Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.C(P(CCCC)(CCCC)[CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1)CCC.CC([O-])(C)C.[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[CH:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1
Reactant: CCCC[PH](CCCC)(CCCC)CC1OCCO1
Reactant: O=Cc1cccn1-c1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccccc1-n1cccc1C=CC1OCCO1
Temperature: 47 °C

Procedure:
3.12 g (12.5 mmol) of 1-(2-Bromo-phenyl)-1H-pyrrole-2-carbaldehyde and 1.2 eqv. of tributyl-[1,3]dioxolan-2-ylmethyl-λ5-phosphane and 1.5 eqv. KOtBu in 20 ml DMSO was stirred for 2 hours. The reaction mixture was heated to 47° C. and stirred over night. The reaction mixture was cooled down to room temperature and poured into 200 ml of water and extracted with diethyl ether, dried over Na2SO4 and the solvent was evaporated. An oily residue was obtained which crystallised over night. The precipitate was washed with diethyl ether, filtered and dried. A mixture of E and Z isomers was obtained. Purification by column chromatography yielded 2 g (50%) of the E isomer 3b.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:9]1[N:10]=[CH:11][C:12]([N:36]2[CH2:40][C@@H:39]3[CH2:41][CH2:42][CH:43](CS([O-])(=O)=O)[C@H:38]3[CH2:37]2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:56]=[N+:57]=[N-:58].[Na+]>CN(C=O)C>[N:56]([CH:43]1[C@@H:38]2[CH2:37][N:36]([C:12]3[N:13]=[C:14]([C:15]4[O:16][C:17]([C:20]5[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:28])[C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:22][CH:21]=5)=[N:18][N:19]=4)[C:9]([N:8]([C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[N:10][CH:11]=3)[CH2:40][C@@H:39]2[CH2:41][CH2:42]1)=[N+:57]=[N-:58]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5CCC(CS(=O)(=O)[O-])[C@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5CCC(N=[N+]=[N-])[C@@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Yield: 94.3 %

Procedure:
A solution of [(3aR,6aS)-2-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-6-yl]methanesulfonate (460 mg, 0.58 mmol) and sodium azide (190 mg, 573 μL, 2.9 mmol) in DMF (4 mL) was heated at 70° C. for 48 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with H2O, followed by washing with brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-azido-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (401 mg, 93%). LC/MS m/z 733.7 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([O:37][CH3:38])[C:8]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:9]=2[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:12]#[N:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:39]=[N+:40]=[N-:41].[Na+].O>C1(C)C=CC=CC=1>[CH:1]1([CH:7]([O:37][CH3:38])[C:8]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:9]=2[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:12]2[N:39]=[N:40][NH:41][N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1)C1CCCCC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To solution of (2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)benzyl)cyanamide (144 mg, 0.26 mmol) in toluene was added sodium azide (84.9 mg, 1.31 mmol) followed by TEA-HCl (178.8 mg, 1.3 mmol). The mixture was stirred at 115° C. overnight. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 5-50% ethyl acetate in heptane) to afford the title compound (90.9 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 0.90-1.16 (m, 5H) 1.23-1.32 (m, 1H) 1.49-1.61 (m, 3H) 1.69 (s, 1H) 1.97 (d, J=12.45 Hz, 1H) 3.21 (s, 3H) 4.05 (d, J=7.88 Hz, 1H) 4.74-4.93 (m, 4H) 7.31 (s, 1H) 7.41 (d, J=7.88 Hz, 1H) 7.52 (d, J=7.88 Hz, 1H) 7.69 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.O>[OH:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH:14]=[CH2:15]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 106.5 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (166 g, 0.77 mol) and Et3N (214 mL) in THF (2.5 L) was added methyl chloroformate (71.2 mL, 0.93 mol) at 0-5° C. The reaction mixture was stirred for 15 min and filtered to remove TEA salt. To the filtrate was added a solution of NaBH4 (60 g, 1.54 mol) in a small amount of water at 0-5° C. The reaction was stirred at RT for 1 h and quenched with saturated NH4Cl solution. The reaction mixture was concentrated to remove most of THF and extracted with EtOAc (700 mL×3). The organic layers were washed with water, NaOH (1 N) and brine, dried over Na2SO4, and concentrated to give (S)-tert-butyl 1-hydroxypent-4-en-2-ylcarbamate (165 g), which was used without further purification. LRMS (M+H+) m/z 202.1.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=O)[O:3][CH:2]=1.C(O)(=O)[CH2:9][C:10]([OH:12])=[O:11].N1CCCCC1.Cl>N1C=CC=CC=1.O>[O:3]1[CH:2]=[CH:1][CH:5]=[C:4]1[CH:6]=[CH:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccco1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccco1
Temperature: 100 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
The mixture of 2-furfural (15 g, 0.15 mol), malonic acid (17.9 g, 0.17 mol) and piperidine(1.5 ml, 0.016 mol) in 80 ml of pyridine was stirred for 5 hours at 100° C. and then refluxed for 20 min, which was cooled down to room temperature and poured into water (180 ml), and resultant mixture was acidified with concentrated HCl. The generated precipitate was collected by filtration and dried under the reduced pressure to give 3-(furan-2-yl)-acrylic acid (16.8 g). 1H NMR (400 MHz, DMSO-d6) ppm 12.44 (brs, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.40 (d, J=15.9 Hz, 1H), 6.93 (d, J=3.3 Hz, 1H), 6.63 (dd, J=1.8, 3.3 Hz, 1H), 6.17 (d, J=15.7 Hz, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH:11]2[CH2:13]O2)=[CH:8][CH:7]=1.[Cl-].[NH4+].[C:18](#N)C>O>[N:1]([CH2:18][CH2:13][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([Cl:5])=[CH:7][CH:8]=1)=[N+:2]=[N-:3]
Reactant: Clc1ccc(OC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: CC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCCOc1ccc(Cl)cc1
Yield: 76 %

Procedure:
A solution of sodium azide (0.977 g, 15 mmol) in water (1 ml) was added to a solution of rac-(4-chlorophenoxy)oxirane (1.85 g, 10 mmol) in acetonitrile (11 ml). The mixture was heated to reflux for overnight. Saturated ammonium chloride solution (20 ml) was added and the mixture was extracted with ethyl acetate (3 times 25 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/heptane=1:1) to yield a colorless liquid (1.73 g, 76%); MS (EI): 227.1 ((M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19](OC)=[O:20])=[CH:15][CH:14]=1)=[CH:7]2)([O-])=O.[CH3:23][N:24]([CH3:32])[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.[CH3:33][N:34]([CH3:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1>>[CH3:33][N:34]([CH3:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:20])[NH:29][C:28]4[CH:30]=[CH:31][C:25]([N:24]([CH3:32])[CH3:23])=[CH:26][CH:27]=4)=[CH:17][CH:18]=2)=[CH:7]3)=[O:40])=[CH:37][CH:36]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: CN(C)c1ccc(N)cc1
Reactant: COC(=O)c1ccc(-c2cc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Product: CN(C)c1ccc(NC(=O)c2ccc(-c3cc4cc(NC(=O)c5ccc(N(C)C)cc5)ccc4[nH]3)cc2)cc1

Procedure:
Compound 246 was prepared according to the procedure similar to that described in Scheme III from 5-nitro-2-(4-methoxycarbonylphenyl)indole, 4-dimethylaminoaniline, and 4-dimethylaminobenzoic acid. [M+H]+ calcd for C31H30N6O2: 519.25; found: 519.59.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][C:25]1([C:38]([OH:40])=[O:39])[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1>>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C:25]([NH:24][CH2:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:18][CH3:19])[N:9]=[CH:8][N:7]=[C:6]3[NH:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=2[F:23])([C:38]([OH:40])=[O:39])[CH2:26]1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(N)(C(=O)O)C1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCCN(C(=O)OC(C)(C)C)C1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 3-amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Isomer 1) using an analogous method to that described for the equivalent step in Example 1 to give 1-(tert-butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid (Isomer 1); 1H NMR Spectrum: (DMSO d6+d4 AcOH) 1.27 (s, 9H); 1.46 (m, 1H); 1.92 (m, 3H); 3.08 (m, 1H); 3.52 (m, 2H); 3.72 (m, 2H); 3.86 (d, 1H); 3.96 (s, 3H); 7.19 (s, 1H); 7.28 (dt, 1H); 7.48 (t, 1H); 7.56 (m, 1H); 8.31 (s, 1H); 8.43 (s, 1H). Mass Spectrum: (M+H)+ 560.5.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.IC.[C:13](=O)(O)[O-].[Na+]>CN(C)C=O.O>[C:1]1([CH3:10])[C:2]([C:7]([O:9][CH3:13])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccccc1C
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
A mixture of o-toluic acid (15 g, 0.11 mole), iodomethane (51 g, 0.36 mole) and anhydrous sodium bicarbonate (25.2 g, 0.3 mole) in dry dimethylformamide (60 ml) was stirred at 70° (oil bath temperature) under an atmosphere of nitrogen for 3.5 hours. The resulting mixture was diluted with water (200 ml) and extracted with ethyl ether (3×100 ml). The combined extracts were washed several times with water, dried over anhydrous MsGO4 and evaporated in vacuo to give the title ester compound (15 g, 90.6%) as an oil with a consistent H1 -NMR spectrum.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.O1[CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:16]([C:18]1[C:27]([CH3:28])=[C:26]([O:29][C:30](=[O:32])[CH3:31])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=O>O>[CH:16](/[C:18]1[C:27]([CH3:28])=[C:26]([O:29][C:30](=[O:32])[CH3:31])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:12][CH2:13][CH2:14][CH3:15].[CH:16](/[C:18]1[C:27]([CH3:28])=[C:26]([O:29][C:30](=[O:32])[CH3:31])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)Oc1c(C)c(C=O)nc2ccccc12
Reactant: C1CCOC1
Agent: CN(C)P(N(C)C)N(C)C
Solvent: O
Product: CCCCCCC/C=C/c1nc2ccccc2c(OC(C)=O)c1C
Product: CCCCCCC/C=C\c1nc2ccccc2c(OC(C)=O)c1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 10 %
Yield: 12 %

Procedure:
This solution was cooled to -78° C., after which 1.43 g (8 mmols) of hexamethylphosphorus triamide was added and stirred for 5 minutes, followed by further addition of 2 ml of a tetrahydrofuran solution of 91.6 mg (0.40 mmols) of 2-formyl-3-methyl-4-acetoxyquinoline and stirring at -78° C. for 15 minutes and subsequently at -42° C. for 30 minutes. The reaction mixture was added to 20 ml of water and extracted with ethyl acetate, followed by washing with a saturated sodium chloride aqueous solution and drying with sodium sulfate. After removal of the solvent by distillation under reduced pressure, the residue was purified by silica gel column chromatography [Wako Gel C-200 (available from Wako Junyaku Co., Ltd.) (solvent n-hexane : ethyl acetate=15:1)] to obtain 13 mg of 2-(trans-1-nonenyl)-3-methyl-4-acetoxyquinoline (yield 10%) and 15 mg of 2-(cis-1-nonenyl)-3-methyl-4-acetoxyquinoline (yield 12%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].C([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])C.[CH2:16](O)[CH3:17]>>[N:11]1[CH:12]=[CH:13][C:16]([CH:17]2[C:3]3[CH:4]=[CH:5][S:1][C:2]=3[CH2:6][CH2:7][NH:8]2)=[CH:15][CH:14]=1
Reactant: CCO
Reactant: CCN(CC)CC
Reactant: NCCc1cccs1
Product: c1cc(C2NCCc3sccc32)ccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-(2-Thienyl)-ethylamine (2 g, 15.7 mmol) 4-pyridylaldehyde (1.68 g, 15.7 mmol), triethylamine (1 ml) and ethanol (15 ml) were mixed and the reaction mixture was stirred at room temperature for 15 hours, then evaporated in vacuo. The crude oil was added trifluoroacetic acid (75 m) at once (strongly exothermic reaction). The reaction mixture was stirred at room temperature for 0.5 hour, then evaporated in vacuo. The residue was dissolved in dichloromethane (150 ml) and washed with 2 N sodium hydroxide (100 ml). The aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic phases were dried with MgSO4, filtered and evaporated in vacuo to give an oil (3.21 g) which was crystallised from a mixture of dichloromethane and hexane to afford 2.4 g (71%) of the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[N:18]([CH2:22][O:23][CH2:24][CH3:25])[CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[Li+]>O1CCCC1.CO.O>[CH2:26]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[N:18]([CH2:22][O:23][CH2:24][CH3:25])[CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:27][CH3:28]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nccn2COCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccn2COCC)c1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a stirred solution of the ester from step 1 (756 mg, 1.95 mmol) in 2:1:1 tetrahydrofuran/methanol/water (12 mL) is added lithium hydroxide (170 mg, 4 mmol). The reaction mixture is stirred at room temperature for 42 h, and concentrated under reduced pressure. The residue is partitioned between water (10 mL) and chloroform (10 mL). The aqueous layer is acidified to pH 4–5 with 1 N hydrochloric acid and extracted with 3:1 chloroform/2-propanol (3×30 mL). The combined organic layers are dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 8.51 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.17 (s, 1H), 5.39 (s, 2H), 3.62 (q, J=7 Hz, 2H), 3.51 (m, 2H), 3.27 (m, 2H), 1.72 (m, 2H), 1.59 (m, 2H), 1.21 (t, J=7 Hz, 3H), 1.00 (m, 3H), 0.75 (m, 3H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[N:11]([C:12]2[CH:13]=[C:14]([CH2:22][OH:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[N:10]=[N:9][N:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:23][CH2:22][C:14]1[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=[C:12]([N:11]2[C:7]([CH3:6])=[N:8][N:9]=[N:10]2)[CH:13]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnnn1-c1cc(CO)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nnnn1-c1cc(COS(C)(=O)=O)cc(C(F)(F)F)c1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
Methanesulfonyl chloride (0.26 ml, 0.39 g, 3.4 mmol) was added dropwise to a stirred, cooled (-30° C.) solution of 3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethanol (725 mg, 2.8 mmol) and triethylamine (0.59 ml, 0.43 g, 4.2 mmol) in dichloromethane (15 ml). The mixture was stirred at -30° C. for 45 minutes, diluted with dichloromethane (20 ml), washed with aqueous citric acid (10%, 20 ml) and saturated aqueous sodium hydrogen carbonate (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give 1-(methanesulfonyloxymethyl)-3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)benzene as a yellow oil (877 mg, 93%), 1H (CDCl3) δ 7.86 (1H, s), 7.81 (2H, s), 5.38 (2H, s), 3.14 (3H, s), and 2.69 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.O.C(O)C.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>[Cl:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: ClCCCOc1ccc(Br)cc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: ClCCCOc1ccc(-c2ccncc2)cc1
Yield: 53.3 %

Procedure:
To a mixture of 1-bromo-4-(3-chloropropoxy)benzene (1.25 g) and tetrakistriphenylphosphinepalladium (58 mg) in toluene (12 mL) and potassium carbonate (2.07 g) in water (6 mL) is added pyridine-4-boronic acid (380 mg) dissolved in ethanol. The mixture is heated for five hours at a temperature close to 80° C. Solvents are removed under reduced pressure and the residue dissolved in ethyl acetate. The organic phase is washed with a 10% aqueous solution of potassium hydroxide, then with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography over silica gel (eluent dichloromethane/methanol from 100/0 to 95/5) to give 408 mg of 4-(4-(3-chloropropoxy)phenyl]pyridine as an ochre oil used without further purification.
Reaction SMILES: [CH2:1]([N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[C:21]([O-])=[O:22].[Na+]>CN(C=O)C>[CH2:14]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]1[CH:9]=[CH:10][C:11]([CH:21]=[O:22])=[CH:12][CH:13]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN(CCCCCC)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)c1ccc(C=O)cc1
Temperature: 95 °C
Yield: 84 %

Procedure:
To a solution of dry DMF (1.1. mL) under Argon at 0° C. was added of POC13(375 μL, 4 mmol). N,N-Dihexylaniline (1.04 g, 4 mmol) was added dropwise and the solution was mixed with rapid stirring to form a green solution. The reaction mixture was heated at 95° C. for 2 h. The solution quickly turned red/brown. After 2 h the solution was cooled. It was poured into ice/water 20 mL and aq. saturated NaOAc (20 mL) was added. The partially neutralized solution was partitioned between ether and water. The ether layer was washed with aq. saturated NaHCO3 and dried over sodium sulfate. After concentrating to approximately 20 mL. DMF oiled out of the solution. The solution was transferred from the oil and concentrated under reduced pressure. The resultant residue was purified via flash column chromatography, using a gradient of 0→20% ethyl acetate; petroleum ether as eluent to give N,N-Dihexyl-4-aminobenzaldehyde (32) (970 mg, 84%). 1H NMR (CDCl3) δ 9.72 (s, 1H CHO); 7.70 (d, 2H, ArH); 6.64 (d, 2H, ArH); 3.32 (t, 4H, 2×NCH2); 0.89 (t, 6H 2×CH2CH3). TLC (silica gel): Rf=0.75 (20% ethyl acetate;petroleum ether).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)([O-])=O.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1.C(Cl)Cl.CCOC(C)=O>C1COCC1>[O:31]=[C:30]1[N:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:6][C:5]2[C:4](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2[N+](=O)[O-])CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reaction time: 16 h
Yield: 24.4 %

Procedure:
To a solution of tert-butyl 4-(2-nitrobenzylamino)piperidine-1-carboxylate (13.2 g, 43.2 mmol) in THF (400 ml) was added a solution of CDI (7.7 g, 47.5 mmol) in 1:1 DCM: THF (100 ml) dropwise over 1 hour followed by stirring the reaction mixture for a further 16 hours. The reaction mixture was evaporated to give an oil that, when treated with EtOAc, precipitated the desired product. The precipitate was washed with cold EtOAc and dried to give a yellow solid (3.5 g). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=332; tR=3.01.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16](=[O:24])[CH2:15][CH2:14]1)(=[O:12])=[O:11].[C:25]([O:33][CH2:34][C@H:35](O)[CH2:36][OH:37])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[Si](C)(C)C)(C)C.O>ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[C:25]([O:33][CH2:34][C@H:35]1[CH2:36][O:37][C:16]2([CH2:15][CH2:14][CH:13]([S:10](=[O:12])(=[O:11])[NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[O:24]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Reactant: O=C(OC[C@H](O)CO)c1ccccc1
Agent: CC(C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OC[C@H](COC(=O)c1ccccc1)O2
Yield: 80.9 %

Procedure:
100 mg (0.27 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 69 mg (0.35 mmol) of (R)-2,3-dihydroxypropyl benzoate were dissolved in 2 ml of dichloromethane and 0.19 ml (1.05 mmol) of isopropoxytrimethylsilane and 2 μl (0.014 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added thereto with stirring under ice-cooling, followed by stirring at the same temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate 1:1), to give 121 mg of ethyl (2R)-2-benzoyloxymethyl-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as a pale yellow oil (yield: 81%).