Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Product: Cc1noc(NS(=O)(=O)c2ccco2)c1Br
Yield: 20 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide was prepared by the method of Example 1 with 5-amino-4-bromo-3-methyl-isoxazole (0.266 g, 1.5 mmol), NaH (60% oil dispersion) (0.15 g, 3.8 mmol) and furan-2-sulfonyl chloride (Example 36A) (0.30 mg, 1.8 mmol). Flash chromatography (50% EtOAc/hexane) and recrystallization from CHCl3 and hexane provided 90 mg (20% yield) of light yellow crystals (m.p. 117-119° C.).
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C(O)(=O)C.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: [Na]
Solvent: CC(=O)O
Product: c1ccc(COc2ncnc3nc[nH]c23)cc1
Temperature: 100 °C
Reaction time: 120 h
Yield: 28 %

Procedure:
Sodium (2.5 g, 109 mmol) was added to distilled benzyl alcohol (45 ml) under nitrogen. 6-Chloropurine (1.0 g, 6.47 mmol) was dissolved in distilled benzyl alcohol (73 ml) and the above solution (27 ml, 64.7 mmol) was added. The reaction was stirred at 100° C. under nitrogen for 5 days. After cooling to room temperature and neutralisation using glacial acetic acid, the solvent was removed in vacuo. Water (70 ml) was added and the product was extracted into ethyl acetate (3×30 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed. After further drying in vacuo, the product was recrystallised from acetone to yield the title compound as a white crystalline solid (0.39 g, 28%), m.p. 173-175° C.; (Found: C, 63.14; H, 4.29; N, 24.80. Calc. for C12H10N4O: C, 63.71; H, 4.46; N, 24.76%); δH (200 MHz, d6-DMSO) 8.480 (1H, s, C(2)H or C(8)H), 8.307 (1H, s, C(2)H or C(8)H), 7.522-7.301 (5H, m, Ph), 5.592 (2H, s, OCH2); m/z 226 (M+, 36%), 197 (8), 120 (35), 91 (Bn+, 100%), 81 (9), 65 (24), 57 (23), 43 (16), 32 (8).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([NH:22][NH2:23])=[O:21]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][C:9]([S:12][CH3:13])=[N:8][C:7]=1[NH:23][NH:22][C:20]([C:16]1[O:15][CH:19]=[CH:18][CH:17]=1)=[O:21])=[O:5])[CH3:2]
Reactant: NNC(=O)c1ccco1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Product: CCOC(=O)c1cnc(SC)nc1NNC(=O)c1ccco1

Procedure:
Compound ee was obtained using 5-ethoxycarbonyl-4-chloro-2-methylthiopyrimidine and 2-furoic hydrazide in the same manner as in Reference Example 19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH:32](OC(C)C)(C)[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH2:32][CH3:33])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)OC(C)C
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Product: CCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 313, the title compound was synthesized using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde. Crystals (diisopropyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1O)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].P(Br)(Br)([Br:22])=O>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[Br:22])=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1O
Reactant: O=P(Br)(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Br
Yield: 51 %

Procedure:
To a stirred solution of 6-chloro-4-hydroxy-2-isopropyl-quinoline-3-carboxylic acid methyl ester (800 mg, 2.86 mmol) in DCM (15 ml) was added POBr3 (1.23 g, 4.3 mmol) at 25° C. and the resulting reaction mixture was refluxed for 6 h. The reaction mixture was diluted with cold water, extracted with DCM, washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (eluting with 5% EtOAc in hexane on 100-200 mesh silica gel column chromatography) to afford pure 4-bromo-6-chloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (500 mg, 51%) as an off white solid. LC-MS: 343 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].Cl[CH:31]([O:33][CH2:34][CH3:35])[CH3:32]>O1CCCC1>[CH2:31]([O:33][CH:34]([N:3]1[C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]1[CH3:1])[CH3:35])[CH3:32]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CCOC(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(C(C)OCC)C(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
In 50 ml. of anhydrous tetrahydrofuran was dissolved 5 g. of diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine 3,5-dicarboxylate in a nitrogen gas stream and after adding to the solution 1 g. of a 50% oil dispersion of sodium hydride, the mixture was maintained at room temperature for 10 minutes. Then, 3 ml. of 1-chloro-1-ethoxyethane was added to the mixture under cooling to -40° C. and after removing the cooling bath, the resultant mixture was stirred for 30 minutes. After the reaction was over, 1 ml. of glacial acetic acid was added to the product and then the product was diluted with ethyl acetate. The reaction product was washed with water, saturated aqueous sodium bicarbonate solution, and then water, dried over anhydrous magnesium sulfate, and then the solvent was distilled away under a reduced pressure to provide crude diethyl N-(1-ethoxyethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. By purifying the product by means of a silica gel column chromatography and by using a 20:1 benzeneethyl acetate mixed solvent, 1 g. of faint-yellow oily diethyl N-(1-ethoxyethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained. The product was confirmed in the infrared absorption spectra, the nuclear magnetic responance spectra, and the mass analysis spectra to completely coincide with the presumed structure.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:24])=[CH:17][CH:18]=1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc3oc4c(c3c2)CCCC4)cc1
Yield: 62.2 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), anisoyl chloride (0.91 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (25 mL) provided 4-methoxy-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (1.0 g). Mp 197.0-197.5° C.; Anal. Calcd. for C20H19NO3: C, 74.75; H, 5.96; N, 4.36; Found: C, 74.67; H, 5.87; N, 4.46.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 138 %

Procedure:
{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (300 mg, 0.94 mmol), 2-fluoronitrobenzene (100 μl, 0.95 mmol) and potassium carbonate (150 mg, 1.08 mmol) were stirred together at room temperature in N,N-dimethylformamide (1 ml) for 2 days. The reaction mixture was concentrated in vacuo and the residue partitioned between water (30 ml) and ethyl acetate (100 ml). The layers were separated and the organic phase washed with water (2×20 ml), dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow gum (570 mg, 100%). HRMS ESI+ m/z 440.2537 [MH]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][S:7]([O-:10])(=O)=[O:8])[CH2:2]1.[Na+].C1(C)C=CC=CC=1.S(Cl)([Cl:21])=O>CN(C)C=O>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][S:7]([Cl:21])(=[O:10])=[O:8])[CH2:2]1
Reactant: O=S(=O)([O-])CC1CCOC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CC1CCOC1

Procedure:
Sodium tetrahydrofuran-3-ylmethanesulfonate (1.0 g) [see Preparation 10] was dissolved in dimethylformamide (0.05m)) and thionyl chloride (5.3 ml) was added. The reaction mixture was heated under reflux for 5 hours, cooled and toluene (10 ml) added. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried over magnesium sulphate and the solvent removed under reduced pressure to afford tetrahydrofuran-3-ylmethanesulfonyl chloride (0.22 g) as a yellow oil. 1H-NMR (CDCl3) δ: 3.95 (1H, m), 3.90-3.60 (2H, m), 3.45 (1H, m), 3.00 (2H, m), 2.30 (1H, m), 2.10 (1H, m), 1.80 (1H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:15][N:16]([C:21](=[O:23])[CH3:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].CCOC(C)=O>>[ClH:30].[ClH:30].[CH:24]1([CH:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15][N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:21](=[O:23])[CH3:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CC(=O)N(CC(C)C)CC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N(CC(C)C)CC(C1CCCCC1)N1CCNCC1

Procedure:
A solution of the product from Step I (500 mg, 1.2.1 mmol) in 1N HCl/EtOAc (25 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and solid washed twice with Et2O to afford the title compound as a white solid. MS m/z 310.3 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CCCCCCC.C(Cl)Cl>[C:22]([C:4]1[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=1)#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Reactant: C#CCCCCC
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCCCCC#Cc1cc(C(F)(F)F)n(C)n1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (100 mg, 82%); 1H NMR δ (CDCl3): 6.63 (s, 1H), 3.95 (s, 3H), 2.38 (t, J=7.34 Hz, 2H), 1.64-1.56 (m, 2H), 1.46-1.28 (m, 4H), 0.90 (t, J=7.36 Hz, 3H); LCMS m/z: 244.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[N:7][N:6]=[C:5]2[C:9]2[N:14]=[C:13]([NH:15]C(=O)OCC3C=CC=CC=3)[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1>[Pd]>[CH:1]1([N:4]2[CH:8]=[N:7][N:6]=[C:5]2[C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)n1)OCc1ccccc1
Agent: [Pd]
Product: Nc1cccc(-c2nncn2C2CC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of benzyl 6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-ylcarbamate (660 mg, 1.96 mmol, 1.0 eq) and Pd/C (80 mg 10% Pd loading, 40 mg/mmol) was loaded into a flask and purged with nitrogen. Ethanol (0.4 M) was added and the flask was charged with hydrogen (1 atm balloon pressure). The reaction was stirred at room temperature for 90 minutes, and judged to be complete by TLC. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give 395 mg (95%) of 6-(4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-ylamine. C10H11N5. 202.1 (M+1). 1H NMR (DMSO) d 8.14 (s, 1H), 7.54 (t, J=8 Hz, 1H), 7.46 (d, J=7 Hz, 1H), 6.60 (d, J=8 Hz, 1H), 4.70 (br s, 2H), 3.85-3.88 (m, 1H), 1.04-1.07 (m, 2H), 0.85-0.88 (m, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=2)[C:10](=[O:19])[N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.N#N>ClCCl>[CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10](=[O:19])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)N(C(=O)OC(C)(C)C)C2=O
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: O=C1NC(Cc2ccccc2)c2cc(O)ccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred and cold (−5° C.-1-10° C.) solution of tert-butyl 3-benzyl-5-methoxy-1-oxoisoindoline-2-carboxylate (0.92 g, 2.59 mmol) in dichloromethane (9 mL) was added BBr3 (7.8 mL, 7.78 mmol) dropwise under N2. This was stirred at −5° C. for 3 hours, then room temperature for overnight. TLC showed complete conversion. The reaction mixture was poured into ice-water, extracted 3× with dichloromethane. The combined organic layer was washed 1× with water, 1× with saturated NaHCO3, 1× with saturated NaCl solution, dried over Na2SO4, concentrated down to a light yellow solid (620 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH:42]([OH:44])[CH:41]([NH2:45])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:43][CH:42]([OH:44])[CH:41]([NH:45][C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CC(O)C(NC2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
3-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-Amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(CC)CC>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.O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])=[N:3][CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(O)C#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.6 mmol), Cul (141 mg, 0.74 mmol), Pd(PPh3)4, (367 mg, 0.32 mmol) and 2-Methyl-3-butyn-2-ol (1.5 mL, 15.8 mmol) was added 1-methyl-2-pyrorolidone (20 mL) followed by Et3N (6 mL, 22 mmol). After stirring for 4 h 30 min at room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel (EtOAc/Hexanes, 2:98, then 5:95) to provide 4-(5-chloro-3-nitro-pyridin-2-yl)-2-methyl-but-3-yn-2-ol. MS m/z: 241.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([N:27]([CH3:36])[CH3:26])=[CH:29][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc(Cl)cc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.047 g, 0.11 mmol), ethanol (8 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 20% ethyl acetate in dichloromethane and then 1% and 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.004 g, 7%); 1H-NMR (500 MHz, DMSO-d6) 2.60 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.57 (s, 2H, NCH2), 3.63 (br s, 4H, piperazine N(CH2)2), 6.81 (d, J=9.00 Hz, 2H) and 8.01 (d, J=8.82 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.41 (m, 4H) (3,5-ArH and 2,6-ArH), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.12 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([SH:1])[NH:3][C:4]=4[CH:10]=3)=[O:16])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2nc(S)[nH]c2c1
Solvent: CCOCC
Product: O=C(Nc1ccc2nc(S)[nH]c2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from N-(2-mercapto-3H-benzimidazol-5-yl)-oxalamic acid (Example 60b) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 1c. Melting Point: 286-288° C. (diethylether)
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9]([C@:11]3([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:28]#[N:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.[Cl-].[Na+].O>[C:28]([C:2]1[C:7]2[N:8]=[C:9]([C@:11]3([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:29]
Reactant: C[C@@]1(c2nc3c(Br)cccc3s2)CCCN1C(=O)OCc1ccccc1
Reactant: N#C[Cu]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@]1(c2nc3c(C#N)cccc3s2)CCCN1C(=O)OCc1ccccc1

Procedure:
A mixture of EXAMPLE 5D (100 mg) and copper(I) cyanide (35.3 mg) in N,N-dimethylformamide (2.5 mL) was heated in a microwave reactor at 205° C. for 30 minutes. This reaction was repeated twice, and after cooling, the combined three reaction mixtures were treated with 5% aqueous citric acid and brine and extracted with ethyl acetate. The aqueous layer was treated with 5% aqueous potassium sodium tartrate and ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated, and the residue purified by flash chromatography using 98:2 dichloromethane/ethyl acetate to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C@@H:25]([OH:27])[CH3:26])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25](=[O:27])[CH3:26])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Reaction time: 0.33 h
Yield: 84.9 %

Procedure:
(1S)-1-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanol (Example 135; 100 mg, 0.26 mmol), N-methylmorpholine-N-oxide (46 mg, 0.39 mmol), 4 Å activated molecular sieves (100 mg) and CH2Cl2 (2.6 mL) were combined under N2 and stirred for 20 minutes prior to addition of tetra(n-propyl)ammonium perruthenate (4.6 mg, 0.013 mmol). After a further 20 minutes, the mixture purified by flash chromatography (eluant 40% EtOAc/isohexane) to afford 1-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanone as a white solid (84 mg). δH (400 MHz, d6 DMSO): 8.10 (1H, d, J 7.8), 7.88 (2H, d, J 8.5), 7.80 (3H, dd, J 0.0, 8.7), 7.72-7.68 (3H, m), 7.62 (1H, d, J 6.6), 7.46 (1H, d, J 16.5), 7.32-7.22 (3H, m), 2.61 (3H, s). m/z (ES+) 380 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:29]([OH:30])([CH3:31])[CH3:28])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -42 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (20.0 g, 0.062 mol) was cooled to −42° C. in THF (400 mL). A solution of n-butyllithium (2.5 M in hexanes, 48 mL, 0.12 mol) was added portionwise over 10 min. The mixture gradually turned yellow. The reaction mixture was then allowed to stir at −42° C. for 30 minutes and then anhydrous acetone (10 mL, 0.1 mol) was added at once. The resulting reaction mixture was slowly warmed to 0° C. over a 2 hour period. The mixture was subsequently quenched with water, extracted with EtOAc and dried over MgSO4. The slurry was filtered and concentrated in vacuo to provide 2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)propan-2-ol (23 g, 98%) as a yellow solid. MS (ESI+): m/z 382.1 (M+H+)2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)propan-2-ol