Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][CH:43]=[CH:42][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][CH2:30][O:31]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH:55][C:56](=[O:58])[CH3:57])=[C:49](O)[CH:48]=1>>[C:56]([NH:55][CH2:54][CH2:53][C:50]1[CH:49]=[CH:48][C:47]([F:46])=[CH:52][C:51]=1[O:31][CH2:30][CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:42]=[CH:43][CH:44]=[CH:45][C:2]=3[Cl:1])=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)(=[O:58])[CH3:57]
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOc3ccccc3Cl)cc2)cc1
Reactant: CC(=O)NCCc1ccc(F)cc1O
Product: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOc2ccccc2Cl)cc1

Procedure:
Analogously to Method G, 0.28 g of tert-butyl 4-{4-[3-(2-chlorophenoxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 0.17 g of N-[2-(4-fluoro-2-hydroxyphenyl)ethyl]acetamide (Example 112b) are reacted. The title compound is obtained as a yellow oil. Rf=0.58 (EtOAc); Rt=5.74.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[C@H:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[OH:15].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].Cl>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[OH:15][C@H:14]([C:13]([O:23][CH2:24][CH3:25])=[O:22])[C@H:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)C[C@H](O)C(=O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](O)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
31 ml of 1.69M hexane solution of n-butyllithium was dissolved in 30 ml of tetrahydrofuran, and 7.1 ml of diisopropylamine was added under cooling with ice. The resulting solution was stirred at the same temperature for 30 minutes and then cooled to -78° C. 4.94 g of diethyl (S)-malate in 20 ml of tetrahydrofuran was added dropwise at or below -50° C., and the resulting reaction solution was stirred at -20° C. for 1.5 hours. The reaction solution was cooled to -78° C., and a solution of 5.58 g of tert-butyl bromoacetate and 4.66 g of hexamethylphosphoric triamide in 20 ml of tetrahydrofuran was added dropwise at or below -50° C. The resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into 150 ml of 0.5N hydrochloric acid and extracted with diethyl ether, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1→4/1] to give 3.88 g of the title compound as a yellow oily substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:38]=[C:37]3[C:33]([CH2:34][C:35](=[O:39])[NH:36]3)=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)[CH3:22]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:34]1[C:33]2[C:37](=[CH:38][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=3)=[CH:31][CH:32]=2)[NH:36][C:35]1=[O:39])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-(3-ethoxyphenyl)-2-oxindole (304 mg), and piperidine (2 drops) in ethanol (5 mL) were held at 90° C. overnight. The precipitate that formed was filtered, washed with ethanol. The precipitate, an orange solid, was stirred with potassium hydroxide (4 pellets) in ethanol (3 mL) at 90° C. for 2.5 hours. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 370 mg of 4-(2-Carboxyethyl)-5-[6-(3-ethoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.[N:16]1([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([CH:22]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]3)[CH2:17][CH2:18]2)=[O:13])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(I)cc1NCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetic acid (2.0 g, 5.88 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.84 g, 7.64 mmol), EDCI.HCl (2.26 g, 11.76 mmol), and HOBt (1.59 g, 11.76 mmol) in DMF (3 mL) at 0° C., Et3N (3.28 mL, 23.52 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed by a mixture of ethyl acetate/petroleum ether=1:5 to afford the desired product (2.24 g, 67% yield) as a white solid. ESI-MS m/z: 565.4[M+H]+.
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:13][C@:14]1([C:19]([OH:21])=[O:20])[CH2:16][C@H:15]1[CH:17]=[CH2:18])=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:13][C@:14]1([C:19]([OH:21])=[O:20])[CH2:16][C@H:15]1[CH:17]=[CH2:18]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C[C@@H]1C[C@]1(N)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropanecarboxylic acid (1135 mg, 5 mmol) and methylene chloride (5 mL), and the mixture was stirred at 25° C. for 3 hours. When triethylamine (708 mg, 7 mmol) was added thereto, a solid was precipitated. The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes. Thereafter, the solid was separated by filtration under reduced pressure. The solid was washed with methylene chloride (5 mL), and then was subjected to vacuum drying. Thereby, the titled compound was produced as a white solid (665 mg, yield of 100%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[C:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1>CC(O)=O.O=[Pt]=O>[CH3:1][C@@H:2]1[CH2:6][C:5]2[C:7]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1
Reactant: Cc1cc(N)c2c(c1-c1ccncc1)C[C@@H](C)O2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1cc(N)c2c(c1C1CCNCC1)C[C@@H](C)O2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[The mixture of (R)-2,5-dimethyl-4-(pyridin-4-yl)-2,3-dihydrobenzofuran-7-amine (3h) (0.60 g, 2.4 mmol), PtO2 (240 mg, 35%) and TEA (0.38 mL, 4.9 mmol) in HOAc (40 mL) was introduced H2 and stirred for 24 h at ambient temperature (88 psi). The mixture was filtered, concentrated, and diluted with EtOAc (50 mL). A solution of ammonium hydroxide was added until pH=10, then extracted with EtOAc (150 mL), washed with water, brine, dried and concentrated to give the title compound (3i) as a yellow oil. MS-ESI (m/z): 247 (M+1)+.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21](=[O:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([OH:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium borohydride (50 mg, 1.3 mmol) was added to a solution of methyl 13-cyclohexyl-6,7-dihydro-6-oxo-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (29 mg, 0.074 mmol) in methanol (4 mL) and tetrahydrofuran (2 mL) at rt. The evolution of H2 was instantaneous and stirring was continued for 30 min at rt. The mixture was concentrated on a rotary evaporator and and the residue purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (27.5 mg, 96%). ESI-MS m/z 390 (MH+); 1H NMR (500 MHz, CHLOROFORM-D) δ 1.18-1.31 (m, 1 H) 1.32-1.53 (m, 2 H) 1.60-1.70 (m, 1 H) 1.71-1.84 (m, 2 H) 1.86-2.18 (m, 4 H) 2.38-3.12 (m, 3 H) 3.36-3.83 (m, 1 H) 3.94 (m, 3 H) 4.39-4.68 (m, 2 H) 7.32-7.48 (m, 4 H) 7.76 (t, J=8.39 Hz, 1 H) 7.88 (t, J=8.09 Hz, 1 H) 8.14 (m, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.C([SiH](CC)CC)C.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(C(=O)Cc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CCc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
To a solution of R)-2-(4-phenylacetyl-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.16 mmol) in TFA (1.0 mL) was added triethylsilane (0.2 mL, 0.9 mmol) at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 16 h. The mixture was poured onto 20 mL ice-water solution, neutralized with aq NaOH (2N) to pH=6-7, and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL) and brine (20 mL) and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product (25 mg, 82%); LCMS; 99%, ESI+, Calcd: 281.4. Found m/z: 282.6 M+1). 1H NMR (400 MHz, CDCl3,); δ 1.54-1.61 (m, 1H), 1.74-1.84 (m, 2H), 1.90-1.99 (m, 1H), 2.84-3.07 (m, 6H), 3.49-3.52 (m, 1H), 3.83-3.92 (m, 2H), 6.82 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.16-7.20 (m, 3H)-7.34 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CN(C)C=O>[CH3:19][S:20]([N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1)(=[O:22])=[O:21]
Reactant: Cc1c[nH]c2c1C(=O)CC(c1cccs1)C2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1cccs1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a suspension of 60% sodium hydride (0.11 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydroindol-4-one (0.60 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.36 g) in dimethylformamide (2 ml), and the mixture was stirred at the same temperature for 14 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methanesulfonyl-3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydroindol-4-one (0.28 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C@@H:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][C@@H:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:29])([F:40])[F:41])[CH3:38])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@H](O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, 4.45 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate and 3.02 g of (1S)-1-[2-(trifluoromethyl)phenyl]ethanol are dissolved in 140 ml anhydrous dichloromethane. 7.07 g triphenylphosphine (polymer bound, ˜3 mmol/g) and 4.88 g of di-tert-butyl azodicarboxylate are added. The reaction mixture is stirred at room temperature for 90 minutes and then filtered. The filter cake is washed with 10 ml dichloromethane and 10 ml methanol. The filtrate is concentrated to dryness under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:7]#[N:8])([O-:3])=[O:2].[ClH:15].[CH2:16]([OH:18])[CH3:17]>>[ClH:15].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:7](=[NH:8])[O:18][CH2:16][CH3:17])([O-:3])=[O:2]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
Ethyl 3,5-dinitrobenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, 3,5-dinitrobenzonitrile (25.2 g, 0.130 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 34.5 g (96%) of the target compound as pale-brown crystals.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.[Br:13]N1C(=O)CCC1=O>OS(O)(=O)=O>[Br:13][C:9]1[CH:10]=[C:2]([C:1]([OH:12])=[O:11])[CH:3]=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)cc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of isophthalic acid (10 g, 60.24 mmol, 1.00 equiv) in 98% H2SO4 (60 mL). This was followed by the addition of N-bromosuccinimide (12.80 g, 72.32 mmol, 1.20 equiv), in portions at 60° C. in 10 min. The resulting solution was stirred overnight at 60° C. in an oil bath. The reaction was cooled to room temperature and then quenched by the addition of water/ice. The solids were collected by filtration, and washed with 2×60 mL of hexane. The solid was dried in an oven under reduced pressure. The crude product was purified by re-crystallization from ethyl acetate to give 3 g (20%) of 5-bromoisophthalic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:39]=1[C:40](Cl)=[O:41]>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:40]([C:39]2[C:38]([Cl:37])=[CH:46][CH:45]=[CH:44][C:43]=2[Cl:47])=[O:41])=[CH:24][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[S:7]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCNC(C)=O)CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)C1(CCNC(C)=O)CCCC1
Yield: 106.7 %

Procedure:
To a solution of 4-amino-N-[[1-[2-(acetylamino)ethyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (195 mg, 0.498 mmol) and diisopropylethylamine (0.0950 mL, 0.548 mmol) in dichloromethane (1 mL) was added a solution of 2,6-dichlorobenzoyl chloride (110 mg, 0.523 mmol) in dichloromethane (1 mL). The resultant mixture was stirred overnight then was concentrated in vacuo and transferred to a separatory funnel containing ethyl acetate (50 mL) and water (10 mL). The separated aqueous layer back-extracted with ethyl acetate (1×25 mL). The combined organic layer was washed in turn sat. solution of Na2CO3 and brine, then was dried over MgSO4, filtered and concentrated in vacuo to provide crude N-[[1-[2-(acetylamino) ethyl]cyclopentyl]thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (300 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9]>ClCCl>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9]
Reactant: COC1CCCC[C@H]1O
Solvent: ClCCl
Product: COC1CCCC[C@@H]1O

Procedure:
A 500-ml four-mouth flask equipped with a thermometer, dropping funnel, condenser, and stirrer was charged with 47.8 g (0.13 mol) of diparatoluoyl-L-tartaric acid anhydride, 13.0 g (0.1 mol) of (RS)-2-methoxycyclohexanol, 1.2 g of anhydrous iron trichloride, and 300 ml of toluene. After heating under reflux for 10 hours, the reaction solution was analyzed by liquid chromatography. The result of analysis indicated the formation of diparatoluoyl-L-tartaric acid-mono(2-methoxy)cyclohexyl ester (92%). Time for peak detection was 35 minutes in the case of (R)-2-methoxycyclohexanol ester and 37 minutes in the case of (S)-2-methoxycyclohexanol ester. Diparatoluoyl-L-tartaric acid anhydride remaining unreacted was filtered off, and the filtrate was concentrated and subjected to column chromatography (using a column filled with silica gel “Kieselgel 60”, 60-230 mesh, made by Merck). Chromatographic separation was carried out by using a mixture of acetonitrile and cylohexane in varied ratios. There was obtained 9.5 g of diparatoluoyl-L-tartaric acid-mono(R)-2-methoxycyclohexyl ester in the first eluate. Analysis by liquid chromatography indicated that the ester is composed of (R)-form and (S)-form in a ratio of approximately 99/1. This compound was hydrolyzed by 30 ml in 1N aqueous solution of sodium hydroxide at 30° C. for 5 hours with stirring. The hydrolyzate was extracted three times with 100 ml of dichloroethane. The extract was concentrated to give 2.8 g of concentrated solution containing (R)-2-methoxycyclohexanol. The concentrated solution was distilled under reduced pressure (2.6 kPa) to give 2.2 g of distillate having an angle of rotation of −75° (c=2.10 in dichloromethane). The last eluate obtained by chromatographic separation was treated in the same manner as above to give 2.1 g of (S)-2-methoxycyclohexanol having an angle of rotation of +74° (c=2.00 in dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].[C:29]([N:32]1[C@H:36]([C:37](O)=[O:38])[CH2:35][S:34][CH2:33]1)(=[O:31])[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][C:37]([C@@H:36]1[CH2:35][S:34][CH2:33][N:32]1[C:29](=[O:31])[CH3:30])=[O:38])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Reactant: CC(=O)N1CSC[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)[C@@H]1CSCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 301 mg (0.77 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 7.5 ml of dichloromethane, 135 mg (0.77 mmol) of (R)-3-acetylthiazolidin-4-carboxylic acid, 342 mg (0.77 mmol) of BOP reagent and 0.15 ml (0.86 mmol) of N,N-diisopropylethylamine were added, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 10 ml of semi-saturated saline was added, and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with 0.5M hydrochloric acid, with saturated aqueous sodium hydrogen carbonate solution and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to obtain 309 mg of 2-(((R)-3-acetylthiazolidin-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 73%).
Reaction SMILES: CC1C=CC(S(N[C@H](C[C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])C)(=O)=O)=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:30][N@@:29]2[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)(=[O:33])=[O:32])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:29][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)(=[O:33])=[O:32])[CH2:30][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)[N@]1CC1c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)CC#C[Si](C)(C)C)cc1
Agent: O=S(=O)(c1cccc(C(F)(F)F)c1)[N@@]1CC1c1ccc(F)cc1
Product: C[Si](C)(C)C#CC[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1

Procedure:
Proceeding as described for (51), but using (S)-2-(4-fluorophenyl)-1-(3-(trifluoro-methyl)benzenesulfonyl)aziridine afforded (R)—N-(1-(4-fluorophenyl)-4-(trimethylsilyl)but-3-ynyl)-3-(trifluoromethyl)benzenesulfonamide (53). MS (m/z): 444.3 (M+H) (Calc'd for C20H21F4NO2SSi: 443.54).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][C:4]2[C:5](=[O:19])[O:6][C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=3[C:9]=2[CH3:10])[CH2:33][CH2:34]1)[CH3:21]
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Reactant: CCOc1ccccc1N1CCNCC1
Product: CCOc1ccccc1N1CCN(CCc2c(C)c3c(OC)cc(OC)cc3oc2=O)CC1
Yield: 31 %

Procedure:
Process B: starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 1-(2-ethoxyphenyl)piperazine; yield 31% of crude product.