Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)[N:4]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:5]3[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:6]=3)[CH2:20][CH2:19]2)=[O:23])=[CH:27][CH:26]=1
Reactant: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)O)CC2)n1
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3)CC2)n1
Reaction time: 20 h
Yield: 67.3 %

Procedure:
A mixture of 1-[4-(methylamino)-6-phenyl-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (80.0 mg, 0.255 mmol), 4-chlorobenzylamine (32.0 mg, 0.255 mmol), EDCI (49.0 mg, 0.255 mmol), HOBt (35.0 mg, 0.255 mmol) and N-methylmorpholine (26.0 mg, 0.255 mmol) in CH2Cl2 (5 mL) was stirred for 20 h (reaction progress monitored by LCMS). The solvent was removed under vacuum, and the residue was purified by preparative HPLC to yield 75 mg of the title compound as a white solid. MS (ES+): m/e 437.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][NH:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][N:29]([S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)(=[O:17])=[O:16])[O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1cccc(OCc2ccccc2)c1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1cccc(OCc2ccccc2)c1)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A mixture of 3-benzyloxybenzenesulfonyl chloride (65 mg; 0.230 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol) and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately one hour. An additional quantity of 3-benzyloxybenzenesulfonyl chloride (13 mg, 0.046 mmol) was added and the reaction was heated at reflux for approximately 1 hour. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The phases were separated and the organic layer was then washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[3-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (140 mg, 89%). H1-NMR (chloroform-D3): 1.22 (m, 6H), 1.62 (m, 5H), 2.05 (m, 2H), 2.90 (m, 4H), 3.11 (b, 1H), 3.66 (m, 2H), 3.87 (m, 4H), 4.18 (m, 1H), 4.77 (m, 1H), 4.95 (m, 1H), 5.10 (m, 2H), 5.60 (d, 1H), 7.29 (m, 14H). MS(ESI): 703(M+Na).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12](=O)[NH:13][N:14]=2)[CH:4]=1.P(Cl)(Cl)([Cl:20])=O>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]=[N:13][C:12]([Cl:20])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: O=c1ccc(-c2cccc(C(F)(F)F)c2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1

Procedure:
A mixture of 12.6 g. of 6-(α,α,α-trifluoro-m-tolyl)-3(2H)-pyridazinone and 200 ml. of phosphorus oxychloride is heated on a steam bath for 18 hours. The mixture is concentrated under vacuum and the residue triturated with cold water. The resulting solid is washed with water and air dried to give 13.5 g. of cream colored crystals, m.p. 131°-133° C. Recrystallization from methanol gives 6-(α,α,α-trifluoro-m-tolyl)-3-chloropyridazine as white crystals, m.p. 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([P:6]([C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5].[OH:30]O.[PH3]=O>C(#N)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]([P:6](=[O:30])([C:4](=[O:5])[C:3]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:2]=1[Cl:1])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:24]
Reactant: Cc1ccc(C)c(P(C(=O)c2c(Cl)cccc2Cl)C(=O)c2c(Cl)cccc2Cl)c1
Reactant: OO
Agent: O=[PH3]
Solvent: CC#N
Product: Cc1ccc(C)c(P(=O)(C(=O)c2c(Cl)cccc2Cl)C(=O)c2c(Cl)cccc2Cl)c1
Temperature: 60 °C
Yield: 74 %

Procedure:
The crude bis-(2,6-dichlorobenzoyl)-2,5-dimethylphenylphosphine (50 grams) is dissolved in 1 liter acetonitrile, mixed with 150 ml of 30% hydrogen peroxide, and heated for one hour at 60° C. The formation of the phosphine oxide is accompanied by deepening of the color, and it precipitates in crystalline form, after the addition of water and cooling. Recrystallization from acetonitrile/water yields 37 grams of the captioned compound (74% of theroretical yield in 2 steps)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([OH:32])=O)[CH2:8][CH2:7]1.S(Cl)(Cl)=O.[CH3:37][N:38]([CH:40]=O)[CH3:39]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([NH:6][C:12]2[CH:13]=[CH:14][C:15]([CH2:40][N:38]([CH3:37])[CH:39]3[CH2:25][CH2:24][O:23][CH2:20][CH2:19]3)=[CH:16][CH:11]=2)=[O:32])[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCCOC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-methoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (250 mg) in THF (10 ml) were added thionyl chloride (0.083 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (15 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (138 mg) and triethylamine (0.48 ml) in THF (3 ml) at 0° C. The mixture was stirred at room temperature for 3 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:4→1:3→1:2), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 1-(3-methoxypropyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 103) (264 mg) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16]O>C(Cl)(Cl)Cl>[CH3:16][O:13][C:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=2[CH:9]=1)=[O:14]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitrobenzofuran-2-carboxylic acid (10 g) was dissolved in methanol (200 mL) and chloroform (100 mL), and the mixture was cooled to 0° C. Under stirring conditions was bubbled HCl gas until the solution was saturated. The reaction mixture was stirred at room temperature overnight, and white solid was formed. The precipitate was collected by filtration to afford 9.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[N:9]3[C:12]([CH2:15]O)=[N:13][N:14]=[C:8]3[CH2:7][N:6]=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:4]=2[CH:3]=1.C([N:26](CC)CC)C>C(Cl)(Cl)Cl>[NH2:26][CH2:15][C:12]1[N:9]2[C:10]3[S:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:6][CH2:7][C:8]2=[N:14][N:13]=1
Reactant: CCN(CC)CC
Reactant: OCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: ClC(Cl)Cl
Product: NCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
0.75 g of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol is dissolved in 25 ml of absolute chloroform and there is added thereto 0.7 g of triethylamine and 0.6 g of methanesulphochloride. The mixture is stirred for 2.5 hours at 25° C., then washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The resulting oily methanesulphonic acid ester of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol is dissolved in 10 ml of dimethylformamide and the solution added dropwise at 0°-5° C. to a solution of 1 ml of liquid ammonia in 5 ml of dimethylformamide. The mixture is stirred for 2 hours at room temperature and then partitioned between saturated sodium chloride solution and methylene chloride. The organic phase is dried and evaporated and the residue recrystallized from ethanol. There is obtained 9-aminomethyl-2-chloro- 4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine of melting point 190°-192° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[O:12])=[CH:5][CH:4]=1)#[N:2].[Al](Br)(Br)Br.[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]#[N:26]>>[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]1[N:26]=[C:25]([C:24]([Cl:28])([Cl:27])[Cl:23])[N:26]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[O:12])=[CH:7][CH:8]=2)[N:2]=1
Reactant: CCOCCOC(=O)CSc1ccc(C#N)cc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: Br[Al](Br)Br
Product: CCOCCOC(=O)CSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reaction time: 24 h
Yield: 86 %

Procedure:
A mixed solution containing 10 g of 2-ethoxyethyl 2-(4-cyanophenylthio)acetate (37.7 mmol), 0.8 g of AlBr3 and 50 g of trichloroacetonitrile was bubbled with dry HCl at room temperature. The process of reaction was checked by TLC. The reaction product was formed gradually with the lapse of time while precipitation was formed. After 24 hours, the reaction mixture was quenched and extracted with 500 mL of chloroform. The resultant product was washed with deionized water and dried over anhydrous magnesium sulfate. Volatile substances were removed from the dried product under vacuum and the target product was separated by column chromatography using hexane/ethyl acetate (3/1) as eluent (yield: 86%). Then, the product was subjected to structural analysis by NMR, FT-IR and UV-Vis. spectrophotometers.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[NH:20]1[CH:24]=[C:23]([C:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:22]=[N:21]1>>[F:19][C:3]1[C:2]([C:28]#[C:27][C:25]([OH:29])([C:23]2[CH:24]=[N:20][NH:21][CH:22]=2)[CH3:26])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1cn[nH]c1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cn[nH]c1
Yield: 19 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1H-pyrazol-4-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (46.3 mg, 19%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:6][C:4]=1[NH2:5].[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[C:32]=1[N:39]1[C:43](=[O:44])[CH2:42][C:41](OCC)=[N:40]1.ClC1C=C(Cl)C(OCCCCCCCCCCCCCCCC)=CC=1N>>[Cl:38][C:33]1[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[C:32]=1[N:39]1[C:43](=[O:44])[CH2:42][C:41]([NH:5][C:4]2[CH:6]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:8]([Cl:10])=[CH:9][C:3]=2[Cl:2])=[N:40]1
Reactant: CCOC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)c(Cl)cc1Cl
Agent: CCCCCCCCCCCCCCCCOc1cc(N)c(Cl)cc1Cl
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c(Cl)cc1Cl

Procedure:
Using 18 g of 2,4-dichloro-5-octadecyloxyaniline hydrochloride and 13 g of 1-(2,4,6-trichlorophenyl)-3-ethoxy-2-pyrazolin-5-one, which were prepared in a manner similar to Steps (1) and (2) of Synthesis Example 1, similar procedures to Step (3) of Synthesis Example 1, were carried out and recrystallization was performed from 100 ml of ethanol to obtain 15 g of the desired coupler. The melting point thereof was 98 to 99° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:36])[CH3:35]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC1C=C(C=CC=1)C(OO)=[O:26]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)/[C:12]#[N+:13][O-:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C(C#N)=C/c2ccncc2)cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(/C(C#[N+][O-])=C/c2ccncc2)cc1OC
Yield: 94 %

Procedure:
Compound 30 (266 mg) was dissolved in anhydrous dichloromethane (50 mL). m-chloroperoxybenzoic acid (266 mg) was added dropwise to the solution under stirring in an ice bath. The mixture was stirred for about 15 minutes under argon which was fed by means of a separately provided balloon filled with argon. The mixture was returned to room temperature, followed by stirring for 3 hours. The reaction mixture was extracted with purified water and chloroform. The organic layer was washed with brine, and the washed organic layer was dried over sodium sulfate anhydrate. The solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (chloroform-methanol), to thereby yield the target product (yield: 265 mg, 94%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:54]3[CH:59]=[CH:58][C:57](O)=[CH:56][CH:55]=3)[C:50]([O:52][CH3:53])=[O:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][O:20][C:57]1[CH:58]=[CH:59][C:54]([C@@H:49]([NH:48][C:46]([O:45][CH2:44][CH:42]2[C:43]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:47])[C:50]([O:52][CH3:53])=[O:51])=[CH:55][CH:56]=1)=[O:30])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of 0.465 g (1.77 mmol) of triphenylphosphine in 10 mL of THF was added 0.286 g (1.77 mmol) of tert-butyl N-(2-hydroxyethyl)-carbamate followed by 0.476 g (1.18 mmol) of methyl (2R)-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}(4-hydroxyphenyl)ethanoate and 0.279 mL (1.77 mmol) of diethyl azodicarboxylate. The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to give 0.383 g of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl){[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethanoate as a white solid. Electrospray Mass Spec 547.2 (M+)+
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([N:6]3C(OC(C)(C)C)=O)[CH2:4]1)[CH2:10]2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:7]12[CH2:12][C:3]3([CH2:2][OH:1])[CH2:10][CH:9]([CH2:11][CH:5]([CH2:4]3)[NH:6]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(CO)(C3)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCC12CC3CC(C1)NC(C3)C2
Reaction time: 4 h
Yield: 97 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer tert-butyl 5-(hydroxymethyl)-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-15 (0.12 g, 0.45 mmol) in DCM (5 mL) was added. The reaction mixture was cooled to 00° C. followed by addition of trifluoroacetic acid (0.26 g, 2.2 mmol). This mixture was stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) reaction mixture was concentrated followed by trituration with mixture of hexane:ether (1:1) to give Intermediate-16 (0.12 g, yield=97%) as an oily mass.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]([CH2:17][OH:18])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:28][O:29][CH2:30]Cl>ClCCl>[CH2:1]([S:8][C:9]1[C:10]([CH2:17][O:18][CH2:28][O:29][CH3:30])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=[N+]([O-])c1scc(CO)c1SCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1csc([N+](=O)[O-])c1SCc1ccccc1

Procedure:
[4-(benzylthio)-5-nitrothien-3-yl]methanol (3.9 g, 13.9 mmol) in dichloromethane (8 mL) was reacted with diisopropylethylamine (7.42 mL, 3 equivalents) and methoxymethyl chloride (2.38 mL, 2.25 equivalents) at 25° C. 16 hours. The reaction was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel using a Biotage-40m column eluting with dichloromethane to give 3-(benzylthio)-4-[(methoxymethoxy)methyl]-2-nitrothiophene as a yellowish oil, (4.32 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
An oven-dried 300 mL round-bottomed flask was charged with 2-methylphenol (15.0 g, 139 mmol), finely powdered K2CO3 (38.3 g, 277 mmol), and anhydrous DMF (60 mL) and the resulting solution was cooled to 0° C. Next, ethyl bromoacetate (18.5 mL, 167 mmol) was added dropwise at 0° C., and the reaction was stirred vigorously at room temperature for 1 h. The reaction mixture was cooled using an ice-water bath, water (180 mL) was added and the product was extracted twice with AcOEt (200 mL and 100 mL). The combined organics were sequentially washed with 2×100 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a slightly yellow oil which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 5% AcOEt/hexane—10% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to provide compound 10.1 as a colorless oil (29.3 g). 1H NMR (300 MHz) (CDCl3) δ 7.26-7.13 (2H, m); 6.90 (1H, t, J=7.3 Hz); 6.71 (1H, d, J=8.0 Hz); 4.63 (2H, s); 4.27 (2H, q, J=6.9 Hz); 2.30 (3H, s); 1.30 (3H, t, J=6.9 Hz).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](=[O:16])[N:9]([CH2:14][CH3:15])[N:10]=[CH:11][C:12]=1[OH:13].Br[CH2:18][C:19]1[S:20][C:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:8](=[O:16])[N:9]([CH2:14][CH3:15])[N:10]=[CH:11][C:12]=1[O:13][CH2:18][C:19]1[S:20][C:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)s1
Reactant: CCn1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc(OCc2ccc(C(=O)c3ccc(Cl)cc3)s2)c(Cl)c1=O
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To 20 ml of N,N-dimethylformamide were added 1.9 g of 4-chloro-2-ethyl-5-hydroxy-3(2H)-pyridazinone, 3.2 g of 2-bromomethyl-5-(4-chlorobenzoyl)-thiophene and 1.5 g of potassium carbonate, and the mixture was stirred at 50° to 60° C. for 2 hours. After cooling, the reaction mixture was poured into 50 ml of water and extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to obtain 4.0 g of a crude product. The crude product was recrystallized from 2-propanol to obtain 3.1 g of 4-chloro-5-[{5-(4-chlorobenzoyl)-2-thienyl}-methyloxy]-2-ethyl-3(2H)-pyridazinone, m.p. 168.0°~168.5° C.
Reaction SMILES: O[CH:2]([CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].CCN(S(F)(F)[F:25])CC.CO>O1CCOCC1>[F:25][CH:2]([CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=[N+]([O-])c1nccn1CC(O)CN1CCCCC1
Solvent: CO
Solvent: C1COCCO1
Product: O=[N+]([O-])c1nccn1CC(F)CN1CCCCC1

Procedure:
To a solution of 2.2 g (8.65 mmol) of 1-(2'-hydroxy-3'-piperidylpropyl)-2-nitroimidazole in 20 ml of dry dioxane, 2.5 g (15.5 mmol) of DAST was dropwise added with cooling by ice and reacted for 5 hours at room temperature. After reaction, to the solution, 10 ml of methanol was added to decompose excess DAST. Then, the solution was concentrated and partitioned between chloroform and water. The pH of the aqueous phase was adjusted to 12 by the addition of an aqueous solution of sodium hydroxide and the liquid was again partitioned between chloroform and water. The chloroform phase was dried on magnesium sulfate and filtered. The filtrate was concentrated and subjected to isolation and purification by silica gel chromatography to give 1-(2'-fluoro-3'-piperidylpropyl)-2-nitroimidazole, which was treated with hydrochloric acid to form a hydrochloride and crystallized from ethanol to give 560 mg of crystalline hydrochloride of 1-(2'-fluoro-3'-piperidylpropyl)-2-nitroimidazole.