Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[CH2:4][CH2:3]1.CC(O[CH2:21][C:22]1[CH2:31][S:30][C@@H:25]2[C@H:26]([NH2:29])[C:27](=[O:28])[N:24]2[C:23]=1[C:32]([OH:34])=[O:33])=O.C(=O)(O)[O-].[Na+]>O>[NH2:29][CH:26]1[C:27](=[O:28])[N:24]2[C:23]([C:32]([OH:34])=[O:33])=[C:22]([CH2:21][S:16][C:15]3[N:11]([CH2:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[N:12]=[N:13][N:14]=3)[CH2:31][S:30][C@H:25]12
Reactant: CN1CCN(CCCn2nnnc2S)CC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(CCCn2nnnc2SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)CC1
Temperature: 64 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[3-(4-methyl-1-piperazinyl)propyl]-1H-tetrazole-5-thiol.dihydrochloide (75.32 g) in water (6 l) was added 7-aminocephalosporanic acid (60.0 g) and the mixture was adjusted to pH 5.4 with a saturated aqueous solution of sodium bicarbonate and stirred for 2 hours at 64° C. The reaction mixture was cooled and adjusted to pH 6.84 with a saturated aqueous solution of sodium bicarbonate. The resulting mixture was subjected to column chromatography (CM-Cephadex, H-type: 3 l), eluting with water, 0.5% aqueous solution of sodium chloride and 2% aqueous solution of sodium chloride. The fiactions containing the object compound were collected. The resulting mixture (about 7 l) was adjusted to pH 4.5 with a saturated aqueous solution of sodium bicarbonate and then subjected to column chromatography (Non-ion adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries: 3l) and eluting with water, 2% isopropyl alcohol and 15% isopropyl alcohol. The fractions containing the object compound were collected and then concentrated. The concentrate was lyophilized to give a powder of 7-amino-3-[1-[3-(4-methyl-1-piperazinyl)propyl]-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (34.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][N+:11]([O-:13])=[O:12]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C=C[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Using the same reaction procedure and workup as described in Example 1, step 1, 2-methoxy-benzaldehyde (5 g, 36.7242 mmol) in ethanol (166 mL) was reacted with nitro methane (1.98 mL, 36.7242 mmol) and 10N NaOH (1.39 g, 34.9602 mmol). The resulting mixture was stirred at 0° C. for 1 hr to afford 4.5 g of the product (83.89% yield).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:23][O:22][C:20]([CH2:19][O:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1)=[O:21]
Reactant: COC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)COc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was dissolved into a 40% TFA/methylene chloride solution, and stirred at room temperature for 4 hours. Evaporation of the solvent gave 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid in quantitative yield.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[F:12][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(F)ccc(F)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1c(F)c(F)cc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
2,3,6-Trifluorobenzoic acid (21.0 g) is added to conc. sulfuric acid (120 ml) under ice-cooling. To the mixture is added dropwise a solution of potassium nitrate (14.5 g) in conc sulfuric acid (30 ml) at below 20° C. After the addition, the mixture is stirred at room temperature for one hour. The reaction mixture is poured into ice water and extracted with diethyl ether. The extract is dried over magnesium sulfate, and then the solvent is distilled off. The residue is recrystallized from dichloromethane--n-hexane to give 2,5,6-trifluoro-3-nitrobenzoic acid (22 g), as colorless prisms, m.p. 98°-99° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[C:12]2[N:13]=[CH:14][N:15]([C:31]=2[N:32]=[C:33]([NH:35]C(=O)COC2C=CC=CC=2)[N:34]=1)[C@@H:16]1[O:30][C@H:27]([CH2:28][OH:29])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>CC#N>[CH2:3]([O:10][C:11]1[C:12]2[N:13]=[CH:14][N:15]([C:31]=2[N:32]=[C:33]([NH2:35])[N:34]=1)[C@@H:16]1[O:30][C@H:27]([CH2:28][OH:29])[C@@H:18]([O:19][Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:22])[CH3:21])[CH2:17]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(OCc4ccccc4)nc(NC(=O)COc4ccccc4)nc32)O[C@@H]1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(OCc4ccccc4)nc(N)nc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.2 %

Procedure:
NaOH (2 M, 21 mL, 42.3 mmol) is added to a solution of 9 (2.56 g, 4.23 mmol) dissolved in CH3CN (13 mL) and stirred at room temperature for 21 h. Water (20 mL) is added to the reaction and the pH is adjusted to 7 with HCl. The solution is extracted with CH2Cl2 (2×30 mL), and the organic extracts are combined, dried over MgSO4, and filtered. The solvent is removed under reduced pressure to yield 10 as a white solid (1.86 g, 93.4%). 1H NMR (DMSO-d6) δ 8.11 (1H, s, H-8), 7.51-7.48 (2H, m, Bn Ar), 7.42-7.33 (3H, m, Bn Ar), 6.50 (211, br s, N2H2, exchanges with D2O), 6.21 (1H, dd, J=8.0, J=6.0, 11-1′), 5.50 (2H, s, CH2-Ph), 5.04 (1H, t, J=5.6, 5′-OH, exchanges with D2O), 4.53 (1H, ddd, J=5.2, J=2.4, J=2.4, H-3′), 3.82 (1H, ddd, J=4.4, J=4.4, J=2.4, H-4′), 3.55 (H-1, ddd, J=11.6, J=5.2, J=5.2, H-5′), 3.49 (1H, ddd, J=11.6, J=5.2, J=4.8, H-5′), 2.70 (1H, ddd, J=13.2, J=8.0, J=5.6, H-2′), 2.21 (1H, ddd, J=12.8, J=5.6, J=2.4, H-2′), 0.90 (9H, s, Si—C(CH3)3), 0.11 (6H, s, Si—(CH3)2). Anal. (C23H33N5O4Si) C, H, N.
Reaction SMILES: Cl[CH2:2][CH:3]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4]Cl.[CH2:20]([NH2:22])[CH3:21]>>[CH2:20]([N:22]1[CH2:4][CH:3]([O:6][CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2]1)[CH3:21]
Reactant: ClCC(CCl)OC(c1ccccc1)c1ccccc1
Reactant: CCN
Product: CCN1CC(OC(c2ccccc2)c2ccccc2)C1
Yield: 47.5 %

Procedure:
Following the procedure of Preparation 13, the title compound was prepared from 1,3-dichloro-2-diphenylmethoxypropane (44.0 g, 0.15 mol) and ethylamine (100 ml) in 47.5% yield; bp 135°-142° C./0.10 mm.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.F[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]>>[F:14][C:12]1[CH:11]=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([CH:13]=1)[O:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O[C@H]1CCOC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CCOC1

Procedure:
Prepared analogously to example I.1 from (S)-(+)-3-Hydroxytetrahydrofuran and 2,4-difluornitrobenzol
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([C@H:8]1[CH2:9][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])=[CH:17][CH:16]=2)[CH2:11][CH2:12][N:13]1[C:31](=[O:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45 mg of 3-(S)-benzyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine was dissolved in dichloromethane, 1.1 equiv. of acetylchloride and 1.5 equiv. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature under nitrogen overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford 51 mg of the title compound as free base. Yield 84%, Treatment with 1 equiv. of 1M HCl in dioxane gave the HCl salt. ES MS(+) m/z 453
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[N:17]=[N:16][C:15]([C:18](=[S:20])[NH2:19])=[CH:14][CH:13]=1.CO[C:28](OC)([N:30]([CH3:32])[CH3:31])[CH3:29]>C1(C)C=CC=CC=1>[CH3:31][N:30]([CH3:32])[C:28](=[N:19][C:18]([C:15]1[N:16]=[N:17][C:12]([S:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)=[CH:13][CH:14]=1)=[S:20])[CH3:29]
Reactant: NC(=S)c1ccc(SCCCCOc2cccc(C(F)(F)F)c2)nn1
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=NC(=S)c1ccc(SCCCCOc2cccc(C(F)(F)F)c2)nn1)N(C)C
Yield: 99.8 %

Procedure:
A mixture of intermediate 12 (0.009 mol) and N,N-dimethylacetamide dimethyl acetal (0.015 mol) in toluene (100 ml) was stirred and refluxed for 3 hours. The solvent was evaporated, yielding 4.1 g (100%) of N-[1-(dimethylamino)ethylidene]-6-[[4-[3-(trifluoromethyl)phenoxy]butyl]thio]-3-pyridazinecarbothioamide (intermediate 13).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f25) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[C:5]([F:13])=[C:4]([CH2:14][NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]=1.Br[C:24]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[N:22]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:14][C:4]2[CH:3]=[C:2]([F:1])[C:7]3[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=3[C:5]=2[F:13])[CH:24]=1
Reactant: CSc1nc2c(F)cc(CNc3ncccc3N)c(F)c2s1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Product: CSc1nc2c(F)cc(Cn3cnc4cccnc43)c(F)c2s1

Procedure:
6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluoro-2-(methylthio)benzo[d]thiazole was synthesized as a orange solid (220 mg) using a procedure analogous to that described in Step 3 of Example 41, substituting N2-((4,7-difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine from the previous step for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 349 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([Cl:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([Cl:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(Cl)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1cc(Cl)c2c(C(=O)O)cc(Br)cc21
Temperature: 55 °C
Yield: 56 %

Procedure:
To a solution of methyl 6-bromo-3-chloro-1-(1-methylethyl)-1H-indole-4-carboxylate (1.2 g, 3.63 mmol) in THF (2.368 ml) and MeOH (14.21 ml) was added 3N NaOH (1.573 ml, 4.72 mmol). The resulting mixture was heated at 55° C. for 4 h. The reaction was removed from the heat and the solvent removed in-vacuo. The remaining residue was dissolved with water (12 ml) and made acidic dropwise with 1N HCl. The product precipitated and the slurry became too thick to stir and was diluted with water (10 ml). After the precipitation halted no more acid was added. The solid was collected by vacuum filtration, washed with water, and air dried under vacuum overnight to give 6-bromo-3-chloro-1-(1-methylethyl)-1H-indole-4-carboxylic acid (650 mg, 2.033 mmol, 56.0% yield over 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.09 (d, J=1.77 Hz, 1H), 7.89 (s, 1H), 7.45 (d, J=1.77 Hz, 1H), 4.88 (quin, J=6.63 Hz, 1H), 1.43 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 316.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]#[C:29][C:30](O)=[O:31]>ClCCl.CO>[CH2:15]([N:3]([CH2:1][CH3:2])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:30](=[O:31])[C:29]#[C:28][C:19]2[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=2[Cl:17])=[CH:11][CH:12]=1)[CH3:16]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)C(C)COc1ccc(N)cc1
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)C(C)COc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 67 mg (0.3 mmol) of 4-(2-diethylaminopropoxy)phenylamine and 75 mg (0.3 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 71 mg (52% of theory); melting point: 172° C.-176° C.; C23H24ClF3N2O2 (M=452.90); calc.: molecular ion peak (M+H)+: 453/455; found: molecular ion peak (M+H)+: 453/455; Rf value: 0.30 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:36]=[CH:35][C:29](/[CH:30]=[CH:31]/B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:31]=[CH:30]/[C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:36][CH:35]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Temperature: 120 °C
Yield: 79.1 %

Procedure:
A microwave vial was charged with 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) (5 g, 15.30 mmol), (E)-4-(trifluoromethyl)styrylboronic acid (4.96 g, 22.95 mmol), potassium carbonate (7.40 g, 53.6 mmol) and tetrakis(triphenyl phosphine)palladium(0) (0.530 g, 0.459 mmol). The reaction was evacuated and purged with nitrogen before dioxane (3.40 ml) was added and the whole was heated under vacuum. Water (1.7 ml) was then added and the reaction mixture heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and then brine and the combined organics were dried (MgSO4) and concentrated in vacuo to give the desired compound as an orange solid (5.6 g, 79%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:23])[C@@H:6]([NH:14][C:15]1[C:16](=O)[C:17](=[O:21])[C:18]=1[O:19]C)[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[N+:2]=[N-:3].Cl.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][O:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1.CCN(CC)CC>C(#N)C>[N:1]([CH2:4][C@@H:5]([OH:23])[C@@H:6]([NH:14][C:15]1[C:18](=[O:19])[C:17](=[O:21])[C:16]=1[N:34]1[CH2:35][CH2:36][CH2:37][CH:32]([CH:31]([O:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:33]1)[CH2:7][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)=[N+:2]=[N-:3]
Reactant: COCCCOC(c1ccccc1)C1CCCNC1
Reactant: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN=[N+]=[N-])c(=O)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCCOC(c1ccccc1)C1CCCN(c2c(N[C@@H](CC3CCCCC3)[C@H](O)CN=[N+]=[N-])c(=O)c2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
3-((2S,3R)-4-Azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-methoxycyclobut-3-ene-1,2-dione (35 mg, 0.11 mmol), the HCl salt of 3-((3-methoxypropoxy)(phenyl)methyl)piperidine (48 mg, 0.16 mmol), and Et3N (100 μL, 0.7 mmol) were dissolved in acetonitrile (1 mL). The reaction was allowed to stir at rt overnight. The solvent was evaporated and the product was isolated by preparative HPLC to give 3-((2S,3R)-4-azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione (41 mg). MS m/z 554 (M+H+).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[N:27]=[CH:26][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:24]=4)[CH:21]=3)[N:16](C3CCCCO3)[N:15]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:24]1[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:10]2[CH:9]=[C:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:13]=[CH:12][CH:11]=2)=[N:27][CH:26]=[N:25]1
Reactant: CC(C)(C)NC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
To a stirred solution of N-(tert-butyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.334 g, 0.486 mmol) was added 4.0 M hydrochloric acid in dioxane (10.0 mL) and the mixture was stirred at ambient temperature for 20 h. The mixture was cooled and poured into saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0964 g, 55% yield). 1H NMR (CD3OD) δ 8.77 (m, 1H), 8.37 (m, 1H), 8.35 (br s, 1H), 8.16 (d, 1H), 8.11 (d, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.64 (t, 1H), 1.51 (s, 9H). ES-MS (m/z) 361 [M+1]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:10])[CH2:8][CH3:9])[S:5][CH:6]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:10])[CH2:8][CH3:9])[S:5][CH:6]=1
Reactant: CCC(O)c1cc(Br)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)cs1
Reaction time: 14 h

Procedure:
11.5 g (52 mmol) of 1-(4-bromo-2-thiophenyl)-1-propanol are dissolved in 300 mL of dichloromethane. 60 g (690 mmol) of manganese dioxide are added and the reaction medium is stirred for 14 hours and then filtered. The desired product is obtained in the form of an orange-coloured oil (m=11.4 g; Y=99%).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[CH:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[CH:5]=[C:4](/[CH:6]=[N:14]/[S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13])[N:3]=[CH:2]1
Reactant: O=Cc1cocn1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1cocn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
In a round-bottomed flask, oxazole-4-carbaldehyde (300 mg, 3.09 mmol) was dissolved in THF (7 ml) and 2-methylpropane-2-sulfinamide (450 mg, 3.71 mmol) and titanium(IV) ethoxide (1.3 ml, 6.18 mmol) were added. The reaction mixture was stirred at room temperature overnight then slowly quenched by dropwise addition of brine (2 ml) which resulted in the formation of a thick light yellow precipitate. The reaction mixture was diluted with ethyl acetate and stirred vigorously at room temperature for 30 min. The suspension was filtered over Celite and rinsed with ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-40% EtOAc) to afford 552 mg (89%) of 2-methyl-propane-2-sulfinic acid 1-oxazol-4-yl-meth-(E)-ylideneamide as a white solid.
Reaction SMILES: [F:1][C:2]([C:14]([F:17])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23]>C(Cl)(Cl)Cl>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH:23][S:6]([CH2:5][CH2:4][CH2:3][C:2]([F:1])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:7]
Reactant: CN(C)CCCN
Reactant: O=S(=O)(Cl)CCCC(F)(C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)CCCNS(=O)(=O)CCCC(F)(C(F)(F)F)C(F)(F)F
Yield: 93 %

Procedure:
The 4,5,5,5-tetrafluoro-4-trifluoromethyl-pentanesulfonyl chloride (7.1 grams) can be dissolved in 40 mL of chloroform and added to a solution of 8.6 mL of 3-dimethylaminopropylamine in 40 mL of chloroform at 0° C.-5° C. drop-wise over 45 minutes (Tmax=5° C.) to form a mixture. The mixture can be washed successively with saturated bicarbonate solution (80 mL), water (80 mL), and brine (80 mL). The organic layer can be separated, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford 8 grams (93%) of 4,5,5,5-tetrafluoro-4-trifluoromethyl-pentane-1-sulfonic acid (3-dimethylamino-propyl)-amide by NMR and LC/MS analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C([NH:30][CH2:31][C:32]([OH:34])=[O:33])(C)(C)C>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:30][CH2:31][C:32]([O:34][C:3]([CH3:18])([CH3:4])[CH3:2])=[O:33])=[CH:18][C:3]=1[C:4](=[O:5])[NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2
Reactant: CC(C)(C)NCC(=O)O
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Product: CC(C)(C)OC(=O)CNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 80.1 %

Procedure:
Prepared according to the method of Example 1 using 2-chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.2 g) and tertbutyl glycine (0.26 g) to deliver the sub-title compound as a brown foam (0.10 g).