Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(N(CC)CC)C.Cl[CH2:12][C:13]([O:15][C:16]([CH:19]1[CH2:24][CH2:23][C:22]([O:26][C:27](=[O:30])[CH2:28]Cl)([CH3:25])[CH2:21][CH2:20]1)([CH3:18])[CH3:17])=[O:14].[C:31]([O:34]CC)(=[O:33])C>>[CH:1]([O:3][CH2:12][C:13]([O:15][C:16]([CH:19]1[CH2:24][CH2:23][C:22]([O:26][C:27](=[O:30])[CH2:28][O:34][CH:31]=[O:33])([CH3:25])[CH2:21][CH2:20]1)([CH3:18])[CH3:17])=[O:14])=[O:2]
Reactant: O=CO
Reactant: CC1(OC(=O)CCl)CCC(C(C)(C)OC(=O)CCl)CC1
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(OC(=O)COC=O)CCC(C(C)(C)OC(=O)COC=O)CC1
Reaction time: 0.5 h

Procedure:
Formic acid (67) (0.921 g, 20 mmol) and triethylamine (2.226 g, 22 mmol) were combined and stirred for 30 minutes. Compound (109) (0.623 g, 1.9 mmol) was then added and stirred for three days. The solution was dissolved in 10 mL of ethyl acetate and the precipitate was filtered and washed with 10 mL diethylether. The combined filtrate was then washed with brine and dried with sodium sulfate. The solvent was evaporated to get dark brown viscous oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC.[Cu]I>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=2)=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Reactant: Cc1cc(I)ccc1N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: CCOCC
Product: Cc1cc(C#Cc2ccc(C(C)(C)C)cc2)ccc1N

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 1-tert-butyl-4-ethynylbenzene (25b, 158 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((4-tert-butylphenyl)ethynyl)-2-methyl benzene amine (26b) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((4-tert-butylphenyl)ethynyl)-2-methylbenzenamine (26b, 263 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29b). Reaction of 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methyl quinazolin-4(3H)-one (29b, 406 mg, 1 mmol) with 2,4-dihydroxybenzaldehyde (30d, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (5d) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:43][NH2:44]>>[CH3:43][NH:44][CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.422 g, 0.786 mmol) in 2.0 M methylamine in THF (8.0 mL, 16 mmol). was stirred for 15 hours at 70° C. in a sealed tube. After cooling to ambient temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine. The aqueous phases were extracted with chloroform, and both organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.75% ammonium hydroxide/7.5% methanol in chloroform. Methyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine was obtained as a light yellow foam (0.209 g, 67.2%). Methanol and ethereal hydrochloride were added to the compound. The resulting solution was concentrated and dried for 14 hours at 84° C. in vacuo. The hydrochloride was obtained as a light yellow foam (0.217 g). Mass Spectrum (−EI, [M−H]−) m/z 394. 1HNMR (500 MHz, DMSO-d6): δ14.16 (s, 1H), 8.74-8.76 (m, 1H), 8.67 (s, br, 2H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.70-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.19 Hz), 7.08-7.11 (m, 1H), 4.09 (t, 2H, J=5.98 Hz), 3.05 (s, br, 2H), 2.55 (s, 3H), 2.05-2.11 ppm (m, 2H). Elemental Analysis for C21H21N3O3S.1.00 mol HCl.0.45 mol H2O: Calcd: C, 57.32; H, 5.25; N, 9.55; Found: C, 57.64; H, 5.33; N, 9.39.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C.O>C(O)C>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COc1ccc(CNc2ncc(F)cn2)c(OC)c1
Temperature: 50 °C
Yield: 51.6 %

Procedure:
2-Chloro-5-fluoropyrimidine (4.05 g, 30.6 mmol), 2,4-dimethoxybenzylamine (5.0 mL, 31 mmol) and triethylamine (3.72 g, 36.7 mmol) were stirred in ethanol (200 mL) and heated at 50° C. for 48 hours. The cooled reaction mixture was poured into water and extracted with ethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes to ethyl acetate gradient elution) then triturated with ethyl ether:hexanes. The solid was collected by filtration and dried in vacuo to afford the title compound as a white solid (4.16 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:61]1([CH2:67][SH:68])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:67]([S:68][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: SCc1ccccc1
Reactant: Cc1c(Br)cccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1SCc1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
2,6-dibromotoluene (20 g, 100 mmol) in dioxane (160 ml) was stirred under argon. Then, DIPEA (30.9 ml, 160 mmol), xantphos (2.77 g, 4.8 mmol) and Pd2(dba)3 (2.4 g, 2.4 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (9.4 ml, 80 mmol) was slowly added and the reaction stirred for 6 h. The reaction was quenched by the addition of 150 ml of H2O. After extraction (three times) with ethyl acetate, the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([CH:44]([CH3:46])[CH3:45])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([CH2:10][CH2:11][O:12][Si](C(C)(C)C)(C)C)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([CH:44]([CH3:46])[CH3:45])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO[Si](C)(C)C(C)(C)C)c4ccccc43)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a solution of Intermediate 10d (100 mg, 0.15 mmol) in THF (2 mL), TBAF (1M in THF, 0.23 mL, 0.23 mmol) was added at RT and stirred for 10 min. The reaction mixture was diluted with H2O (5 mL) and DCM (5 mL). The layers were separated, and aqueous layer was extracted with DCM (3×5 mL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and then purified by FCC using 0-5% [2M NH3 in MeOH] in DCM). The residue was washed with water and purified by HPLC (30%-100% MeCN in H2O, 0.1% formic acid) to give the title compound as a white powder (47 mg, 57%). Rf=0.2 (5% [2M NH3 in MeOH] in DCM) LCMS (Method 5): Rt 3.59 min, m/z 532 [MH+]. 1H NMR (400 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): 1.25 (s, 9H), 1.43 (d, J=6.9 Hz, 3H), 1.46 (d, J=6.9 Hz, 3H), 1.92-2.30 (m, 4H), 3.25 (p, J=6.9 Hz, 1H), 3.95 (t, J=4.7 Hz, 2H), 4.15 (dd, J=5.3, 3.5 Hz, 2H), 5.09-5.16 (m, 1H), 5.92 (d, J=8.0 Hz, 1H), 6.12 (s, 1H), 6.92 (dd, J=9.8, 1.9 Hz, 1H), 7.22-7.27 (m, 2H), 7.33 (td, J=5.8, 3.0 Hz, 1H), 7.40 (s, 1H), 7.43 (br s, 2H), 7.47 (d, J=7.8 Hz, 1H), 7.70 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[C:18]([NH:20][CH:21]2[CH2:26][CH2:25]S[CH2:23][CH2:22]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH:39][S:40]([O-:42])=O.[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[C:18]([NH:20][CH:21]2[CH2:22][CH2:23][S:40](=[O:42])(=[O:39])[CH2:25][CH2:26]2)=[O:19])[CH2:15][CH2:16]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCSCC2)CC1
Reactant: O=S([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCS(=O)(=O)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-(tetrahydro-2H-thiopyran-4-yl)acetamide (Example 193, 0.21 g, 0.54 mmol) and m-chloroperbenzoic acid (0.29 g, 1.13 mmol) in ethyl acetate (10 mL) was stirred at 0° C. for 2 h. Then the mixture was added saturated NaHSO3 solution and stirred for 1 h. The mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 60:40 to 0:100 then ethyl acetate/methanol 100/0 to 70/30) to give the title compound (0.20 g, 88%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].[CH3:17]C([N-]C(C)C)C.CI.[NH4+].[Cl-]>C1COCC1>[CH3:17][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18a, 2.14 g, 10 mmol) was dissolved in dry THF (20 mL) and the solution was cooled to −78° C. LDA (1.8 M in THF, 6.6 mL) was added to the mixture dropwise and the mixture was stirred for 15 min. Then CH3I (1.87 mL, 30 mmol) was added to the mixture at −78° C. and the reaction was allowed to warm up to room temperature. The reaction was stirred overnight. NH4Cl (aq.) was added to quench the reaction which was extracted with ethyl acetate (50 mL×3). The combined organics was washed with water and brine and dried over Na2SO4. After concentration, the residue was purified by column chromatography (0-50% ethyl acetate in hexane) which gave ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18b) (2.09 g) as an oil. HPLC-MS tR=1.68 min (UV254 nm); mass calculated for formula C12H20O4 228.1, observed LCMS m/z 229.1 (M+H).
Reaction SMILES: [CH2:1]1[O:8]C(=O)C[O:4][C:2]1=[O:3].[C:9]1(=[O:16])[O:15][CH2:14][CH2:13][O:12][C:10]1=[O:11]>>[C:2]([OH:4])(=[O:3])[CH2:1][OH:8].[C:9]1(=[O:16])[O:15][CH2:14][CH2:13][O:12][C:10]1=[O:11]
Reactant: O=C1COC(=O)CO1
Agent: O=C1OCCOC1=O
Product: O=C(O)CO

Procedure:
Polymerization and post-treatment were performed in the same manner as in Polymer Preparation Example 1 except that a mixture of 196 g of glycolide and 4 g of ethylene oxalate (1,4-dioxane-2,3-dione) was used in place of 200 g of glycolide, thereby obtaining a glycolic acid-ethylene oxalate copolymer [Polymer (P-2)]. The same process was conducted repeatedly to prepare a necessary amount of Polymer (P-2).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Yield: 100.4 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-n-butyl-3-L-rhamnopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.5 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-L-rhamnopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:23][O:24][CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:10]([O:11][CH2:23][O:24][CH3:25])=[CH:9][C:8]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc2c(Cl)c(O)cc3c2n1CCCCC3=O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)c(OCOC)cc3c2n1CCCCC3=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-chloro-10-hydroxy-8-oxo-4H-azocino[3,2,1-hi]indole-2-carboxylate (0.95 g, 2.93 mmol), chloromethyl methyl ether (0.35 g, 4.40 mmol), potassium carbonate (1.22 g, 8.80 mmol) and N,N-dimethylformamide (25 ml) was stirred at room temperature for 1 hour. The insoluble material was filtered off and the filtrate was poured into ice water and extracted twice with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 0.51 g of ethyl 5,6,7,8-tetrahydro-11-chloro-10-methoxymethyloxy-8-oxo-4H-azocino[3,2,1-hi]indole-2-carboxylate.
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:16])=C.C([Zn]CC)C.CCC[CH2:51][CH2:52][CH3:53].ICI.[Cl:57]CCl>Cl>[ClH:57].[ClH:57].[CH:51]1([O:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[C:15]([N:17]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])[CH2:21][NH:20][CH2:19]2)=[O:16])[CH2:52][CH2:53]1
Reactant: CCCCCC
Reactant: ClCCl
Reactant: C=COCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: CC[Zn]CC
Agent: Cl
Solvent: ICI
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCOC1CC1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[({1-[2-(ethenyloxy)ethyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (323 mg) and 1M diethylzinc-hexane solution (2.5 ml) in dichloromethane (5 ml) was added dropwise diiodomethane (443 μl) at room temperature over 5 min, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 ml), 4M hydrogen chloride-ethyl acetate (5 ml) was added and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (35 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([CH3:24])=[C:22]([C:25]([OH:27])=O)[N:21]=[N:20]2)=[C:15]([CH:28]2[CH2:30][CH2:29]2)[CH:14]=1.[NH2:31][C:32]1[C:33](=[O:46])[N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[N:35]([CH3:38])[C:36]=1[CH3:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([CH3:24])=[C:22]([C:25]([NH:31][C:32]3[C:33](=[O:46])[N:34]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[F:45])[N:35]([CH3:38])[C:36]=3[CH3:37])=[O:27])[N:21]=[N:20]2)=[C:15]([CH:28]2[CH2:30][CH2:29]2)[CH:14]=1
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1C1CC1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2c(C)n(C)n(-c3ccccc3F)c2=O)nnn1-c1ccc(Cl)cc1C1CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of oxalyl chloride (0.035 ml, 0.396 mmol) and DMF (0.056 ml, 0.720 mmol) in DCM (10 ml) was added 1-(4-chloro-2-cyclopropylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 0.360 mmol) and the mixture was stirred for 30 mins. Further oxalyl chloride (0.035 ml, 0.396 mmol) was added to the reaction mixture and it was stirred for 1 hr. 4-Amino-2-(2-fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate B) (88 mg, 0.396 mmol) was added followed by triethylamine (0.151 ml, 1.080 mmol) and the mixture was stirred at RT for 1 hr. The resulting mixture was diluted with DCM, washed with 0.1 M HCl(aq) and sat. NaHCO3(aq). The organic extracts were passed through a phase separating cartridge and concentrated under reduced pressure to give an oil. The oil was absorbed onto silica and purified by chromatography eluting with 0-10% MeOH in TBME. The product fractions were combined and concentrated under reduced pressure to give a yellow glassy solid which was recrystallised from EtOH. The solid was collected by filtration and dried on the vacuum line to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH2:19][C@H:20]([OH:23])[CH2:21][OH:22])=[CH:17][C:16]([O:24][CH3:25])=[C:15]2[C:10]=1[C@@H:11]1[CH2:26][C@H:14]2[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:22][CH2:21][C@@H:20]([OH:23])[CH2:19][C:18]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=2)[C@H:14]2[CH2:26][C@@H:11]3[CH2:12][CH2:13]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: COc1cc(C[C@H](O)CO)c(OCc2ccccc2)c2c1[C@@H]1CC[C@H]2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1cc(C[C@H](O)COS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c2c1[C@@H]1CC[C@H]2C1

Procedure:
Treatment of (2S*)-3-[(1R*,4S*)-5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl]propane-1,2-diol (13.95 g, 39.56 mmol) with p-toluenesulfonyl chloride (8.25 g, 43.92 mmol) in anhydrous pyridine (350 mL) generally according to the procedure described for Intermediate 18 gave (2S*)-3-[(1R*,4S*)-5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl]-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the tosylate with palladium on carbon (10 wt. %, 1.6 g) generally according to the procedure described for Intermediate 4 provided 12.77 g (77%) of (2S*)-2-hydroxy-3-[(1R*,4S*)-5-hydroxy-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl]propyl 4-methylbenzenesulfonate. Treatment of the phenyl (12.73 g, 30.4 mmol) with triphenylphosphine (8.78 g, 33.5 mmol) followed by diethylazodicarboxylate (5.83 g, 33.5 mmol) generally according to the procedure described for Intermediate 5 afforded 7.67 g (48%) of [(2R*,6R*,9S*)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-methanonaphtho[1,2-b]furan-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C22H24O5S: C, 65.98; H, 6.04. Found: C, 65.61; H, 5.92.