Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=2[CH:15]=1.O>CN(C=O)C>[N:1]1[C:5]2[C:4](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:3]([CH2:13][C:14]2[CH:24]=[CH:23][C:17]3[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=3[CH:15]=2)[CH:2]=1
Reactant: CSc1nc2ccc(CCl)cc2o1
Reactant: c1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
To a stirred solution of 4-azabenzimidazole (304 mg, 2.55 mmol) in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 107 mg, 2.68 mmol) and the mixture was stirred at 0° C. for 20 min. The mixture was allowed to warm to rt and stirred for a further 20 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (600 mg, 2.81 mmol) from Step 3 of this Example in DMF (5 mL). The mixture was stirred at rt for 15 h. To the reaction mixture was added water and the mixture was extracted with DCM. The combined organic layers were washed with brine. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (290 mg, 38%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.38 (dd, J=1.2, 4.6 Hz, 1H), 8.10 (dd, J=1.2, 8.0 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.25-7.41 (m, 2H), 5.61 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 297 (M+H)+.
Reaction SMILES: [N:1]1(C2(C#N)COC2)CCC[CH2:2]1.[C:12]1(=O)[CH2:15][CH2:14][CH2:13]1.C(O)(=O)C(O)=O.[CH2:23]1[C:26]2([CH2:29][NH:28][CH2:27]2)[CH2:25][O:24]1>>[CH2:23]1[C:26]2([CH2:29][N:28]([C:12]3([C:2]#[N:1])[CH2:15][CH2:14][CH2:13]3)[CH2:27]2)[CH2:25][O:24]1
Reactant: O=C1CCC1
Reactant: C1NCC12COC2
Reactant: N#CC1(N2CCCC2)COC1
Agent: O=C(O)C(=O)O
Product: N#CC1(N2CC3(COC3)C2)CCC1

Procedure:
The title compound was prepared in accordance with the general method of intermediate A from cyclobutanone and 2-oxa-6-aza-spiro[3.3]heptane oxalate (CAS 1045709-32-7).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13]3[N:14]=[C:15]([CH3:28])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]4)[C:12]=3[S:11][C:10]=2[CH3:29])=[C:4]([CH3:30])[CH:3]=1.I[CH2:32][CH3:33].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:32]([O:26][C:25](=[O:27])[CH2:24][CH:21]1[CH2:20][CH2:19][N:18]([C:17]2[C:12]3[S:11][C:10]([CH3:29])=[C:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:30])[C:13]=3[N:14]=[C:15]([CH3:28])[N:16]=2)[CH2:23][CH2:22]1)[CH3:33]
Reactant: CCI
Reactant: Cc1nc(N2CCC(CC(=O)O)CC2)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCN(c2nc(C)nc3c(-c4c(C)cc(Br)cc4C)c(C)sc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A mixture of {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-yl]-piperidin-4-yl}-acetic acid (30 mg), iodoethane (97 mg) and K2CO3 (17 mg) in DMF (1 mL) was stirred at room temperature for 16 hours. To the reaction mixture were added H2O and EtOAc and separated. The organic layer washed brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: Hexane/EtOAc=4:1) to obtain the title compound (22 mg) as a white crystal.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][C@:5]1([CH3:30])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25]O)[C:19]=3[S:18](=[O:28])(=[O:27])[N:17]=2)[C:6]1=[O:29].N12CCCN=C1CCCCC2.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1>ClCCl>[N:58]([CH2:25][C:24]1[C:19]2[S:18](=[O:28])(=[O:27])[N:17]=[C:16]([C:7]3[C:6](=[O:29])[C@@:5]([CH2:4][CH2:3][C:2]([CH3:32])([CH3:31])[CH3:1])([CH3:30])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:21][C:20]=2[S:22][CH:23]=1)=[N+:59]=[N-:60]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN=[N+]=[N-])csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A solution of Example 185 (1 g, 2.11 mmol) in 25 mL of dichloromethane was cooled to to 0° C., treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.7 mL, 11.2 mmol) and diphenylphosphoryl azide (2.3 mL, 10.9 mmol), allowed to warm to room temp, stirred for 16 h, and concentrated onto silica gel. The crude material was chromatographed on silica gel with hexane, hexane/dichloromethane (1:1), followed by dichloromethane, and methanol/dichloromethane (1:99) to afford the title compound (610 mg, 59% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (td, J=12.7, 3.3 Hz, 1 H), 0.72 (s, 9 H), 0.81 (td, J=13.1, 4.6 Hz, 1 H), 1.57 (s, 3 H), 2.05 (m, 1 H), 2.22 (td, J=12.6, 4.6 Hz, 1 H), 4.56 (s, 2 H), 7.29 (m, J=8.6, 8.6 Hz, 1 H), 7.54 (s, 1 H), 7.74 (m, J=4.0 Hz, 2 H), 8.13 (d, J=7.7 Hz, 1 H), 14.09 (s, 1 H); MS (APCI+) m/z 498 (M+H)+.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:22][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([O:40][C:41]([C@H:43]1[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[C@H:45](O)[O:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CC#N>[CH2:33]([O:40][C:41]([C@H:43]1[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[C@H:45]([O:20][C:19](=[O:21])[CH2:18][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][C:8]3[CH:22]=[CH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][C:7]=3[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=2)[O:44]1)=[O:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@H]1O
Reactant: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COc1ccc(CC(=O)O[C@@H]2O[C@@H](C(=O)OCc3ccccc3)[C@H](O)[C@@H](O)[C@@H]2O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (0.200 g, 0.44 mmol), (2R,3R,4R,5S,6R)-3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.200 g, 0.7 mmol; prepared according to the procedure described in Tetrahedron 2007, 63, 7596), HATU (0.266 g, 0.7 mmol), and N-methylmorpholine (0.1 mL, 0.7 mmol) were combined in MeCN, and the reaction was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by preparative HPLC to give (2R,3R,4R,5S,6S)-6-(2-{3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester, which was subsequently treated with palladium hydroxide on carbon and stirred under an atmosphere of H2 overnight. The crude material was purified by preparative HPLC to give (2R,3R,4R,5S,6S)-6-(2-{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]=[CH:13][C:12]=2[OH:24])=[O:10])[CH:5]=[CH:6][CH:7]=1.[I:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.N1CCCCC1.C1CCN2C(=NCCC2)CC1>C(O)(CC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][CH:14]=[C:15]([O:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[CH:16]=3)[O:24][CH:30]2[C:29]2[CH:32]=[CH:33][C:26]([I:25])=[CH:27][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: O=C(Cc1cccc(Br)c1)c1cc(OC2CCCCO2)ccc1O
Solvent: CCC(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCNCC1
Product: O=C1c2cc(OC3CCCCO3)ccc2OC(c2ccc(I)cc2)C1c1cccc(Br)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of 2-(3-bromophenyl)-1-(2-hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone (5.28 g, 13.5 mmol), 4-iodobenzaldehyde (3.29 g, 14.2 mmol), piperidine (0.66 mL, 4.4 mmol), and DBU (0.44 mL, 4.5 mmol) in s-butanol (27 mL) was heated at reflux. Using a Dean-Stark trap, half (13 mL) of the solvent was removed over 40 min, and the reaction was kept at reflux without further concentration for additional 4.5 h. The reaction mixture was cooled to 90° C., i-propanol (27 mL) was added, and the reaction was allowed to cool to room temperature. The large solid pieces were broken down with spatula, and the suspension was stirred overnight (Note #1). The precipitate was collected by filtration to yield 3-(3-bromophenyl)-2-(4-iodophenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one (7.23 g, 88%) as a white solid. 1H NMR (DMSO-d6): δ 7.67 (d, 2H), 7.43 (m, 1H), 7.38 (m, 1H), 7.36-7.30 (m, 2H), 7.21 (dd, 2H), 7.18-7.10 (m, 2H), 7.07 (dd, 1H), 5.95 (d, 1H), 5.47 (m, 1H), 4.76 (d, 1H), 3.73 (m, 1H), 3.55 (m, 1H), 1.93-1.68 (m, 3H), 1.68-1.48 (m, 3H).
Reaction SMILES: Cl[C@@H:2]1[C@H:19]2[O:20][C@:18]32[C@:13]([CH3:22])([CH2:14][CH2:15][C@H:16]([OH:21])[CH2:17]3)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:23])[C@H:6]2[CH2:24][C@@H:5]12.O1CCCC1>C(O)(=O)C.[Zn]>[OH:21][C@H:16]1[CH2:15][CH2:14][C@@:13]2([CH3:22])[C@:18]([OH:20])([CH:19]=[CH:2][C@@H:3]3[C@@H:12]2[CH2:11][CH2:10][C@@:8]2([CH3:9])[C@H:4]3[C@@H:5]3[CH2:24][C@@H:6]3[C:7]2=[O:23])[CH2:17]1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](Cl)[C@H]4O[C@]45C[C@@H](O)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
107.5 g of 7α-chloro-5,6β-epoxy-3β-hydroxy-15β,16β-methylene-5β-androstan-17-one is dissolved in 500 ml of acetic acid and 500 ml of tetrahydrofuran and, after the addition of 324 g of zinc dust in three portions, stirred at room temperature for 16 hours. The zinc is then filtered off, the filtrate is diluted with methylene chloride, and washed with sodium bicarbonate solution and water. After drying over sodium sulfate, the product is concentrated under vacuum. By trituration of the thus-obtained solid with ethyl acetate, 91.5 g of 3β,5-dihydroxy-15β,16β-methylene-5β-androst-6-en-17-one is produced, mp 196° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](O)=[O:14])[C:11]=1[OH:19])([O-:9])=[O:8].[C]=O.[CH3:22][NH:23][CH3:24]>ClCCl.CN(C)C=O.O1CCCC1>[OH:19][C:11]1[C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:23]([CH3:24])[CH3:22])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Agent: [C]=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
42.9 ml (0.50 mol, 3 eq) of oxalyl chloride were added dropwise to a suspension of 30 g (0.16 mol, 1 eq) of 3-nitrosalicylic acid in 1200 ml of dichloromethane. 30 drops of N,N-dimethylformamide were added (large amount of gas given off, adaptation of a system for trapping toxic carbon monoxide vapors). The reaction medium was stirred at ambient temperature for 24 hours. The reaction medium was cooled to 0-5° C. and then 246 ml (0.49 mol, 3 eq) of a 2 N solution of dimethylamine in tetrahydrofuran were added. The reaction medium was stirred at ambient temperature for 2 days. The reaction medium was concentrated to dryness and the residue was dissolved in 300 ml 1 N sodium hydroxide. The aqueous solution (red) was extracted 3 times with 300 ml of dichloromethane. The aqueous phase was cooled in a water-ice bath, and the pH was adjusted to 2 with approximately 50 ml of 6 N hydrochloric acid. The mixture (which had become yellow) was extracted 3 times with 300 ml of dichloromethane. The organic phases were combined, washed twice with 250 ml of water and then once with 250 ml of a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. 33.5 g of 2-hydroxy-N,N-dimethyl-3-nitrobenzamide were obtained in the form of a yellow cotton solid. Yield=97%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][N:4]=1)#[N:2].N1C=CC=CC=1.C1(C)C=CC(S([Cl:26])(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:26])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ccc(CO)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
2-Cyano-5-hydroxymethylpyridine (13.4 g) and pyridine (8.7 g) were dissolved in toluene (150 ml), and a solution of p-toluenesufonyl chloride (19.1 g) in toluene (50 ml) was added dropwise at room temperature to the solution. After the addition, the mixture was gradually heated, and stirred at 70° to 80° C. for 4 hours. The reaction mixture was cooled to room temperature, and washed with water. The organic layer was dried. Toluene was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 2-cyano-5-pyridylmethyl chloride (7.7 g) as colorless crystals.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](SC)[N:6]=1>CCO>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:2][NH2:3])[N:6]=1
Reactant: CSc1nccc(C)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccnc(NN)n1
Temperature: 0 °C
Reaction time: 50 h
Yield: 21562.2 %

Procedure:
Based on a reported procedure (Vanderhaeghe, Claesen, Bull. Soc. Chim. Belg. 1959, 68, 30). Hydrazine monohydrate (334.7 ml, 6.90 mmol) was added in one portion to a solution of 4-Methyl-2-methylsulfanyl-pyrimidine (357.9 g, 2.55 mol) in abs. EtOH (890 ml). The resulting mixture was refluxed for 50 h, then hydrazine monohydrate (200 ml) was added and refluxing was continued for 50 h (the reaction was monitored by 1H NMR). Then it was cooled to 0° C. to crystallize and 213 g of crude product was isolated by filtration. Recrystallization from ethanol gave the title compound (184.7 g, 59%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ, ppm: 2.40 (s, 3H), 4.00 (broad, 2H), 6.512 (d, 1H, 5 Hz), 7.03 (broad, 1H), 8.24 (d, 1H, 5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:17]=[CH:16][NH:15][C:14](=O)[C:13]1=[O:19].CN(C)C=O.C(Br)(=O)C([Br:28])=O>C(Cl)Cl>[Br:28][C:14]1[C:13](=[O:19])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[Cl:1])[C:6]([O:8][CH3:9])=[O:7])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccc(Cl)c(-n2cc[nH]c(=O)c2=O)c1
Reactant: O=C(Br)C(=O)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(-n2ccnc(Br)c2=O)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 4-chloro-3-(2,3-dioxo-3,4-dihydropyrazin-1(2H)-yl)benzoate (Example 330d, 8 g) in DCM (80 mL) was treated with N,N-dimethylformamide (0.220 mL) and oxalyl bromide (2.94 mL) dropwise over 5 min at room temperature under nitrogen. The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture turned black and was evaporated to afford crude product. Purification (SiO2 chromatography eluting with 30% diethyl ether in dichloromethane) gave the subtitle compound (6.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[CH:12][CH:11]=2)=[C:4]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)(=[O:30])=[O:29])[CH:3]=1>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[CH:14][CH:15]=2)=[C:4]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:39])([F:40])[F:41])[CH:32]=2)(=[O:30])=[O:29])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: O=CO
Product: O=C(O)CNC(=O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)phenyl]carbonyl}amino)acetate (90 mg, 0.14 mmol) in formic acid (2 ml) was stirred at room temperature overnight. Formic acid was removed under vacuum and the desired product (72 mg, 88%) was re-crystallized from 10% MeOH in CH2Cl2.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[CH2:7]([O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OCc1ccccc1
Product: Cc1cc(Nc2cc3ccccc3c(OCc3ccccc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from phenyl-methanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-benzyloxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 331 (MH+).
Reaction SMILES: [O:1]=[S:2](=[O:24])([CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][C:4]([OH:6])=[O:5].[CH3:25]O>S(=O)(=O)(O)O>[O:1]=[S:2](=[O:24])([CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][C:4]([O:6][CH3:25])=[O:5]
Reactant: CCCCCCCCC#CCC#CCC#CCS(=O)(=O)CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCCCCCC#CCC#CCC#CCS(=O)(=O)CC(=O)OC

Procedure:
A solution of 1 g of 3,3-dioxo-3-thia-5,8,11-eicosatriynoic acid in 50 cm3 of methanol is heated under reflux in the presence of a sulfuric acid catalyst for 48 hours. The mixture is then filtered at ambient temperature. The methanol is evaporated off under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8].CS(N1C2C(=CC=C(C[Br:28])C=2)C=C1)(=O)=O.CS(N1C2C(=CC=C(CO)C=2)C=C1)(=O)=O>>[Br:28][CH2:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1c(Cl)cc(CO)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)n1ccc2ccc(CBr)cc21
Agent: CS(=O)(=O)n1ccc2ccc(CO)cc21
Product: Cc1c(Cl)cc(CBr)cc1[N+](=O)[O-]

Procedure:
5-Bromomethyl-1-chloro-2-methyl-3-nitrobenzene was prepared from (3-chloro-4-methyl-5-nitrophenyl)methanol in a manner similar to that described in Example 10 for the preparation of N-methanesulfonyl-6-bromomethylindole from N-methanesulfonyl-6-hyroxymethyl indole.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:13][OH:14])[NH:8]CCOC)=[N:4][O:5][N:6]=1.O.[OH-].[K+].[C:18]([O:21][CH2:22]C)(=O)[CH3:19]>CCCCCC>[OH:14][N:13]=[C:7]([C:3]1[C:2]([NH:1][CH2:19][CH2:18][O:21][CH3:22])=[N:6][O:5][N:4]=1)[NH2:8]
Reactant: CCOC(C)=O
Reactant: COCCNC(=NO)c1nonc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: COCCNc1nonc1C(N)=NO
Temperature: 100 °C
Yield: 81 %

Procedure:
4-Amino-N′-hydroxy-N-(2-methoxyethyl)-1,2,5-oxadiazole-3-carboximidamide (248.0 g, 1.23 mol) was mixed with water (1 L). Potassium hydroxide (210 g, 3.7 mol) was added. The reaction was refluxed at 100° C. overnight (15 hours). TLC with 50% ethyl acetate (containing 1% ammonium hydroxide) in hexane indicated reaction completed (product Rf=0.6, starting material Rf=0.5). LCMS also indicated reaction completion. The reaction was cooled to room temperature and extracted with ethyl acetate (3×1 L). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (201 g, 81%) as a crude off-white solid. LCMS for C6H12N5O3 (M+H)+: m/z=202.3 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 6.22 (s, 2H), 6.15 (t, J=5.8 Hz, 1H), 3.45 (t, J=5.3 Hz, 2H), 3.35 (m, 2H), 3.22 (s, 3H).
Reaction SMILES: [OH-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]>O1CCCC1.O>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]1[O:16][CH2:8]1
Reactant: O=Cc1ccccc1Cl
Reactant: C[S+](C)C
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccccc1C1CO1

Procedure:
A mixture of 42.0 g of 57% sodium hydroxide dispersed in oil and 700 ml of dimethyl sulfoxide is stirred at 70°-75° for one to one and one-half hours. The solution is diluted with 700 ml of dry tetrahydrofuran and cooled to 0°, under nitrogen. A 200 g of (1.0 mol) sample of trimethylsulfonium iodide is added in portions, maintaining the temperature between 0°-5°. The mixture is stirred for 15 minutes and then a solution of 70.4 g (0.50 mol) of o-chlorobenzaldehyde in 300 ml of dry tetrahydrofuran is added dropwise. The resulting mixture is stirred at room temperature for four hours, poured into water and extracted with ether. The extract is washed with brine, dried and evaporated in vacuo to leave o-chlorostyrene oxide.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.[C:11]([O-:14])([O-])=[O:12].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C.Br[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:35]=[CH:34]2>CN1C(=O)CCC1.Cl[Cu]>[CH2:40]([N:36]1[C:37]2[C:33](=[CH:32][C:31]([O:1][C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=3[CH2:4][C:11]([OH:14])=[O:12])=[CH:39][CH:38]=2)[CH:34]=[N:35]1)[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)Cn1ncc2cc(Br)ccc21
Reactant: O=C(O)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)Cn1ncc2cc(Oc3ccccc3CC(=O)O)ccc21
Temperature: 145 °C
Yield: 36.3 %

Procedure:
To a degassed suspension of 2-hydroxybenzoic acid (2.4 g, 15.8 mmol) and Cs2CO3 (7.72 g, 23.7 mmol) in NMP (13 mL), 2,2,6,6-tetramethyl-heptane-3,5-dione (0.41 mL, 1.97 mmol) and compound 14p (2.0 g, 7.90 mmol) was added followed by small amount of NMP for rinsing. The resulting mixture was degassed again with nitrogen and then CuCl (0.39 g, 3.95 mmol) was added and reaction again degassed. The mixture was heated to 140-150° C. After mixing for 22 hours, the reaction mixture was poured into ether/H2O. The two layers were separated and the aqueous layer (pH ˜11) was washed with ether. The aqueous layer was acidified to pH 7 and extracted with ether (4×) and the combined organic layers were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The precipitate was formed gradually in a small volume of a mixed solvent of ether/hexane/DCM and collected through filtration to obtain the desired compound (15p) (0.93 g, 36% isolation yield). 1H NMR (400 MHz, CDCl3) δ 7.87 (br s, 1H), 7.38-7.28 (m, 2H), 7.25-7.17 (m, 2H), 7.13 (d, J=9.39 Hz, 1H), 7.10-7.03 (m, 1H), 6.79 (d, J=8.61 Hz, 1H), 4.15 (br s, 2H), 3.79 (s, 2H), 2.40-2.27 (m, 1H), 0.93 (s, 3H), 0.92 (s, 3H); MS (APCI+) m/z 325 (M+H), MS (APCI−) m/z 322.8 (M−H) and 646.8 (2M−H) detected.