Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=C.C[OH:14]>>[CH:10]([CH:4]([CH2:1][CH:2]=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:12])[CH3:11]
Reactant: C=CCC(C(=O)OCC)C(C)C
Reactant: CO
Product: CCOC(=O)C(CC=O)C(C)C
Yield: 89 %

Procedure:
In 100 g of methanol were dissolved 10.0 g of ethyl α-allylisovalerate (general formula [XI] wherein R=--CH2CH3) and, under cooling at -20°~-10° C. and stirring, ozone gas was bubbled into the solution for 8 hours. Then, at room temperature, the reaction mixture was added to 100 g of dimethyl sulfide and the mixture was stirred at that temperature overnight. The reaction mixture was then distilled under reduced pressure to remove the low-boiling fraction and the residue was diluted with 50 g of diethyl ether. Following the addition of 4 g of anhydrous calcium chloride, hydrogen chloride gas was bubbled into the mixture at room temperature for 10 minutes. Then, 5 g of anhydrous potassium carbonate were added and the mixture was thoroughly stirred. The diethyl ether solution was taken, washed with water, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the low-boiling fraction. By the above procedure there were obtained 9.0 g of ethyl 2-isopropyl-3-formyl-propionate (general formula [XII] wherein R=--CH2CH3) yield: 89% based on ethyl α-allylisovalerate; the NMR spectrum of the aldehyde (60 MHz) δHMSCDCl3 : 9.74].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[OH-].[Na+].[Cl:14][C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[Cl:14][C:15]1[S:19][C:18]([S:20]([NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])(=[O:22])=[O:21])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: N[C@@H](CCC(F)(F)F)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of the crude 5,5,5-trifluoronorvaline (0.785 g, 4.59 mmol) and NaOH mixture dissolved in THF (10 ml) and 2N NaOH (10 mL) was added dropwise a solution of 5-chlorothiophene-2-sulfonyl chloride (1.32 g, 5.04 mmol) in THF (10 ml) over 30 min. After 60 min, the reaction mixture was allowed to warm gradually to 25° C. and stirred for 16 h. THF was removed in vacuo and the mixture was acidified to a pH of about 2 with 1N HCl. After 15 min, a precipitate began to crash out of the milky white solution. After 60 min, the mixture was cooled to 0° C. for 45 min and then filtered. The precipitate was washed with 1N HCl (10 mL) to provide a white solid. The white solid gummed out. It was dissolved in EtOAc (100 mL). The aqueous was washed with EtOAc (3×50 mL) and the organic layers were washed with saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoronorvaline as a dark red oil (1.1 g, 68.3%). Mass Spectrum (−ESI): 350 (M−H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:3]1>CCCCCC.CCO>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CC1CCCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1
Solvent: CCO
Solvent: CCCCCC
Product: C[C@H]1CCCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1

Procedure:
1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea (50 mg, 0.12 mmol, Example 78) was separated by chiral HPLC (Chiraltech Chiralcel OJ 50×4.6 mm i.d.) using hexane/EtOH/DEA (90:10:0.2) to give a white solid. MS m/z: 409.3 (M+H). Calc'd for C21H24N6OS-408.52.
Reaction SMILES: CC[O-].[Na+].[Na].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>CCO>[CH2:21]([CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13])[CH2:20][CH:19]=[CH2:18]
Reactant: C=CCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: C=CCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of NaOEt, prepared from the treatment of 1 L EtOH with sodium metal (19.5 g, 0.813 mol), was cooled to 0° C. and diethyl malonate (3-1, 100 g, 0.625 mol) was added dropwise over 0.5 h. After the addition was complete, the reaction was stirred for an additional 0.5 h, then a solution of 1-bromo-3-butene (76.1 mL, 0.75 mol) in 100 mL EtOH was added dropwise over forty-five minutes. The reaction was heated to reflux for 18 h, cooled and the solvent was removed in vacuo. The residue was dissolved in H2O and washed with EtOAc. The organic layer was dried with brine and MgSO4, filtered and evaporated. Fractional distillation of the residue (0.25-0.4 mm Hg, 70°-80° C.) gave 3-2 as a clear liquid.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O>CN(C)C=O>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:37][C:38]([F:41])([F:40])[F:39])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC(F)(F)F)C1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 51, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless foam (73%).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ncccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)sc2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a mixture of ethyl 3-[{(4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (335 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (281 mg, 89%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH:16]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH:22]2[NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:11])[NH2:9])=[CH:4][C:3]=3[S:12](=[O:14])(=[O:13])[NH:15]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: O=CC1CCCCC1
Product: NS(=O)(=O)c1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)N2

Procedure:
2-Amino-5-sulfamoylbenzenesulfonamide (see compound 101) was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 252–254° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][CH2:35][OH:36])=[O:32])[NH:28][C:27]=1[C:37]([OH:39])=O.[NH2:40][CH2:41][C:42]1[C:43]([F:59])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:53]#[N:54])[C:45]([Cl:48])=[CH:46][CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][CH2:35][OH:36])=[O:32])[NH:28][C:27]=1[C:37]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([C:53]#[N:54])[CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:43]=1[F:59])=[O:39]
Reactant: O=C(NCCO)c1cc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(=O)NCCO)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a DMF (2 mL) solution of 3-chloro-5-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylic acid (0.037 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), and DIPEA (0.028 mL, 0.161 mmol). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. The residue was subjected to silica gel column chromatography (EtOAc/hexanes) to afford an impure solid. A second purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.014 g, 15%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.00 (br. s., 1H), 7.86 (d, 1H), 7.63 (s, 1H), 7.33-7.52 (m, 3H), 6.86 (d, 1H), 4.71 (d, 1H), 3.65 (t, 1H), 3.39-3.57 (m, 5H). LCMS: m/z 525.3 (M+1).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49](C1C=CC=CC=1CS(Cl)(=O)=O)#[N:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=1[C:49]#[N:50])(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ccccc1CS(=O)(=O)Cl
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: N#Cc1ccccc1CS(=O)(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 72 %

Procedure:
The title compound was prepared from 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (2-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7 as a white solid in 72% yield.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)[C:10]=1[C:11]([N:13]1[CH2:17][CH:16]2[CH2:18][N:19]([C:21](=[NH:23])[NH2:22])[CH2:20][CH:15]2[CH2:14]1)=[O:12].C[O-].[Na+].[F:36][C:37]([F:48])([F:47])[C:38](=O)[CH2:39][C:40](=O)[C:41]([F:44])([F:43])[F:42]>C(O)CCC>[F:36][C:37]([F:47])([F:48])[C:38]1[CH:39]=[C:40]([C:41]([F:42])([F:43])[F:44])[N:22]=[C:21]([N:19]2[CH2:18][CH:16]3[CH:15]([CH2:14][N:13]([C:11]([C:10]4[C:24]([N:28]5[N:32]=[CH:31][CH:30]=[N:29]5)=[CH:25][CH:26]=[CH:27][C:9]=4[F:8])=[O:12])[CH2:17]3)[CH2:20]2)[N:23]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: N=C(N)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC2CN(c3nc(C(F)(F)F)cc(C(F)(F)F)n3)CC2C1
Yield: 6.2 %

Procedure:
Crude 5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboximidamide—TFA salt (66 mg) was diluted with n-butanol (4 mL) and treated with sodium methoxide (51.9 mg, 0.961 mmol). The reaction is heated to reflux for 1 hour, then cooled and 1,1,1,5,5,5-hexafluoropentane-2,4-dione (400 mg, 1.92 mmol) is added prior to re-heating the reaction to reflux for 19 hours. The mixture was then cooled and concentrated, then diluted with DCM and saturated sodium bicarbonate. Extract with DCM and concentrate. Reverse phase HPLC gave the title compound (4.6 mg). MS (ESI): mass calculated for C21H16F7N7O, 515.39; m/z found 416.2 [M+H]+. Rotamers observed in 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: Fc1cccc(CBr)c1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (99) and 3-fluorobenzyl bromide according to General Procedure B. Yield 297 mg (38%), MP 211° C.; 1H-NMR (DMSO-d6): δ 3.72 (m, 4H), 3.95 (m, 4H), 5.52 (s, 2H), 6.67 (dd, J=1.6, 3.6, Hz, 1H), 7.06-7.10 (m, 4H), 7.33 (m, 1H), 7.89 (d, J=1.6 Hz, 1H), 8.18 (dd, J=2.8, 9.2 Hz, 1H), 8.78 (d, J=2.8 Hz, 1H); EIMS: 476 (M+1). Anal. (C25H19F2N5O3) C, H, N.
Reaction SMILES: [CH2:1]([Si:7]([CH3:10])([CH3:9])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.C(Cl)([Cl:18])=O>ClCCCl>[CH2:1]([Si:7]([CH3:10])([CH3:9])[Cl:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[Si](C)(C)O
Reactant: O=C(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCC[Si](C)(C)Cl
Yield: 91.1 %

Procedure:
To the same reactor as used in Example 1 were added 40.1 g (0.25 mole) of hexyldimethylsilanol, 160 g of 1,2-dichloroethane and 1.83 g (0.025 mole) of N,N-dimethylformamide, and 27.2 g (0.275 mole) of phosgene was introduced into the resulting mixture at a temperature of from 40° to 45° C. over 2 hours with stirring. After completion of the introduction, the same procedure as in Example 7 was carried out to obtain 40.7 g of hexyldimethylchlorosilane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([F:17])[C:13](F)=[N:14][CH:15]=1.CCOC(C)=O>CN(C=O)C>[Br:9][C:10]1[CH:11]=[C:12]([F:17])[C:13]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[N:14][CH:15]=1
Reactant: Nc1cc(O)ccn1
Reactant: Fc1cc(Br)cnc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ncc(Br)cc2F)ccn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
Mix 2-aminopyridin-4-ol (1.13 g, 10.3 mmol), 5-bromo-2,3-difluoro-pyridine (2 g, 10.3 mmol) in DMF (10 mL). Stir the mixture at 120° C. for 3 hrs. TLC (EtOAc:PE=1:1) shows the reaction is complete. Filter, add water (50 mL) to the filtrate, extract with EtOAc (50 mL×3). Combine the organic layers, dry over anhydrous Na2SO4. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (1.35 g, 46.3%). MS: (M+1): 284.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.[C:17]([O:21][C:22]([N:24]1[CH2:27][CH:26](OS(C)(=O)=O)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:27][CH:26]([N:14]2[CH:15]=[C:11]([B:6]3[O:7][C:8]([CH3:9])([CH3:10])[C:4]([CH3:16])([CH3:3])[O:5]3)[CH:12]=[N:13]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (60% in mineral oil, 222 mg, 5.6 mmol) is added portionwise to a stirred solution of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.10 g, 5.56 mmol) in DMF (20 ml). The resulting mixture is stirred for 1 h at 0° C. and then allowed to warn to RT. A solution of 3-Methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (as obtained in preparation 80, 1.39 g, 5.56 mmol) in DMF (3 ml) is then added dropwise. After complete addition, the reaction mixture is heated at 95° C. for 5 h. The reaction is quenched with water and extracted with EtOAc several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 40 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient CH2Cl2: TBDME from 1:0=>0:1) to afford the title compound as a colorless foam, Rt=1.200 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 350 (M+1)+.
Reaction SMILES: [OH:1][C:2]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4].O[C@H]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[H-].[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:3]([O:5][C@H:6]1[CH2:23][CH2:22][C@H:21]([N:24]([C:25]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:31])[CH3:32])[CH2:20][CH2:19]1)=[O:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 155 °C

Procedure:
To a solution of methyl hydroxy(di-2-thienyl)acetate (5.8 g, 0.02 mol) (prepared according to Acta Chemica Scandinavica 24 (1970) 1590-1596) in anhydrous toluene (95 mL) was first added a solution of tert-butyl (trans-4-hydroxycyclohexyl)-methylcarbamate (intermediate 3; 6 g, 0.02 mol) in anhydrous toluene (95 mL) and secondly sodium hydride (60%, 0.45 g, 0.01 mol). After few minutes the mixture was warmed to 155° C. and the solvent was distilled and simultaneously replaced. This procedure was carried on during 1 hour and a half. The mixture was cooled to room temperature and diluted with ether (300 mL). The organic layer was washed with sodium bicarbonate 4% (2×200 mL) and brine, dried, filtered and evaporated over reduced pressure giving the title compound as a yellow solid (69%), which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19](Cl)[N:18]=2)[CH:12]=1)[CH2:8][CH3:9])(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][NH2:34])[CH:29]=[CH:30][CH:31]=1>>[CH2:8]([NH:7][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:34][CH2:33][CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:9]
Reactant: NCCc1cccc(F)c1
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C(=O)OC(C)(C)C
Product: CCNCc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 37 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 351. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.5 (s, 2H) 8.5 (m, 2H) 8.2 (d, 1H) 7.8 (d, 1H) 7.6 (m, 1H) 7.5 (ms, 1H) 7.3 (m, 1H) 7.1 (m, 2H) 7.0 (m, 1H) 4.2 (s, 2H) 3.8 (m, 2H) 2.9 (m, 4H) 1.2 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]23[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[N:10](C)[N:9]=1.[CH3:29][N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH3:29])[C:11]([C:13]23[CH2:18][CH2:17][C:16]([CH2:21][CH2:22][CH2:23][C:24](=[O:26])[CH3:25])([CH2:15][CH2:14]2)[CH2:19][CH2:20]3)=[N:10][N:9]=1
Reactant: CC(O)CCCC12CCC(c3nc(-c4ccc(O)cc4Cl)nn3C)(CC1)CC2
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CC(=O)CCCC12CCC(c3nnc(-c4ccc(O)cc4Cl)n3C)(CC1)CC2
Reaction time: 0.25 h

Procedure:
3-Chloro-4-{5-[4-(4-hydroxypentyl)bicyclo[2.2.2]oct-1-yl]-4-methyl-4H-1,2,4-triazol-3-yl}phenol (5-K) (0.0035 g, 0.00869 mmol) was stirred in 0.5 mL of dry methylene chloride over activated 4 Å sieves. N-methylmorpholine N-oxide (0.0015 g, 0.013 mmol) was added. The mixture was allowed to stir under N2 for 15 min. Tetrapropylammonium perruthenate (0.00112 g, 0.00956 mmol) was added and the reaction was allowed to stir for 2 h. The mixture was filtered through celite filtering agent. The product, 5-{4-[5-(2-chloro-4-hydroxyphenyl)-4-methyl4H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-one (6-L), was purified by preparative reverse phase HPLC on a C-18 silica gel column using a gradient of acetonitrile-water buffered with 0.1% trifluoroacetic acid. The effluent containing the pure triazole was basified with 10% NaHCO3, evaporated in vacuo to remove most of the acetonitrile, and extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated, and the residue dried under vacuum to provide the desired compound. MS (ESI+)=402.3 (M+1).
Reaction SMILES: C(OC([CH:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[N:13][C:12]([S:15][CH2:16][C:17]([NH:19][CH2:20][C@@H:21]2[O:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:22]2)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+]>FC(F)(F)C(O)=O.[Cl-].[Na+].O>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[CH2:27][N:23]1[CH2:24][CH2:25][O:26][C@@H:21]([CH2:20][NH:19][C:17](=[O:18])[CH2:16][S:15][C:12]2[N:13]=[N:14][C:9]([CH3:8])=[CH:10][CH:11]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)nn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resultant product (940 mg) of (217-3) was dissolved in trifluoroacetic acid (6 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH=4 with a 1 mol/L aqueous sodium hydroxide solution. Saturated brine was added to the obtained solution, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (265 mg) as a white solid.