 mm.
Reaction SMILES: [CH3:1][C@@:2]1([OH:20])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=[CH:11]1.[Br:21]N1C(=O)CCC1=O>CN(C=O)C>[Br:21][C:11]1[N:10]([C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=1)[C@@H:3]1[O:4][C@H:5]([CH2:8][OH:9])[C@@H:6]([OH:7])[C@@:2]1([CH3:1])[OH:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(Br)nc2c(N)ncnc21
Reaction time: 48 h
Yield: 21.1 %

Procedure:
To a solution of 2′-C-methyladenosine [for preparation, see J. Med. Chem. 41: 1708 (1998)] (138 mg, 0.5 mmol) in DMF (4 mL) was added N-bromosuccinimide (231 mg, 1.35 mmol). The solution was stirred protected from light at rt for 2 d and then evaporated in vacuo. The crude product was purified on a silica gel column (3×9 cm) using dichloromethane/methanol (25/1, 20/1 and 15/1) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (38 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@@H:7]1[C@@H:27]([N:28]2[CH2:33][CH2:32][O:31][C:30]([CH3:35])([CH3:34])[CH2:29]2)[CH2:26][C@@:25]2([CH3:36])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:37])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:20])[CH2:18][OH:19])[CH2:8]1.O.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[OH:6][C@@H:7]1[C@@H:27]([N:28]2[CH2:33][CH2:32][O:31][C:30]([CH3:35])([CH3:34])[CH2:29]2)[CH2:26][C@@:25]2([CH3:36])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:37])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:20])[CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C(=O)CO)CC[C@@H]43)C[C@@H]2O)CCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C(=O)COS(C)(=O)=O)CC[C@@H]43)C[C@@H]2O)CCO1
Temperature: -25 °C
Reaction time: 1.5 h

Procedure:
A solution of methanesulfonyl chloride (2.48 ml) in dry pyridine (9.6 ml) was added to a solution of the 3,21-dihydroxy compound of Example 9 (3.26 g) in dry pyridine (33 ml) at -25° C. over ca. 5 min. The solution was stirred at -25° C. for 1.5 h and poured into water (400 ml). Aqueous sodium carbonate was added until the pH exceeded 9 and the precipitated solid was filtered off and dissolved in dichloromethane. The solution was dried over sodium sulfate and the solvent was removed under reduced pressure to give (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-21-[(methylsulfonyl)oxy]pregnan-20-one (3.80 g). δ (CDCl3) 0.65 (s,3H), 0.86 (s,3H), 3.22 (s,3H) and 4.79 (m,2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:10]([Cl:22])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24].FC(F)(F)C(O)=[O:29].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:29])=[C:10]([Cl:22])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24]
Reactant: NC(=O)c1nnn(Cc2ccc(Sc3ccc(Cl)cc3)c(Cl)c2)c1N
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1nnn(Cc2ccc(S(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 83.3 %

Procedure:
A stirred suspension of 5-amino-1-(3-chloro4-[4-chlorophenylthio]benzyl)-1,2,3-triazole-4-carboxamide (475 mg, 1.20 mmol) in methanol (160 ml) was treated with trifluoroacetic acid (278 μl, 411 mg, 3.61 mmol), warmed until homogeneous, and cooled to ambient temperature. To this solution was added m-chloroperbenzoic acid (244 mg of 85% technical grade, 1.20 mmol), the mixture was stirred 75 minutes, an additional portion of m-chloroperbenzoic acid (33.1 mg of 85% technical grade, 0.163 mmol) was added, and the mixture was stirred an additional 45 minutes. The mixture was treated with 2.5N aqueous sodium hydroxide (2.5 ml), stirred until crystallization commenced, concentrated to approximately 40 ml under vacuum at 30° C., and chilled to 0° C. The precipitate was filtered, washed with methanol, and dried to afford 410 mg (83%) of 5-amino-1-(3-chloro-4-[4-chlorophenylsulfinyl]benzyl)-1,2,3-triazole- 4-carboxamide, m.p. 237°-238° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19](C)(C)[O:20][SiH2]C(C)(C)C)[CH:18]=[C:13]3[C:12]([C:28]3[CH:29]=[C:30]([CH:51]=[CH:52][CH:53]=3)[CH2:31][NH:32][C:33]([C:35]3[C:36](=[O:50])[N:37]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=4)[CH:38]=[CH:39][CH:40]=3)=[O:34])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O>C(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][OH:20])[CH:18]=[C:13]3[C:12]([C:28]3[CH:29]=[C:30]([CH:51]=[CH:52][CH:53]=3)[CH2:31][NH:32][C:33]([C:35]3[C:36](=[O:50])[N:37]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=4)[CH:38]=[CH:39][CH:40]=3)=[O:34])=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CO)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 1-neck round-bottom flask was dissolved 1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-[1-benzenesulfonyl-5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzylamide (0.17 mmol, 0.00017 mol) in ethanol (3.00 mL, Fisher;). To this was added 12 M of hydrogen chloride in water (1.00 mL, 0.012 mol; Fisher) and the reaction was stirred at room temperature for 1 h and then evaporated to give the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH2:16])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.O.C(=O)(O)[O-].[Na+].[F:24][C:25]([F:36])([F:35])[C:26]([F:34])([F:33])[C:27]([F:32])([F:31])[C:28](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[CH:6][C:5]2[NH:16][C:28]([C:27]([F:31])([F:32])[C:26]([F:33])([F:34])[C:25]([F:36])([F:35])[F:24])=[N:17][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 2 %

Procedure:
A solution of 4-chloro-5-(4-fluorophenoxy)benzene-1,2-diamine (400 mg, 1.58 mmol) in heptafluorobutanoic acid (3 ml) was stirred overnight at 110° C. in an oil bath. The solution was poured into water (150 ml), adjusted pH to 8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×100 ml). The combined organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenoxy)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a off-white solid (12.0 mg, 2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][NH:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:15]2[CH2:16][C@H:12]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[CH2:13][C@H:14]2[C:17]([O:19][CH3:20])=[O:18])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 74.3 %

Procedure:
To a solution of (2S,4R)-4-(4-chlorophenyl-sulfonylamino)-2-methoxycarbonylpyrrolidine (10.0 g) in dichloromethane (200 ml) were added triethylamine (4.8 ml) and 4-chlorobenzenesulfonyl chloride (6.62 g) in an ice bath and the mixture was stirred in an ice bath for 3 hours. The resulting solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (11.5 g).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:26]([F:29])([F:28])[F:27])=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:11]=1)(=O)=O.[F:30][C:31]1[CH:36]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:34]=[CH:33][C:32]=1O>>[CH2:24]([C:21]1[CH:22]=[N:23][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([N:10]3[CH:11]=[C:7]([CH2:6][O:5][C:32]4[CH:33]=[CH:34][C:35]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:36][C:31]=4[F:30])[C:8]([C:26]([F:27])([F:28])[F:29])=[N:9]3)[CH2:17][CH2:16]2)=[N:19][CH:20]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC(n3cc(COS(C)(=O)=O)c(C(F)(F)F)n3)CC2)nc1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Product: CCc1cnc(N2CCC(n3cc(COc4ccc(S(C)(=O)=O)cc4F)c(C(F)(F)F)n3)CC2)nc1

Procedure:
The compound was synthesized using (1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl methanesulfonate and 2-fluoro-4-(methylsulfonyl)phenol in a manner similar to that described in Example 1. 1H NMR (CDCl3): δ 8.25 (2H, s), 8.17 (1H, s), 7.71 (2H, m), 7.52 (1H, m), 5.30 (2H, s), 4.90 (2H, m), 4.65 (1H, m), 3.13 (3H, s), 3.05 (2H, m), 2.47 (2H, q), 2.20 (2H, m), 1.98 (2H, m), 1.18 (3H, t).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:14][S:15]SC.N(OC(C)(C)C)=O.O>C(Cl)(Cl)Cl>[CH3:14][S:15][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CSSC
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CSc1cc(CO)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-amino-5-(trifluoromethyl)phenyl]methanol (319 mg, 1.67 mmol) (Step A, Example 24) in CHCl3 (5 mL) was added dimethyl disulfide (296 μL, 3.34 mmol). Next, t-butyl nitrite (285 μL, 2.4 mmol) was added dropwise by syringe. The reaction was stirred at room temperature for two hours and then poured into H2O (15 mL). The mixture was extracted with EtOAc (50 mL), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 0% to 50% EtOAc/hexanes afforded [3-(methylthio)-5-(trifluoromethyl)phenyl]-methanol. The [3-(methylthio)-5-(trifluoromethyl)phenyl]methanol was contaminated with minor impurities that were removed after the next step. Rf=0.53 (50% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.63 (s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 4.71 (s, 2H), 2.51 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[K+].[Br-]>>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])=[CH:13][CH:12]=1
Reactant: COc1ccc(N)cc1
Reactant: N#Cc1ccccn1
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(NC(=N)c2ccccn2)cc1
Yield: 86.7 %

Procedure:
The title compound was prepared from 2-cyanopyridine (8.46 g, 81 mmol) and 4-methoxyaniline (10 g, 81 mmol) by following the procedure described in preparation 10 (16 g, yield 86.7%, mp 73-75° C., purity 97.6% by HPLC). 1H-NMR (CDCl3):δ 3.81 (s, 3H), 5.5-6 (bs, 2H, D2O exchangeable), 6.91-6.98 (m, 4H), 7.37-7.4 (m, 1H), 7.79-7.83 (m, 1H), 8.39-8.41 (d, 1H), 8.56-8.57 (d, 1H). IR (KBr) cm−1: 3456, 3540, 3410, 1663. MS m/z:228.2 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(OC([N:21]1[CH:26]([C:27]2[CH:32]=CC=C[CH:28]=2)[CH2:25][C:24]2[NH:33][N:34]=[CH:35][C:23]=2[CH2:22]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:21]2[CH:26]([CH:27]([CH3:32])[CH3:28])[CH2:25][C:24]3[NH:33][N:34]=[CH:35][C:23]=3[CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2CC1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C1Cc2[nH]ncc2CN1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Benzyl 2-isopropyl-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example 3 using isopropylmagnesium chloride, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](OC)=[CH:11][C:10]=1[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)O)C1C=CC=CC=1.Cl.[CH3:28]O>[OH-].[Pd+2].[OH-]>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:17][C:10]2[CH:11]=[C:12]([CH3:28])[CH:13]=[CH:14][C:9]=2[OH:8])=[CH:24][CH:23]=1
Reactant: CO
Reactant: COc1ccc(C(O)c2cc(OC)ccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: COc1ccc(Cc2cc(C)ccc2O)cc1
Reaction time: 72 h
Yield: 80 %

Procedure:
To a solution of (2-benzyloxy-5-methoxyphenyl)-(4-methoxyphenyl)-methanol (1.46 g, 4.3 mmol) in methanol (20 ml), a 20% palladium hydroxide catalyst (73 mg) was added and furthermore 36% HCl (0.1 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 72 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (0.8 g, 80%).
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][N:5]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(F)(COc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1

Procedure:
A mixture of EXAMPLE 173A (0.4 g), methanesulfonyl chloride (0.113 g), and triethylamine (0.64 mL) in dichloromethane (5 mL) was stirred overnight. The reaction mixture was loaded onto a silica gel column and eluted with 100:1 ethyl acetate:methanol to give the clean product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10](=O)[O:11]C1C=CC=CC=1)=[O:8].Cl.[NH:20]1[CH2:25][CH2:24][C:23](=[CH:26][C:27]2[CH:28]=[C:29]([CH:41]=[CH:42][CH:43]=2)[O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=2)[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:39][C:37]([F:40])([F:38])[C:34]1[CH:35]=[CH:36][C:31]([O:30][C:29]2[CH:28]=[C:27]([CH:43]=[CH:42][CH:41]=2)[CH:26]=[C:23]2[CH2:24][CH2:25][N:20]([C:10]([NH:9][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:8])=[O:11])[CH2:21][CH2:22]2)=[N:32][CH:33]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(NC(=O)c1ccccn1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1)c1ccccn1
Temperature: 50 °C
Yield: 66.7 %

Procedure:
Phenyl picolinoylcarbamate (145 mg, 0.599 mmol, from Step 1), 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (175 mg, 0.472 mmol) (from Example 1, Step 5), and diisopropylethyl amine (0.16 mL, 0.92 mmol) were combined in acetonitrile (5 mL) and warmed to 50° C. After 3 hours the mixture was cooled to room temperature and concentrated to form a residue. The residue was purified by silica gel chromatography (20-75% EtOAc in CH2Cl2) to provide the title compound (0.152 g). MS APCI M+ 483.1, 376.1, 335.1; M− 481.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.45-2.72 (m, 4H) 3.64 (m, 4H) 6.47 (s, 1H) 6.96-7.06 (m, 2H) 7.08-7.20 (m, 2H) 7.40 (td, J=7.65, 0.91 Hz, 1H) 7.63 (ddd, J=7.63, 4.76, 1.23 Hz, 1H) 8.02 (td, J=7.75, 1.69 Hz, 1H) 8.08 (ddd, J=8.71, 2.55, 0.61 Hz, 1H) 8.18 (dt, J=7.86, 1.08 Hz, 1H) 8.42 (td, J=1.72, 0.80 Hz, 1H) 8.67 (ddd, J=4.76, 1.69, 0.95 Hz, 1H).