Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].P([O-])([O-])(OCCCCCCCCCCCC)=O.[P:23]([O-:44])([O:38][CH2:39][CH:40]([CH2:42][OH:43])[OH:41])([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24]>>[P:23]([O:44][CH2:1][CH:2]([CH2:4][OH:5])[OH:3])([O:38][CH2:39][CH:40]([CH2:42][OH:43])[OH:41])([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24]
Reactant: CCCCCCCCCCCCOP(=O)([O-])OCC(O)CO
Reactant: OCC1CO1
Agent: CCCCCCCCCCCCOP(=O)([O-])[O-]
Product: CCCCCCCCCCCCOP(=O)(OCC(O)CO)OCC(O)CO

Procedure:
While keeping the reaction system at 60° C., 36.9 g of glycidol (oxirane value=683.7) was gradually dadded, followed by their reaction at 70° C. for 10 hours. The acid value of the reaction system was AV1=39.6, AV2=57.3, revealing that the reaction system contained about 27 mole % of unreacted monododecyl phosphate and about 33 mole % of the corresponding phosphoric diester, i.e., dodecyl glyceryl phosphate and about 40 mole % of the corresponding phosphoric triester, i.e., dodecyl diglyceryl phosphate were formed.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[O:15]1[CH2:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1.O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:18]2[CH2:19][CH2:20][O:15][CH2:16][CH:17]=2)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Br
Temperature: 100 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a microwave vial containing a suspension of ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (300.0 mg, 0.8849 mmol, prepared as in MPI10-008P1M) and 3,6-dihydro-2h-pyran-4-boronic acid pinacol ester (204 mg, 0.973 mmol) in 1,4-dioxane (8.98 mL, 115 mmol) and water (0.925 mL, 51.3 mmol) were added tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.0885 mmol) and cesium carbonate (865 mg, 2.65 mmol). The vial was sealed, degassed by bubbling argon through for 10 minutes, and then heated at 100° C. with stirring for 24 h. The reaction was then cooled to room temperature and partitioned between EtOAc and water. Layers were separated, and, the aqueous layer was extracted 2× with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Residue was subjected to column chromatography as a solution in DCM (40 g column, gradient elution 0 to 25% EtOAc/hexanes) to afford ethyl 3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate as a white solid (183 mg, yield 63%). LCMS: (FA) ES+ 342, 344; 1H NMR (400 MHz, DMSO) δ 6.86-6.79 (m, 1H), 4.36-4.27 (m, 4H), 3.82 (dd, J=5.4, 5.4, 2H), 2.53 (ddd, J=2.1, 4.9, 10.0, 2H), 1.30 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([N:28]([CH3:29])[CH3:27])[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Reactant: CNC
Product: CN(C)c1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure C from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and dimethylamine (33% aqueous solution); δH (CDCl3) 9.00 (1H,s), 8.52 (1H,s), 7.59 (2H,d), 7.40 (4H,m), 7.23 (1H,s), 7.13 (2H,d), 6.35 (1H,s), 5.10 (2H,s), 3.20 (6H,s); m/z (M+1)+395.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1>>[CH3:12][C@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:18]1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1

Procedure:
A mixture of 2-chloro-3-trifluoromethylpyridine (1.45 g, 8 mmol, Aldrich) and (R)-(−)-2-methylpiperazine (1.0 g. 10 mmol, Aldrich) was reacted under the conditions of Example 43a to give the title compound as a off-white solid. MS (ESI, pos. ion) m/z: 246 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6]([Cl:27])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1C1CCC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C1CCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 3-cyano-5-cyclobutyl-4-methoxybenzoic acid (190 mg), toluene (2.0 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.07 mL) were added, and the mixture was stirred at 60° C. for 3 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (204 mg) as a brown oily substance.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[CH:9][CH:8]=2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[C:32]([CH2:38][CH2:39][CH3:40])=[N:31][C:30]([OH:41])=[CH:29]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:15]([O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[C:4]([CH2:3][C:29]1[C:28]3[C:33](=[CH:34][C:35]([O:36][CH3:37])=[C:26]([O:25][CH3:24])[CH:27]=3)[C:32]([CH2:38][CH2:39][CH3:40])=[N:31][C:30]=1[OH:41])=[CH:13]2)[CH3:16]
Reactant: CCOc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OCC)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(2-(3-(chloromethyl)-6-ethoxyquinolin-2-ylamino)ethyl)acetamide hydrochloride SMA 44092 (231 mg, 0.65 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (159 mg, 0.65 mmol) followed by a 2 N aq. LiOH solution (0.65 mL, 1.29 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) provided N-(2-(6-ethoxy-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of 0.49 M HCl in MeOH (2 mL) and the solution was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford N-(2-(6-ethoxy-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide dihydrochloride 88 as a yellow solid (25 mg, 6% yield).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:31]([CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[ClH:47]>C1COCC1.CCOCC>[ClH:47].[ClH:47].[CH3:7][N:8]([CH3:30])[CH2:9][CH:10]=[C:43]1[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:41][CH2:42]1
Reactant: O=C1CCN(CCOc2ccccc2)CC1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CC=C1CCN(CCOc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (9.13 ml, 2.5M solution in hexanes) was added to a suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide (9.46 g) in dry THF (60 ml) under nitrogen at 0° C. over 5 minutes. The mixture was stirred at 0° C. for 30 minutes and then 1-(2-phenoxyethyl)-4-piperidone (5.0 g) in THF (15 ml) was added dropwise over 5 minutes. The mixture was warmed to ambient temperature and then heated at 60° C. for 5 hours. The mixture was left at ambient temperature for 18 hours and then quenched with water and diluted with ethyl acetate. 2M Hydrochloric acid was added and the mixture was separated. The organic layer was extracted with 2M hydrochloric acid and the combined acidic layers were basified and extracted with dichloromethane to give an oil. The oil was purified by flash column chromatography on silica using dichloromethane and then dichloromethane/methanol (1:1) as the mobile phase. The oil obtained after chromatography was dissolved in ether and treated with ethereal hydrogen chloride. The ether was decanted off and the residual semi-solid was triturated with acetone/ether (1:1) and filtered to give a solid which was recrystallised from IMS to give 4-(2-dimethylaminoethylidene)-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 234°-235° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH2:11][CH2:10]1.[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:44](O)=[O:45])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:44]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:14][CH2:13]1)=[O:45])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Reactant: OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First, 3 g of 2,3-difluoro-1-[trans-4-(13-hydroxytridecyl)cyclohexyl]benzene, 3 g of 2,2-bis(6-benzyloxyhexyl)acetic acid, 2.2 g of triphenylphosphine, and 30 ml of tetrahydrofuran were placed in a 100 ml flask. Then, 1.5 g of ethyl azodicarboxylate was added dropwise to the reaction mixture under ice water cooling. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 5.4 g of 13-[trans-4-(2,3-difluorophenyl)cyclohexyl]tridecyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 97%). The compound thus obtained had a purity of 93.7% by HPLC.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.[NH2:32][C:33]1[CH:34]=[C:35]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:36]([Cl:39])=[N:37][CH:38]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:39][C:36]1[C:35]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:34][C:33]([NH:32][C:2]2[C:3]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:38][N:37]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (0.157 g, 0.368 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330 step 2, 0.103 g, 0.462 mmol) in THF (2 mL) in 20 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 1.47 mL, 1.47 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The mixture was partitioned between a mixture of saturated aqueous sodium chloride (10 mL)/buffer (pH 5.0, citric acid/NaOH) (10 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50 g, eluent: iPrOH in CHCl3 0% to 10%) to afford N-(2-chloro-5-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-morpholinoethyl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide (0.169 g, 73% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 13.18 (s, 1H) 9.78 (d, J=1.96 Hz, 1H) 8.83 (d, J=2.54 Hz, 1H) 8.63 (d, J=2.54 Hz, 1H) 8.36 (d, J=2.35 Hz, 1H) 8.31 (s, 1H) 6.76 (br. s., 1H) 5.85-5.90 (m, 1H) 4.17-4.24 (m, 1H) 3.79-3.88 (m, 1H) 3.73 (t, J=4.50 Hz, 4H) 3.51-3.59 (m, 1H) 3.14 (s, 3H) 2.94 (s, 3H) 2.45-2.62 (m, 4H) 2.01-2.22 (m, 3H) 1.66-1.93 (m, 3H) 1.48 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion): 628.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[OH:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].O>CN(C=O)C>[Si:5]([O:14][CH:15]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:16]([O:18][CH3:19])=[O:17])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: COC(=O)C(O)c1ccc(OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
TBDMSCl (1.5 g, 9.94 mmol) and imidazole (1.0 g, 14.6 mmol) were added to a solution of methyl hydroxy-(4-methoxyphenyl)acetate (Teodozyj Kolasa et al., J. Org. Chem., 1987, 22, 4978-4984) (1.3 g, 6.62 mmol) in DMF (8 mL) and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to give the title compound (2.0 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])=[O:17])=[CH:13][CH:14]=2)=[O:38])=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Sc2ncc(Br)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(S(=O)c2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
To a stirred solution of 6n (1.0 g, 2.11 mmol) in DCM (50 mL) at 0° C. was added MCPBA (0.364 g, 2.11 mmol) in portions. The resulting mixture was stirred at room temperature for 6 h and then diluted with water and made slightly basic with Na2CO3 solution. The DCM layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried and evaporated to give a residue that was purified by silica gel flash column chromatography (ethyl acetate-methanol 5:1) to give 8g, yield 48%. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br, s, 1H), 10.38 (br, s, 1H), 9.15 (s, 2H), 8.20 (m, 1H), 7.88 (m, 1H), 7.72-7.80 (m, 6H); EI-MS m/z 489 [M]+, 491 [M+2]+; HRMS calculated for C18H12BrN5O5SNa [M+Na]+: 511.9634, found: 511.9632. Anal. (C18H12BrN5O5S) C, H, N.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:3]1.[Cl:14][C:15]1[C:20]([C:21]2[C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:29])[O:23][N:22]=2)=[C:19]([F:30])[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:2]([NH:1][C:26]([C:25]2[C:21]([C:20]3[C:19]([F:30])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:14])=[N:22][O:23][C:24]=2[CH3:29])=[O:27])[CH2:3]1
Reactant: COC(=O)CC1CCCCC(N)C1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCCCC(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)C1
Yield: 873.9 %

Procedure:
A solution of 4.4 g (24 mmol) of methyl 2-(3-aminocycloheptyl)acetate, 0.03 g (0.46 mmol) of 3-(6-chloro-2-fluorophenyl)-5-methylisoxazole4-carbonyl chloride, and 0.07 ml (0.5 mmol) of triethylamine in dichloromethane (10 ml) was stirred for 12 hours. The solvent was removed in vacuo and replaced with ethyl acetate. The organic layer was washed with 1N HCl, then aq. NaHCO3, followed by brine and dried. The solvent was removed in vacuo then chromatographed on silica gel with hexane/EtOAc 3/1 to yield 1.7 g of the title compound. MS(ES+)m/z=423.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([OH:16])[C@H:12]([NH2:15])[CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:17][CH:18]([Cl:23])[C:19](OC)=[O:20].C(N(CC)CC)C>CO>[Cl:17][CH:18]([Cl:23])[C:19]([NH:15][C@H:12]([CH2:13][F:14])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[OH:16])=[O:20]
Reactant: COC(=O)C(Cl)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
To a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (5 g, 0.02 moles) in methanol (50 ml) was added methyl dichloroacetate (14.5 g; 0.10 g) and triethylamine (2.05 g, 0.02 mole) and stirred at room temperature for 18 hours. After completion of reaction, methanol was distilled off from the reaction mass, toluene (25 ml) and water (5 ml) were added. The product thus precipitated was filtered, washed with methylene chloride (20 ml) and crystallized from 2-propanol/water (5:1) to give 5 g of title compound having purity 99.20% by HPLC.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:9]=[C:8]([CH3:10])[O:7][N:6]=1.O.[NH2:13][NH2:14]>C(O)CCC>[CH3:10][C:8]1[O:7][N:6]=[C:5]([CH2:4][C:3]([NH:13][NH2:14])=[O:2])[CH:9]=1
Reactant: COC(=O)Cc1cc(C)on1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1cc(CC(=O)NN)no1
Yield: 90 %

Procedure:
As described for example 112a, (5-methyl-isoxazol-3-yl)-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 90 min. Evaporation of all volatiles afforded the title compound as a white solid (yield: 90%). 1H-NMR (300 MHz, DMSO): δ=2.36 (d, J=0.7 Hz, 3H), 3.39 (s, 2H), 4.25 (s, 2H), 6.13 (d, J=0.7 Hz, 1H), 9.27 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:45].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl.O>[NH2:45][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:32])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a solution of tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate (96%, 10.0 g, 22.7 mmol) in dichloromethane (150 mL) at rt was added m-CPBA (55%, 7.12 g, 22.7 mmol). After 1.5 h, the mixture was cooled to 0° C. and concentrated ammonium hydroxide (150 mL) was added, followed by TsCl (4.54 g, 23.8 mmol). The reaction was stirred rapidly overnight. More TsCl (1.00 g and 0.47 g) was added as the mixture was stirred an additional 6 h. Water (200 mL) was added and the mixture was extracted with dichloromethane (3×200 mL). The combined organic phases were washed with brine (3×250 mL) and dried over MgSO4, filtered, and concentrated to a foam, which was crystallized from acetonitrile twice. The fine yellow crystals were dried under vacuum to yield 1.60 g (15%) of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate, mp 195-197° C. 1H NMR (CDCl3, 300 MHz) δ 8.04 (dm, J=8.3 Hz, 1H), 7.82 (dm, J=8.3 Hz, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 5.40 (br s, 2H), 4.85 (s, 2H), 4.75 (br s, 2H), 3.93 (br s, 3H), 3.72 (q, J=7.0 Hz, 2H), 3.03 (m, 2H), 1.76 (m, 2H), 1.49-1.40 (m, 2H), 1.42 (s, 9H), 1.27 (t, J=7.0 Hz, 3H); MS (APCI) m/z 456 (M+H+); Anal. calcd for C24H33N5O4: C, 63.28; H, 7.30; N, 15.37. Found: C, 63.32; H, 7.53; N, 15.39.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:20]([S:22][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:9]([CH2:18][OH:19])[CH2:10]1)(=[O:23])[CH3:21]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1CO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
(2R,4R)-1-t-Butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (i.e., a substrate) and potassium thioacetate (KSAc) are dissolved in dimethylformamide (DMF), and the mixture is stirred. The conditions for this reaction are shown in Table 1, Step A-5. The reaction mixture is diluted with ethyl acetate, and ice water is added. The organic layer is taken, successively washed with aqueous sodium hydroxide, hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2R,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol.