Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32](O)=[O:33])=[O:15])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:75][C:76]([F:86])([F:85])[C:77]1[N:82]=[CH:81][C:80]([CH2:83][NH2:84])=[CH:79][CH:78]=1>CN(C)C=O>[F:85][C:76]([F:75])([F:86])[C:77]1[N:82]=[CH:81][C:80]([CH2:83][NH:84][C:32]([C:31]2[CH:35]=[CH:36][N:37]=[C:29]([C:18]3[CH:19]=[C:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH:21]=[CH:22][C:17]=3[NH:16][C:14]([C:13]3[CH:12]=[C:11]([CH:40]=[CH:39][CH:38]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:41])=[O:15])[CH:30]=2)=[O:33])=[CH:79][CH:78]=1
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(C(F)(F)F)nc3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Into a 8-mL sealed tube, was placed a solution of 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid 1.1j (90 mg, 0.16 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), HATU (90 mg, 0.24 mmol, 1.51 equiv), N,N-diisopropylethylamine (30.6 mg, 0.24 mmol, 1.52 equiv), and (6-(trifluoromethyl)pyridin-3-yl)methanamine (54 mg, 0.31 mmol, 1.96 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate. The resulting mixture was washed with water and brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 114.7 mg (crude) of tert-butyl 3-(3-((2-(4-(((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate as red oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17](OC)=[O:18].C1(C)C=CC=CC=1.[H-].C([Al+]C(C)C)(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CCOCC>[OH:18][CH2:17][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2
Reactant: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2n1C
Agent: CC(C)[Al+]C(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1cc2c(cc(CO)n2C)c(OC)c1OC
Reaction time: 1 h

Procedure:
Methyl 1-methyl-4,5,6-trimethoxyindole-2-carboxylate (1.17 g) was dissolved in dry THF under an argon atmosphere at 0° C., a 1 M toluene solution (13.2 mL) of diisopropylaluminum hydride was added dropwise to the solution, and the mixture was stirred for 1 hour as it is. The reaction mixture was diluted with ether, the sodium sulfate decahydrate was added thereto, and the mixture was stirred further for 1 hour. After the reaction mixture was filtered, and the filtrate was concentrated, the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2 to 1:1) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:12]=1[CH2:25][C:26](Cl)=[N:27][OH:28].C(N(CC)CC)C>O1CCCC1>[F:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:12]=1[CH2:25][C:26]1[CH:2]=[C:1]([C:3]2[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=2)[O:28][N:27]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2F)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of the 3-ethynyl-pyridin-2-ylamine (38.4 mg, 0.325 mmol) described in Manufacturing Example 1-2-3 and (2-fluoro-4-(pyridin-2-yloxymethyl)-phenyl)acetohydroximoyl chloride (150 mg, 0.509 mmol) described in Manufacturing Example 204-1-8 was added triethylamine (97.2 μL, 0.697 mmol), which was stirred for 2 hours at 60° C. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2, then 1:1) to obtain the title compound (46 mg, 24%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([O:10]C(OC)=O)=[CH:8][C:7]([N+:15]([O-:17])=[O:16])=[C:6]([F:18])[CH:5]=1.Cl>CO>[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([N+:15]([O-:17])=[O:16])=[C:6]([F:18])[CH:5]=1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A 6N aqueous sodium hydroxide solution (17 ml) was added dropwise to a stirred solution of 4-chloro-2-fluoro-5-methoxycarbonyloxy-1-nitrobenzene (J. Med. Chem., 1999, 42, 5369; 25 g) in methanol (200 ml) which was cooled to 5° C. The reaction mixture was stirred at ambient temperature for 30 minutes. A 12N aqueous hydrochloric acid solution (8.5 ml) was added and the mixture was evaporated. The residue was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulphate and evaporated to give 4-chloro-2-fluoro-5-hydroxy-1-nitrobenzene (18.5 g); NMR Spectrum: (CDCl3) 5.8 (br s, 1H), 7.35 (d, 1H), 7.75 (d, 1H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[N:18]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:20][NH:19]1>C(#N)C>[N:19]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:20][CH2:21][CH:22]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[N:18]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1CCNN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 74.4 %

Procedure:
Sat. aq. K2CO3 (210 mL) was added into a solution of benzyl chloroformate (12.0 ml, 84 mmol) and crude di-tert-butyl pyrazolidine-1,5-dicarboxylate (12.74 g, assumed 46.8 mmol) in acetonitrile (137 ml) at 0° C. The reaction was allowed to warm to room temperature and was stirred for 4.5 hrs. The aqueous phase was extracted with EtOAc (3×100 mL), and the organic layers were dried over Na2SO4. The solvents were removed in vacuo, and the crude product was purified by silica gel chromatography (CombiFlash, Column: 220 g; 0-35% ethyl acetate in hexane; 60 min) to provide the desired product 1-benzyl 2,3-di-tert-butyl pyrazolidine-1,2,3-tricarboxylate (14.15 g, 74% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 1H-1,2,4-triazol (2 g, 29.9 mmol, 1.0 eq) in DMF were added K2CO3 (12.3 g, 88.9 mmol, 3 eq.) and ethyl 2-bromoacetate (4.8 g, 29.9 mmol, 1 eq). The mixture was stirred at RT for 16 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to give the product in 65% yield (3 g). LC-MS (ESI): Calculated mass: 155.0; Observed mass: 156.1 [M+H]+ (rt: 0.113 min).
Reaction SMILES: O=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14]>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[CH2:6][S:5][CH2:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Nc1ccc(I)cc1F
Reactant: COC(=O)C1CSCC1=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1=C(Nc2ccc(I)cc2F)CSC1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
To a mixture of methyl 4-oxotetrahydrothiophene-3-carboxylate (1.75 g, 11 mmol) (commercially available or prepared using procedures similar to those described in Rossy et. al. J. Org. Chem. 1980, 45(4), 617-2) in 15 mL of ethanol was added 2-fluoro-4-iodoaniline (2.6 g, 11 mmol) followed by addition of several drops of acetic acid. The mixture was refluxed for 3 hrs. The mixture was cooled to room temperature and the product precipitated. This product was filtered off, washed with ethyl acetate, ether, dried in vacuo to afford the methyl 4-[(2-fluoro-4-iodophenyl)amino]-2,5-dihydrothiophene-3-carboxylate (1.7 g, 42%). 1HNMR (d6-DMSO): 9.80 (s, 1H), 7.71 (d, 1H), 7.49 (dd, 1H), 7.24 (t, 1H), 4.10 (t, 2H), 3.79 (t, 2H), 3.69 (s, 3H); MS (EI) for C12H11FINO2S: 380 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[C:3]1([CH2:2][O:1][N:33]2[C:34](=[O:43])[C:35]3=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]3[C:37]2=[O:38])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: OCc1cccc2ccccc12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1OCc1cccc2ccccc12
Reaction time: 8 h
Yield: 63 %

Procedure:
1-(hydroxymethyl)naphthalene (1.00 g, 6.33 mmol), triphenyl phosphine (1.73 g, 6.60 mmol, 1.04 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol, 1.09 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture was diluted with 25 mL of Et2O and placed in a freezer for 2 hours. The reaction mixture was then filtered to give a white solid. Recrystallization from EtOH gave the desired product (1.21 g) as a white solid. MS(CI) m/e 321 (M+NH4)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH2:28][CH:29]1[CH2:46][C:32]2[C:33]3[NH:34][C:35](=[O:45])[C:36](=[O:44])[NH:37][C:38]=3[CH:39]=[C:40]([N+:41]([O-:43])=[O:42])[C:31]=2[CH2:30]1>O1CCCC1.CN(C)C=O>[N+:41]([C:40]1[C:31]2[CH2:30][CH:29]([NH:28][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:46][C:32]=2[C:33]2[NH:34][C:35](=[O:45])[C:36](=[O:44])[NH:37][C:38]=2[CH:39]=1)([O-:43])=[O:42]
Reactant: O=C(O)c1cccs1
Reactant: NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1)c1cccs1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of thiophene-2-carboxylic acid (1 mmol) in anhydrous tetrahydrofuran (THF) was treated with carbonyldiimidazole (1.2 mmol) and triethyl amine (1 mL) and heated at 60° C. for 30 min. After cooling to room temperature a solution of 8-amino-6-nitro-4,7,8,9,-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione (1 mmol) in dimethylformamide (DMF) was added. The reaction mixture as stirred at room temperature for 2 h, then heated at 70° C. for 2 h. The solvent was evaporated and the residue triturated with acetone. The solid was collected by filtration, washed with diethyl ether and dried in vacuo. Calc'd for C16H12N4O5S.H2O: C, 49.22; H, 3.61; N, 14.35, found: C, 49.06; H, 312; N, 15.05. MS M+1 (373).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[O:17][CH2:18][C:19]([NH2:21])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC(S(NCCC2C=C(C=CC=2)OCCCC(O)=O)(=O)=O)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[BH4-].[Na+].[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[O:17][CH2:18][CH2:19][NH2:21])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NC(=O)COc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: O=C(O)CCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: [Al+3]
Agent: [BH4-]
Solvent: CCOC(C)=O
Product: NCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 21.6 g (58.6 mmol) 3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetamide and 175 ml dimethoxyethane one adds portionwise at 15°-20° C. 31.3 g (0.234 mol) anhydrous aluminium chloride and allows to stir further for 30min. One then adds 8.85 g (0.234 mol) NaBH4 portionwise thereto at 15°-20° C. within 1/2 hr. After 3 hrs. stirring while cooling, 130 ml ice-water are carefully added dropwise thereto, whereby the internal temperature is not to exceed 25° C. While cooling withice, one brings the pH value to 8.5 by addition of conc. NaOH, adds 75 ml ethyl acetate thereto and filters. The precipitate is after-washed with ethyl acetate. After separation of the phases, the aqueous phase is also extracted with ethyl acetate. The organic extracts are dried, concentratedto about 80 ml and mixed with 20 ml HCl-containing ether. After cooling, one filters off with suction and then washes with ethyl acetate. Yield 16.7 g (73% of theory) of hydrochloride with the m.p. 187°-190° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].C(OO)(=[O:13])C>ClCCl>[O:13]1[CH2:3][CH:2]1[CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10]
Reactant: C=CCc1ccccc1O
Reactant: CC(=O)OO
Solvent: ClCCl
Product: Oc1ccccc1CC1CO1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Allylphenol (10 g, 0.075 mol) was added to a solution of peracetic acid (30 g, 30% active) in dichloromethane (100 ml) that had been dried over anhydrous MgSO4. The reaction mixture was stirred at room temperature for 48 hrs. The dichloromethane solution was washed with water, dilute aqueous NaCO3, dilute aqueous NaSO3 and dried over anhydrous MgSO4. After evaporation of the solvent in vacuo, 2-(2,3-epoxypropyl)phenol was isolated as viscous liquid. MS m/z 150 (M+ calcd for C9H10O2150). H NMR (300 MHz, CDCL3) d 2.65-2.80(m, 2, CH2 epoxypropyl), 2.87-2.93 (m, 1, CH2 epoxypropyl), 3.10-3.21 (m, 1, CH2 epoxypropyl), 3.50-3.60 (m, 1, CH epoxypropyl), 6.80-7.25 (m, 4, aromatic). 2-(2,3-Epoxypropyl)phenol (0.9 g, 0.006 mol) was added to a solution of powdered sodium hydroxide (0.24 g, 0.006 mol) in dimethylacetamide(30 ml) and the solution heated at 80C for 1 hr. The reaction mixture was diluted with water and extracted with dichloromethane, dried over anhydrous MgSO4 and evaporated in vacuo to give a solid that on recrystallization from methanol gave product mp 150-152C. MS m/z 376 (M+ cacld for C22H20N2O4=376). H NMR (300 MHz, CDCl3) d 3.62 (dq, 2, CH2 epoxypropyl), 4.57 (dq, 2, CH2 epoxypropyl), 5.15-5.32 (m, 1, CH epoxypropyl), 6.78-6.93 (m, 2, aromatic), 7.11 (s, 1, heteroaromatic), 7.15-7.28(m, 2, aromatic).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:24]([C:26]([CH3:28])=[CH2:27])[CH:23]=[C:22]([O:29][CH3:30])[C:3]=1[O:4][C:5]1[C:6]2[N:14]=[N:13][N:12]([CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C:7]=2[N:8]=[C:9]([CH3:11])[N:10]=1>C(O)C.[Pt]>[Br:1][C:2]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[C:22]([O:29][CH3:30])[C:3]=1[O:4][C:5]1[C:6]2[N:14]=[N:13][N:12]([CH:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[C:7]=2[N:8]=[C:9]([CH3:11])[N:10]=1
Reactant: C=C(C)c1cc(Br)c(Oc2nc(C)nc3c2nnn3C(CCC)CCC)c(OC)c1
Agent: [Pt]
Solvent: CCO
Product: CCCC(CCC)n1nnc2c(Oc3c(Br)cc(C(C)C)cc3OC)nc(C)nc21
Reaction time: 18 h

Procedure:
Platinum black, 5% (0.19 g) was added to a solution of 7-[2-bromo-6-methoxy-4-(1-methylethenyl)phenoxy]-5-methyl-3-(1-propylbutyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine (0.17 g) in 50 mL of ethanol. The mixture was hydrogenated at a pressure of 40 psi for 18 hours and filtered through celite. The filtrate was stripped of the solvent under reduced pressure and the residue recrystallized from hexane to yield the title compound as a colorless crystalline solid, mp 129-131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([NH:24][C:25]([C:27]3[N:28]=[C:29]([CH3:32])[S:30][CH:31]=3)=[O:26])[C:12]3[C:16]([CH:17]=2)=[N:15][N:14](C2CCCCO2)[CH:13]=3)[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([O:44][CH3:45])=[C:38]([S:40](Cl)(=[O:42])=[O:41])[CH:39]=1.Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[C:11]([NH:24][C:25]([C:27]3[N:28]=[C:29]([CH3:32])[S:30][CH:31]=3)=[O:26])[CH:10]=2)=[CH:3][C:2]=1[NH:1][S:40]([C:38]1[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][C:37]=1[O:44][CH3:45])(=[O:42])=[O:41]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(N)c3)cc3nn(C4CCCCO4)cc23)cs1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
N-[6-(5-Amino-6-chloro-3-pyridinyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-methyl-1,3-thiazole-4-carboxamide (50 mg) was dissolved in pyridine (1 ml) and 5-methyl-2-(methyloxy)benzenesulfonyl chloride (35 mg) was added. The reaction was stirred at RT overnight. Further 5-methyl-2-(methyloxy)benzenesulfonyl chloride (35 mg) was added and the reaction was stirred at RT for 4 h. DMAP (3 mg) followed by 5-methyl-2-(methyloxy)benzenesulfonyl chloride (20 mg) was added and the reaction was stirred at RT overnight. The reaction was neutralised with 2M HCl (aq) and extracted into DCM. The DCM was evaporated and the residue was dissolved in DMSO:methanol (1 ml, 8:1, v/v) and purified by MDAP (method E). The desired fraction was evaporated to dryness and methanol (3 ml) and a few drops of 2M HCl (aq) were added and the reaction stirred for 2 h. The reaction was evaporated to dryness to give title compound (39 mg).
Reaction SMILES: OC(CO)[CH2:3][NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:7]=1.NC[CH2:31][O:32][CH2:33][CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:3][NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:7]=1
Reactant: NCCOCCO
Reactant: COc1ccc(C(=O)NCC(O)CO)cc1/C=C/c1ccc(C(F)(F)F)cc1
Product: COc1ccc(C(=O)NCCOCCO)cc1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-38 and 2-(2-aminoethoxy)ethanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH2:1]([OH:13])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O:18]O)(C)(C)C.O.[OH-].[Na+]>C(Cl)Cl.C(CC(C)(C)C)(C)C.[Cl-].[Na+].O>[CH2:4]([C@H:3]1[O:18][C@H:2]1[CH2:1][OH:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(C)OO
Reactant: CCCCCCCCC/C=C\CO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCCC[C@H]1O[C@H]1CO
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
To a slurry of 500 mg of powdered 4A molecular sieves in 30 ml of dry CH2Cl2 at 0'C. under argon, was added 232 mg (0.82 mmole) of Ti(Oi-Pr)4 followed by 266 mg (1.14 mmole) of L(+)diisopropyl tartrate. The mixture was allowed to stir for 15 min. The mixture was cooled to -20'C and a solution of 0.75 g (4.1 mmole) of cis-2-dodecene-1-ol in 5 ml of CH2Cl2, which has been dried over 3A molecular sieves for 15 min, was then added. After the catalyst had "aged" for 20 min, 2.15 ml of 3.8 M (8.17 mmole) tert-butyl hydroperoxide in isooctane was added slowly by syringe. The reaction was then allowed to stand in the freezer (-30'C) for seven days. The mixture was then warmed to 0'C and 5 ml of H2O was added with stirring. After 30 min, 1.5 ml of 30% NaOH in saturated brine was added and the mixture was allowed to stir 60 min longer. The organic layer was separated and the aqueous layer was washed twice with 20 ml of CH2Cl2. The combined organic layers were dried over MgSO4, filtered and evaporated to afford a sticky white solid. Recrystallization from Et2O: petroleum ether yielded 570 mg of a flocculent white solid mp 55°-6° C. 1H NMR (CDCl3)δ3.86 (ddd, 1, J=4, 8, 12 Hz), 3.7 (m, 1), 3.16 (dt, 1, J=4, 7 Hz) 3.0 (m, 1), 1.6-1.1 (m, 12), 0.88 (t, 3, J=7 Hz). Mass spectra EI; M-31 (--CH2OH), Calc. 169.1592, Found 169.1581.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:11][CH2:10][CH:9]([CH:12]([CH3:21])[CH2:13][NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:8][CH:7]=1.[O:22]1CCCC1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]([CH3:21])[CH2:13][NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:8][CH:7]1[OH:22]
Reactant: CC(CNS(=O)(=O)C(C)C)C1CC=C(c2cccs2)CC1
Reactant: C1CCOC1
Product: CC(CNS(=O)(=O)C(C)C)C1CCC(c2cccs2)C(O)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a 0° C. solution of 1 eq. of N-[2-[4-(2-thienyl)-3-cyclohexen-1-yl]propyl] 2-propanesulfonamide (see example 8) in tetrahydrofuran is added 0.67 eq. of borane dimethyl sulfide complex. The mixture is stirred at 0° C. for 4 hr and slowly quenched with ethanol. To the 0° C. solution is added 3N aqueous sodium hydroxide then 30% aqueous hydrogen peroxide. The mixture is stirred at 0° C. for one hr. The organic portion is separated and the aqueous portion is extracted two times with diethyl ether. The combined organic extracts are dried over MgSO4, filtered and concentrate in vacuo to provide the crude material. Chromatography (silica gel) of the crude material affords the purified title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[C:8]([CH3:23])[C:6]=3[N:7]=2)=[CH:39][N:40]=1
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 50 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A-2 to give 10 mg of Formula Ib (WO 2008/070740, incorporated by reference). MS (Q1) 499.3 (M)+.