Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:53]1[CH:57]=[N:56][N:55]=[C:54]1[C:58]1([NH2:61])[CH2:60][CH2:59]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[S:53]1[CH:57]=[N:56][N:55]=[C:54]1[C:58]1([NH:61][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH2:60][CH2:59]1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: NC1(c2nncs2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(c2nncs2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (90.0 mg, 0.350 mmol) in DMF (2 mL) is added N,N-diisopropylethylamine (243 μL, 1.40 mmol) and HBTU (159 mg, 0.420 mmol). After 20 minutes, a solution of 1-1,3,4-thiadiazol-2-yl-cyclopropylamine (51.0 mg, 0.361 mmol) in DMF (1 mL) is added and the mixture is stirred at room temperature overnight. The reaction mixture is poured into saturated aqueous sodium bicarbonate (50 mL), ethyl acetate (30 mL) is added and phases are separated. The aqueous layer is treated with brine and extracted with ethyl acetate (3×20 mL). The combined organic layers are concentrated in vacuo. The crude material is purified by silica gel chromatography eluting with a gradient of 0-10% methanol in methylene chloride to afford the title compound as a solid.
Reaction SMILES: [OH-].C([NH+](CC)CC)C.[C:9]([NH:12][CH:13]1[C:17](=[O:18])[CH2:16][N:15]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:14]1)(=O)[CH3:10]>C1COCC1>[CH2:22]([O:21][C:19]([N:15]1[CH2:16][C:17]2[O:18][C:9]([CH3:10])=[N:12][C:13]=2[CH2:14]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)NC1CN(C(=O)OCc2ccccc2)CC1=O
Agent: CC[NH+](CC)CC
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2c(o1)CN(C(=O)OCc1ccccc1)C2
Temperature: 65 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
8.5 g methoxycarbonylsulfamoyl)triethylammoniumhydroxid was added to 4.7 g benzyl 3-acetamido-4-oxopyrrolidine-1-carboxylate in 180 mL THF. The reaction was stirred 1 h at 65° C. and evaporated. The residue was purified on silica gel (hexane/ethyl acetate:1/1) to give 1.4 g of the desired product.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:33]([OH:35])=O)[CH2:19][C:20]3[CH:31]=[C:30]([CH3:32])[C:23]4[NH:24][C:25]([N:27]([CH3:29])[CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[NH:3]1.[O:40]1[CH2:45][CH2:44][CH:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:31]=[C:30]([CH3:32])[C:23]4[NH:24][C:25]([N:27]([CH3:28])[CH3:29])=[N:26][C:22]=4[CH:21]=3)[C:33](=[O:35])[N:49]3[CH2:48][CH2:47][N:46]([CH:43]4[CH2:44][CH2:45][O:40][CH2:41][CH2:42]4)[CH2:51][CH2:50]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc(N(C)C)[nH]c12
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc2nc(N(C)C)[nH]c12

Procedure:
Prepared analogously to Example 1h from 90 mg (0.14 mmol, purity 85%) (R)-1-carboxy-2-(2-dimethylamino-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 35 mg (0.21 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:24]([O:31][C:32]1[CH:47]=[C:46](Cl)[CH:45]=[CH:44][C:33]=1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:24]([O:31][C:32]1[CH:47]=[C:46]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:45]=[CH:44][C:33]=1[C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(Cl)cc1OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccc(-c2cccnc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine (0.24 g), tripotassium phosphate (0.46 g), palladium(II) acetate (4.5 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.1 mg) were added to a toluene (5.3 mL) solution of benzyl 2-(benzyloxy)-4-chlorobenzoate (0.35 g), followed by heating to reflux under a nitrogen atmosphere for 3 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.16 g), tripotassium phosphate (0.25 g), palladium(II) acetate (4.5 mg), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.1 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 3 hours and 30 minutes. After cooling the reaction mixture to room temperature, a 10% aqueous solution of citric acid and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0.35 g of benzyl 2-(benzyloxy)-4-(pyridin-3-yl)benzoate.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([Cl:30])[C:18]=1[C:31](Cl)=[O:32]>>[Cl:16][C:17]1[CH:22]=[C:21]([CH:20]=[C:19]([Cl:30])[C:18]=1[C:31]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:32])[C:23]([NH:24][CH2:25][CH2:26][O:27][CH3:28])=[O:29]
Reactant: O=C(Nc1nccc2cc[nH]c12)C1CC1
Reactant: COCCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Product: COCCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1

Procedure:
3,5-Dichloro-4-({7-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)-N-(2-methoxyethyl)benzamide was prepared analogously using N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropane carboxamide and 2,6-dichloro-4-(2-methoxyethylcarbamoyl)benzene carbonyl chloride (Compound No. 16).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.N#N.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][N:29]=[CH:28][C:27]=2[CH:31]=1.C([O-])(O)=O.[Na+]>ClCCl>[O:30]1[C:26]2[CH:25]=[CH:24][C:23]([NH:22][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:31][C:27]=2[CH:28]=[N:29]1
Reactant: Nc1ccc2oncc2c1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3oncc3c2)cc1
Yield: 72 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (171 mg, 0.783 mmol) in dichloromethane (4 mL).was added pyridine (150 μL, 1.86 mmol) and the mixture was stirred under. N2 for 5 min, after which time 5-amino-1,2-benzisoxazole (100 mg, 0.746 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (170 mg, 72%), single spot at Rf 0.68 (1:1 hexane:ethyl acetate). mp 130.0-130.6° C., HPLC purity 99+% (tR 2.44 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.62 (1H, d, J=1.0 Hz), 7.60 (2H, d, J=8.4 Hz), 7.48 (2H, m), 7.19 (3H, m), 6.86 (1H, s, N−H), 2.58 (2H, t, J=7.5 Hz), 1.58 (2H, sextet, J=7.4 Hz), 0.88 (3H, t, J=7.4 Hz). LCMS: 315.14 (M−). FAB-MS (MH+, C16H16N2O3S): calcd 317.0960, found 317.0962.
Reaction SMILES: N1(C(=S)[O-])C=CN=C1.CCCC[SnH](CCCC)CCCC.C1CCC(N=NC2(C#N)CCCCC2)(C#N)CC1.[CH3:40][N:41]([CH3:61])[C:42]1[S:43][C@H:44]2[O:50][C@@H:49]3[CH2:51][O:52]C(C4C=CC=CC=4)[O:54][C@H:48]3[CH2:47][C@H:45]2[N:46]=1.Cl>CN(C=O)C.C1COCC1.CO>[OH:52][CH2:51][C@H:49]1[O:50][C@H:44]2[C@H:45]([N:46]=[C:42]([N:41]([CH3:40])[CH3:61])[S:43]2)[CH2:47][C@@H:48]1[OH:54]
Reactant: CN(C)C1=N[C@@H]2C[C@@H]3OC(c4ccccc4)OC[C@H]3O[C@@H]2S1
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cl
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C1=N[C@@H]2C[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of the above material (0.67 g, 2.0 mmol) and thio-CDI (90% tech, 1.6 g, 8.0 mmol) in anhydrous DMF (20 mL) was stirred at 95° C. overnight. After cooling the solvent was removed under reduced pressure, and the residue was purified on silica gel by flash column chromatography (MeOH/DCM, 1:100 to 5:100), affording a mixture containing O-(-(3aR,4aR,8aS,9R,9aR)-2-(dimethylamino)-7-phenyl-3a,4a,5,8a,9,9a-hexahydro-[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d]thiazol-9-yl) 1H-imidazole-1-carbothioate. This mixture was dissolved in anhydrous THF (30 mL), and Bu3SnH (1.0 g, 3.4 mmol) and ABCN (0.060 mg, 0.24 mmol) was added, and the mixture was stirred at reflux overnight. The solvent was then removed under reduced pressure, and the residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH:DCM, 3:100), affording an pale yellow solid containing -(3aR,4aR,8aS,9aR)-N,N-dimethyl-7-phenyl-3a,4a,5,8a,9,9a-hexahydro-[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d]thiazol-2-amine (0.17 g, impure). The solid was treated with 2% HCl in MeOH (10 mL) at room temperature for 2 h, and then the solvent was removed under reduced pressure. The residue was neutralized with 1.0 M NH3 in MeOH, and subsequently purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH:DCM, 1:10), affording pure -(3aR,5R,6S,7aR)-5-(hydroxymethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as an off-white solid (0.050 g, 11% overall yield). 1H NMR (400 MHz, CD3OD) δ 6.23 (d, J=6.4 Hz, 1H), 4.28-4.24 (m, 1H), 3.74 (dd, J=2.5, 12.0 Hz, 1H), 3.70-3.65 (m, 1H), 3.59 (dd, J=6.2, 12.0 Hz, 1H), 3.53-3.48 (m, 1H), 2.99 (s, 6H), 2.14-2.08 (m, 1H), 2.02-1.95 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 165.60, 92.43, 77.19, 69.67, 65.79, 63.27, 40.15, 34.93; MS, m/z=255 (M+23).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:9]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:7]1[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(OC(F)(F)F)c(C(=O)O)c1
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(OC(F)(F)F)c(-c2nc3ccccc3o2)c1
Temperature: 250 °C
Reaction time: 3.5 h
Yield: 21.7 %

Procedure:
A mixture 750 mg of 5-amino-2-trifluoromethoxybenzoic acid (750 mg, 3.39 mmol) and 2-aminophenol (370 mg, 3.39 mmol) in 10 mL of polyphosphoric acid was heated and stirred at 250° C. for 3.5 hours. The mixture was poured into ice water under stirring, followed by addition of NaHCO3 until pH 8. The mixture was extracted with ethyl acetate. The organic phase was washed with water twice, brine, rinsed with activated charcoal, dried over MgSO4 and evaporated to give an oil, which contained two compounds, according to TLC. This mixture was dissolved in DMF and separated on semi preparative HPLC (Gilson 215 Liquid Handler), stationary phase: RP18, mobile phase: Water/MeCN gradient 95%/5%-5%/95% to afford 216 mg (22%) of 3-benzoxazol-2-yl-4-trifluoromethoxyphenylamine as crystals.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[N:32]([CH2:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3[nH]cc(S(=O)(=O)c4ccccc4)c3c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc2[nH]cc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 100 °C
Yield: 90.5 %

Procedure:
A solution of 2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl 4-methylbenzenesulfonate (0.20 g, 0.44 mmol) in anhydrous DMF (2.5 mL) was added sodium azide (0.14 g, 2.2 mmol) and heated to 100° C. for 6 hours. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (1×15 mL), dried (MgSO4), filtered concentrated under reduced pressure. Silica gel chromatography (40% Ethyl acetate/petroleum ether) gave the azide as a clear glass (0.13 g, 86%) which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:9].C([O-])(C)(C)C.[K+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: Cc1cc[n+]([O-])c(C)c1
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cc(/C=C/c2ccccc2)cc[n+]1[O-]
Yield: 7 %

Procedure:
Following the general method described in example 2a, 2,4-dimethylpyridine 1-oxide was reacted with potassium tert.-butanolate and benzaldehyde. After extraction and chromatography (SiO2 with CH2Cl2/MeOH=97/3) the title compound was obtained as a yellow solid material (yield 7%)). NMR (250 MHz, DMSO): 2.37 (s, 3H, CH3), 7.20 (d, J=16.5 Hz, 1H, CH═CH), 7.25-7.75 (m, 8H, arom-H, CH═CH), 8.22 (d, J=6.8 Hz, 1H, arom-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[CH3:31][CH2:32]N(C(C)C)C(C)C.C(I)C>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH2:31][CH3:32])[CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:27]([F:28])([F:30])[F:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Solvent: ClCCCl
Solvent: CCI
Product: CCc1cn(CC)c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 40 °C
Yield: 39.4 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (60 mg, 0.137 mmol), DIPEA (0.036 mL, 0.205 mmol) in DCE (2 mL) was added EtI (0.013 mL, 0.164 mmol). The mixture was heated at 40° C. for 1 h. Purification via reverse phase flash chromatography then afforded the title compound (25 mg, 0.054 mmol, 39.2% yield). LCMS: rt=3.80 min, [M+H+]=467
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:13]([C:14]#[N:15])=[C:12]([S:16][CH3:17])[S:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18]O.O>S(=O)(=O)(O)O.C(O)(=O)C.C(OC(=O)C)(=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:13]([C:14]([NH2:15])=[O:18])=[C:12]([S:16][CH3:17])[S:11][N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: CSc1snc(OCC2CCCCC2)c1C#N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSc1snc(OCC2CCCCC2)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
3-Cyclohexylmethoxy-5-methylsulfanyl-isothiazole-4-carbonitrile (3) (6.3 g, 23.5 mmol) is dissolved in conc. sulfuric acid (31.5 mL) and stirred at room temperature for 24 hrs. Ice was added and the resulting suspension was filtered and washed with water and then washed with 1N NaOH. The solids were dried in vacuo to obtain crude 3-cyclohexylmethoxy-5-methylsulfanyl-isothiazole-4-carboxylic acid amide (4, 8.7 g). This solid is slurried in acetic acid (37 mL) and acetic anhydride (37 mL). Hydrogen peroxide (30%, 18.5 mL) is then added and the reaction is stirred at room temperature for 18 hours. More hydrogen peroxide (30%, 18.5 mL) is then added and the reaction is stirred at room temperature for 3 days. Water is then added and the suspension is filtered and the solids are further dried in vacuo to provide 5 (5.06 g, 62%). 1H NMR (d6 DMSO): δ 7.97 (1H, s), 7.87 (1H, s), 4.14 (2H, d, J=6.0 Hz), 3.54 (3H, s), 1.59–1.78 (6H, m), 1.09–1.25 (3H, m), 0.94–1.03 (2H, m); LRMS (M+): 318.9.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[C:9]1[CH2:12][CH2:11][CH2:10]1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:9]1(=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)CCCCC=C1CCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCCCCCC=C1CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-cyclobutylidene-hexanoic acid methyl ester (0.60 g, 3.3 mmol) in toluene (30 mL) was added DIBAL-H (8.2 mL, 1 M solution in hexane, 8.2 mmol) dropwise at 0° C. under N2. After stirring at 0° C. for 30 min, the reaction was quenched by MeOH (3 mL). Saturated aqueous sodium potassium tartrate (20 mL) was added to the reaction mixture. After stirrng for 1 h, the organic layer was separated and the aqueous phase was extracted with ether. The combined organic layers were washed with water and brine and dried. Evaporation of the solvent gave 6-cyclobutylidene-hexan-1-ol as a colorless oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][O:11][CH3:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.Cl[C:14]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=1[C:16]#[N:17].[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:14]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])[O:11][CH3:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CONS(=O)(=O)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1C#N)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a solution of 5-chloro-N-methoxy-2-thiophenesulfonamide (0.46 g (2.02 mmol)) and 2-chloro-5-nitrobenzonitrile (0.45 g (2.46 mol)) in DMF (3.0 ml), sodium hydride (60%, 0.09 g (2.25 mmol)) was added bit by bit under cooling with ice and with stirring and the mixture was stirred under cooling with ice for one hour and at room temperature for one hour. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:3) as eluent to give 0.41 g (54%) of the title compound as pale yellow crystals.
Reaction SMILES: C(NCC)C.C(O)(C)(C)C.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:14].[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1)([O-:26])=[O:25]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-].O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][CH2:34][C:33]([C:30]2[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=2)=[O:35])=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCNCC
Solvent: O
Product: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
Anhydrous zinc(II)chloride (2.73 g, 20.00 mmol) was stirred in dry benzene (15 mL) while diethylamine (1.558 mL, 15.00 mmol) and t-butanol (1.435 mL, 15.00 mmol) were added, and the resulting mixture was stirred at room temperature for 90 minutes to give a cloudy solution. To this mixture was added 2-bromo-1-(4-nitrophenyl)ethanone (2.44 g, 10.00 mmol) and 1-(4-nitrophenyl)ethanone (2.477 g, 15.00 mmol), and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was triturated with dichloromethane to give an orange solid that was collected by filtration and dried to give the title compound (2.0 g, 61% yield).
Reaction SMILES: [CH:1]([N:4]1[C:8](Cl)=[N:7][C:6]([OH:10])=[N:5]1)([CH3:3])[CH3:2].[Na].[CH3:12][OH:13]>>[CH:1]([N:4]1[C:8]([O:13][CH3:12])=[N:7][C:6]([OH:10])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nc(O)nc1Cl
Reactant: CO
Agent: [Na]
Product: COc1nc(O)nn1C(C)C
Temperature: -70 °C

Procedure:
An amount of 166 g of 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole is added to a solution of 115 g of sodium in 1000 ml of methanol; the mixture is then refluxed for 15 hours. After separation of filtration of the precipitated sodium chloride, and concentration of the filtrate in vacuo, the residue is taken up in dilute acetic acid and extracted twice with ether. The ether is evaporated off, and the partially crystalline residue dissolved in a little methanol. On cooling of the solution to -70° C, the product crystallises out. There is thus obtained 43.5 g of 1-isopropyl-3-hydroxy-5-methoxy-1,2,4-triazole in the form of white crystals, M.P. 102° -103° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:37]=[CH:36][C:27]4[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=4[CH:25]=3)[CH:17]=2)=[C:11]([CH3:38])[C:10]=1[Cl:39])(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:39][C:10]1[C:11]([CH3:38])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:37]=[CH:36][C:27]4[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=4[CH:25]=3)[CH:17]=2)[C:13]([CH3:15])=[CH:14][C:9]=1[OH:8]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[Si](C)(C)C(C)(C)C)c(Cl)c4C)c3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)c(Cl)c4C)c3)ccc21
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a solution of methyl {(3S)-6-[(4′-{[tert-butyl(dimethyl)silyl]oxy}-3′-chloro-2′,6′-dimethylbiphenyl-3-yl)methoxy]-2,3-dihydro-1-benzofuran-3-yl}acetate (2.01 g, 3.54 mmol) in tetrahydrofuran (20 mL) was added 1 M tetrabutylammonium fluoride tetrahydrofuran solution (3.9 mL, 3.9 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hr under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (1.41 g, yield 88%) as a colorless oil.