Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22]>CCCCCC.C1COCC1>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)CC1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
The title compound was prepared by following general procedure 7. Sodium hydride (34 mg, 0.43 mmol) washed with hexane for removal of oil and dried under vacuum and taken in THF. To this solution 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.43 mmol) in THF was added dropwise at 0° C. Then the reaction mixture was stirred for 0.5 h. The solution of 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (89 mg, 0.51 mmol) in THF was added dropwise in reaction mixture. Then the reaction mixture was stirred at RT for 2 h. The reaction monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water. THF was evaporated and aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to gives 95 mg of desired compound, which was stirred with ethanolic HCl to give the HCl salt of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:27])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:37]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:27])=[O:8])=[CH:29][CH:30]=1)(=[S:37])[NH2:2]
Reactant: S
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1NC(=O)NC(=O)c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1NC(=O)NC(=O)c1ccc(C(N)=S)cc1

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (611 mg), pyridine (70 ml), triethylamine (10 ml) and H2S gas were reacted to give t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-3-methylphenoxyacetate (660 mg) as a yellow solid: NMR Spectrum (DMSO-d6) 1.44 (9H, s), 2.27 (3H, s), 4.61 (2H, s), 6.76 (1H, dd), 6.83 (1H, d), 7.76 (1H, d), 7.95 (2H, d), 8.05 (2H, d), 9.67 (1H, br s), 10.06 (1H, br s), 10.55 (1H, s), 11.12 (1H, s); Mass Spectrum m/Z 466 (M+Na)+.
Reaction SMILES: [CH:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)=[N+:17]=[N-:18].[O-]CC.[Na+].O>C(O)C>[CH:1]1([CH2:7][C:8]2[N:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)[N:17]=[N:18][C:9]=2[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CC1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
Ethyl 4-cyclohexyl-3-oxobutyrate (0.84 g, 3.96 mmol, 1.25 eq.) obtained in Example 102a) and 4-azido-N-ethylbenzamide (0.60 g, 3.15 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (298 mg, 3.96 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 50° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and extracted with ethyl acetate-THF (4:1, 40 ml) and ethyl acetate (30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether and ethyl acetate were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-yellow powder (1.04 g, 2.91 mmol, 92.4%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]2[NH:7][C:8]3[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=3[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:13]3)[C:5]=2[CH:4]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:28]=[CH:27][C:6]2[NH:7][C:8]3[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=3[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:33])[C@@H:14]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:13]3)[C:5]=2[CH:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Temperature: 25 °C

Procedure:
Add (S)-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.167 g, 0.399 mmol), formaldehyde (40.8 mg, 0.499 mmol, 37%), and sodium triacetoxyborohydride (0.127 g, 0.598 mmol) in dichloromethane (3 mL). Stir at ambient temperature over night. Dilute the mixture with water and extract with dichloromethane. Wash the organic with brine twice, dry over sodium sulfate, filter, and concentrate under reduced pressure to give crude residue. Purify the residue by flash chromatography, eluting with 2M ammonia in methanol:dichloromethane (5:95) to give the title compound: mass spectrum (m/e):433.08 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([CH2:14][C:15]#[N:16])(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[CH:24]=O)([CH3:20])([CH3:19])[CH3:18]>>[C:30]([C:27]1[CH:26]=[C:23](/[CH:24]=[C:14](/[S:11]([NH:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:13])=[O:12])\[C:15]#[N:16])[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:28]=1[OH:29])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
N-3-Phenyl-n-propyl cyanomethylsulfonamide and 3,5-di-t-butyl-4-hydroxybenzaldehyde was condensed under the similar conditions as described for example 12 (Part B) to yield the titled compound.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[NH:6][C:5](=[O:14])[CH:4]=1)[NH2:2].[C:15]1([CH:25]=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>CO>[CH2:9]([N:8]1[C:3]([NH:1][N:2]=[CH:25][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:4][C:5](=[O:14])[NH:6][C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(C)Cn1c(NN)cc(=O)[nH]c1=O
Solvent: CO
Product: CC(C)Cn1c(NN=Cc2cccc3ccccc23)cc(=O)[nH]c1=O
Reaction time: 24 h
Yield: 99.2 %

Procedure:
6-hydrazino-1-isobutylpyrimidine-2,4(1H,3H)-dione (1.8 g) was dissolved in warm methanol (90 ml) and treated with 1-naphthaldehyde (1.5 g). After 24 hours, the precipitated solid was filtered and dried to give the subtitle compound (3.03 g).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[C:10](OC)([O:11]C)[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)[CH:2]=[CH2:3].O.C(O)(C(F)(F)F)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[CH2:1]([O:4][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1=O
Yield: 91.5 %

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 3-allyloxy-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (113a) (5.64 g, 18.7 mmol), a water/TFA mixed solution (1/1, 35 mL) and di-tert-butyl dicarbonate (4.8 g, 22 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 4.37 g of the title compound as a light brown oily substance (91%).
Reaction SMILES: Br.C[N+:3]1(CC2CC2)[C@@H:13]2[CH2:14][C:15]3[CH:20]=[CH:19]C(O)=C4O[C@H:7]5[C:8]([CH2:10]C[C@:12]2([OH:23])[C@:6]5([C:16]=34)[CH2:5][CH2:4]1)=O.[Br-].C1C2C[C@H]3N(CC4CC4)CC[C@]45[C@H](C(CC[C@@]34O)=O)[O:47]C(C=25)=C(O)C=1>>[NH2:3][C@H:13]([C:12]([OH:23])=[O:47])[CH2:14][C:15]1[CH:16]=[C:6]2[C:7]([CH:8]=[CH:10][CH:4]=[CH:5]2)=[CH:19][CH:20]=1
Reactant: C[N+]1(CC2CC2)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: Br
Agent: [Br-]
Product: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O

Procedure:
The entry for Example 4 in Table 3 represents the effect of the addition of acid (0.1 equiv. HBr). Incorporation of this reagent increased the yield of the product (naltrexone methobromide) to about 77.5% and decreased the side products to about 5.1%. Addition of HBr suppresses the ionization of the C(3) hydroxide (phenolic hydroxide) of naltrexone to form Nal (see Scheme 4) and thereby reduces the chemical reactivity of the C(3) hydroxide toward MeBr. Further, addition of a strong anhydrous acid (HBr) to the reaction system permits use of partially hydrated naltrexone (Naltrexone.2H2O) as a starting material instead of anhydrous naltrexone thereby eliminating the processing costs associated with dehydration of naltrexone. Since an additional reaction step is required to prepare anhydrous naltrexone from the hydrate (Naltrexone.2H2O), addition of HBr would reduce processing costs.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH2:24][C:25]2[N:26]=[C:27]([NH:30][C:31](=[O:39])[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[S:28][CH:29]=2)=[O:23])=[C:17]([F:40])[CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl>C(Cl)(Cl)Cl.CO>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:31]([NH:30][C:27]2[S:28][CH:29]=[C:25]([CH2:24][C:22](=[O:23])[NH:21][C:18]3[CH:19]=[CH:20][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:6](=[O:7])(=[O:8])[NH2:5])=[CH:16][C:17]=3[F:40])[N:26]=2)=[O:39])=[CH:37][CH:36]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)c(F)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)c(F)c1
Yield: 75.8 %

Procedure:
A solution of 163 mg N-{4-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-4-chloro-benzamide in 8 ml CHCl3/MeOH 3:1 was cooled to −10° C. A stream of HCl gas was passed over the stirred solution for 10 min. The reaction mixture was kept at 4° C. over night, then concentrated. The crude product was purified by chromatography on silica using a gradient from CH2Cl2 to CH2Cl2/MeOH 9:1 in 20 minutes to give 112 mg 4-chloro-N-{4-[(3-fluoro-2′-sulfamoyl-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-benzamide as white solid. MS 545.3 ([M+H]+)
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>C(O)C>[CH:16]1([NH:19][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CNC2CC2)CC1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A sealable reaction vessel was charged with 1,1-dimethylethyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (14.07 mmol), ethanol (70 mL) and cyclopropylamine (42.2 mmol). The vessel was purged with nitrogen, sealed and placed in a 75° C. oil bath for 20 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography (5% methanol in ethyl acetate). The appropriate fractions were concentrated under reduced pressure and dried to afford the title product (3.56 g, 94% yield) as a viscous colorless oil. MS(ES)+ m/e 271.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 4.20 (s, 1 H), 3.59 (d, J=12.6 Hz, 2 H), 3.05 (br. s., 2 H), 2.16-2.00 (m, 2 H), 1.49-1.31 (m, 14 H), 0.42-0.29 (m, 2 H), 0.24-0.13 (m, 2 H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21](Br)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Product: COc1ccccc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Yield: 17.6 %

Procedure:
Prepared similarly to the preparation of example 5.6.9 from 4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazine-1-carboxylic acid isopropyl ester (385.0 mg, 1.1 mmol) and 2-methoxyphenylboronic acid [5720-06-9] (191.8 mg, 1.3 mmol) to afford 76.4 mg of yellow powder as a free base, mp. 57-59° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.32 Hz, 6 H) 3.48-3.54 (m, 4 H) 3.68-3.77 (m, 4 H) 3.87 (s, 3 H) 4.77-4.85 (m, 1 H) 6.76 (d, J=7.83 Hz, 1 H) 6.94-7.07 (m, 2 H) 7.10-7.18 (m, 1 H) 8.38 (dd, J=7.71, 1.64 Hz, 1 H) 8.43 (s, 1 H) 8.71 (d, J=8.08 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 21.95, 44.07, 55.32, 68.14, 96.93, 101.10, 111.29, 120.48, 121.64, 125.83, 127.67, 136.28, 145.00, 154.31, 155.25, 155.51. LRMS (ESI) m/z 396.1 [(M+H)]+, calc'd for C21H26N6O3: 395.47.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[CH2:22]([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1)=[O:26])[CH3:23]
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: CCOC(=O)c1ccccc1B(O)O
Product: CCOC(=O)c1ccccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 272 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and 2-ethoxycarbonylphenylboronic acid. colorless oil (yield 12%).
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15][CH3:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl.O>[Br:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15]([CH3:16])=[O:25])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: CSc1cc(C)nc(S(C)=O)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a solution of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (100 mg,0.311 mmol) in chloroform (2 ml) was added a solution of m-chloroperbenzoic acid (50 mg, 0.327 mmol) in chloroform (0.5 ml), and stirred at room temperature for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:acetone=1:1) to provide 21.4 mg (yield 20%) of 2-bromo-N-[2(methanesulfinyl)-6-methyl-4-(methylthio)-3-pyridyl]acetamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C:13]2=[N:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22](I)[CH:21]=1.C([Li])CCC.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C@:13]2([C:24]3[CH:25]=[C:20]([Br:19])[CH:21]=[CH:22][C:23]=3[F:26])[NH:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Reactant: Fc1ccc(Br)cc1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)cc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (P1) (10.0 g, 40.4 mmol) in toluene (404 mL) was cooled down to −78° C. and then boron trifluoride-diethyl etherate (46.5%, 10.8 mL, 40.8 mmol) was added. The resulting solution was allowed to stir at the same temperature for 30 minutes, with fast stirring. After that time, 4-bromo-1-fluoro-2-iodobenzene (12.3 g, 40.8 mmol) was added to the reaction mixture, followed by the slow addition (temperature never varied more than 5° C.) of n-butyllithium (2.5 M in hexanes; 16.3 mL, 42.7 mmol). The resulting solution was allowed to stir at −78° C. for 90 minutes. At this time, a saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction mixture at −78° C. The reaction mixture was warmed to room temperature and partitioned between ethyl acetate (400 mL) and water (800 mL). The organics were separated and the aqueous layer was extracted with additional ethyl acetate (3×200 mL). The combined organics were then washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a clear oily residue. Purification via silica gel chromatography (Gradient: 10% to 70% ethyl acetate in heptane) afforded the product as an orange solid. Yield: 11.5 g, 27.1 mmol, 67%. 1H NMR (400 MHz, CD3OD) δ 8.01 (dd, J=6.9, 2.6 Hz, 1H), 7.47 (ddd, J=8.8, 4.4, 2.7 Hz, 1H), 7.38-7.28 (m, 4H), 7.07 (dd, J=11.6, 8.7 Hz, 1H), 4.58 (s, 2H), 4.10 (dd, J=11.6, 2.4 Hz, 1H), 3.82-3.78 (m, 2H), 3.72 (d, J=7.2 Hz, 1H), 3.61-3.55 (m, 2H), 3.52 (dd, J=8.8, 4.7 Hz, 1H), 3.16-3.10 (m, 1H), 1.86 (ddd, J=14.1, 7.0, 2.2 Hz, 1H), 1.59 (dtd, J=13.7, 11.8, 1.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])[CH:2]=[CH2:3].[Cl:10][SiH:11]([Cl:13])[Cl:12]>CCCCCC>[C:5]([O:4][CH2:1][CH2:2][CH2:3][Si:11]([Cl:13])([Cl:12])[Cl:10])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCOC(=O)C(=C)C
Solvent: CCCCCC
Product: C=C(C)C(=O)OCCC[Si](Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
There was added dropwise over a period of 30 minutes, 50 grams of allylmethacrylate to a mixture refluxing at 32° C. of 80.6 grams of trichlorosilane and 0.397 grams of a [SG]--S--Pt catalyst sufficient to provide 100 ppm platinum/SiH. The mixture was stirred an additional 2 hours at reflux, cooled to ambient temperature and diluted with 100 ml of hexane and filtered. There was obtained 47.7 grams of a clear, colorless oil upon concentration of the filtrate on a rotary evaporator. Based on method of preparation, NMR and VPC analysis there was obtained a 98% yield of γ-methacryloxypropyltrichlorosilane.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C@@H:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C@@H:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH3:11])=[C:4]([C:30]#[N:31])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])[CH3:46]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C@@H:7]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C@@H:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:51][CH2:50][CH2:49][C:48]([O:47][CH2:45][CH3:46])=[O:52])=[O:17])=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH3:11])=[C:4]([C:30]#[N:31])[CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)[C@@H](Oc1ccc(Br)cc1C#N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)[C@@H](Oc1ccc(Br)cc1C#N)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
The product from step A was dissolved in THF (10 mL) then CDI (1.018 g, 6.28 mmol) was added. After being stirred for one hour, β-alanine ethyl ester hydrochloride (560 mg, 6.28 mmol) was added, then the mixture was stirred overnight at RT. The mixture was diluted with EtOAc then washed with water then brine. The organic layer was dried over MgSO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.72 (d, J=2.5 Hz, 1H); 7.67 (d, J=8.5 Hz, 2H); 7.50 (dd, J=9.0, 2.5 Hz, 1H); 7.37 (d, J=8.0 Hz, 2H); 7.24 (d, J=8.0 Hz, 2H); 7.13 (d, J=8.5 Hz, 2H); 6.81 (d, J=9.5 Hz, 1H); 5.63 (d, J=6.0 Hz, 1H); 4.12 (q, J=7.5 Hz, 2H); 3.61 (t, J=7.0 Hz, 2H); 3.19 (m, 1H); 2.62 (t, J=7.0 Hz, 2H); 2.00-1.94 (m, 1H); 1.73-1.67 (m, 1H); 1.22 (t, J=7.5 Hz, 3H); 1.19-1.16 (m, 2H); 0.83 (t, J=7.0 Hz, 3H). LC2 2.38 min. (M+H)+ 597.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)([OH:3])=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>>[NH:17]([C:1](=[O:3])[CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Reactant: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CC(=O)Nc2ccccc2)cs1)C(=O)O

Procedure:
The title yellow resin (2.9 g) was obtained using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin synthesized in Example 461-4 and aniline as starting materials and by an operation similar to that of Example 461-5. A part of the resin was cleaved with trifluoroacetic acid and the structure was confirmed.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[Br:18][CH2:19][C:20](Cl)=[O:21]>C(OCC)C>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5])=[O:21]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=C(Cl)CBr
Solvent: CCOCC
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
To an iced solution of 266 g (1 mol) of 2-amino-2', 5-dichlorobenzophenone in 3 liters of ethyl ether there are added, drop by drop, 90 cc (1.1 mol) of bromacetyl chloride dissolved in 500 cc of ethyl ether. The batch is allowed to come to room temperature, whereupon it is evaporated to dryness and the crystalline residue extracted with petroleum ether and filtered. In this manner, 371 g of crystals are recovered.
Reaction SMILES: [Br-].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=CO[N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1.[Br:20][CH2:21][C:22]([NH:24]C1C=NC=CN=1)=O>>[Br-:20].[OH:2][C@@H:3]1[CH:8]2[CH2:7][CH2:6][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[N:24][CH:22]=[CH:21][N:15]=3)([CH2:10][CH2:9]2)[CH2:4]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Reactant: O=C(CBr)Nc1cnccn1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1

Procedure:
This compound is prepared by an analogous method to (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) by replacing 2-bromo-N-isoxazol-3-yl-acetamide with 2-bromo-N-pyrazin-2-yl-acetamide [H(i)].