Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH:14]1([C:12](=[O:13])[CH:11]([N:8]2[CH2:9][CH2:10][CH:5]([SH:4])/[C:6](=[CH:24]/[C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)/[CH2:7]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:16][CH2:15]1
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)/C(=C/c2ccco2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-[(furan-2-yl)methylidene]piperidine (100 mg) in methanol (2.5 ml) was added potassium carbonate (50 mg) under ice-cooling, and the resulting mixture was stirred at room temperature for 15 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified using a preparative HPLC [YMC-Pack ODS-A; YMC, mobile phase: a mixture of 70% methanol/water containing acetic acid (0.20%) and triethylamine (0.45%) (70:30, v/v)]. The eluted fraction containing the reaction product was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title compound (40 mg, yield: 45%) as pale brown crystals.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([C:25]3[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:32][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]([CH3:15])=[C:13]2[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccccc3C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)O)cc3ccc(F)cc23)cc1
Reaction time: 15 h
Yield: 55.7 %

Procedure:
To a solution of {6-fluoro-3-methyl-4-[4-(toluene-2-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (20 mg, 0.04 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (19.3 mg, 0.46 mmol) in water (1 mL) at room temperature. The resulting clear solution was stirred for 15 hours and then THF was removed under vacuum. Water (30 mL) was added and the mixture was acidified with 1.0N hydrochloric acid. The resulting solids were collected by filtration and washed with water and hexanes. After drying in air, {6-fluoro-3-methyl-4-[4-(toluene-2-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (10 mg, 52%) was isolated as off-white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.27 (d, J=7.9 Hz, 1 H), 8.04 (d, J=8.2 Hz, 2 H), 7.88 (dd, J=8.8, 6.0 Hz, 1 H), 7.81 (s, 1 H), 7.61 (t, J=7.5 Hz, 1 H), 7.48-7.55 (m, 1 H), 7.48 (d, J=8.2 Hz, 2 H), 7.40 (d, J=7.5 Hz, 1 H), 7.22 (td, J=8.8, 2.1 Hz, 1H), 6.65 (dd, J=11.2, 2.1 Hz, 1 H), 3.86 (s, 2 H), 2.52 (s, 3 H), 2.11 (s, 3 H). HRMS (ES−) calcd. for C26H20FO4S [(M−H)−] 447.1072, obsd. 447.1070.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](F)=[C:6]([CH3:8])[CH:7]=1.CN(C)C=O.[CH3:16][S-:17].[Na+]>O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([S:17][CH3:16])=[C:6]([CH3:8])[CH:7]=1
Reactant: C[S-]
Reactant: Cc1cc(Br)cc(C)c1F
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(C)cc(Br)cc1C
Temperature: 50 °C
Yield: 14.2 %

Procedure:
Add 5-bromo-2-fluoro-1,3-dimethyl-benzene (3.5 g, 17.2 mmol) to dimethylformamide (DMF, 30 mL) at ambient temperature followed by sodium thiomethoxide (1.32 g, 17.9 mmol). Heat at 50° C. for 8 hours and dilute with water (10 mL) and diethyl ether (100 mL). Separate the layers, wash the organics with brine, and dry with magnesium sulfate before concentrating to a residue. Chromatograph the residue on a SiO2 column eluting with diethyl ether (20%) in hexane to give 566 mg (14%) of 5-bromo-1,3-dimethyl-2-methylsulfanyl-benzene.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH2:2]([O:1][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:3]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCCCCCC(=O)OCC
Yield: 35.2 %

Procedure:
0.5 M sodium ethoxide (1.6 ml, 4.31 mmol) was added to a solution of ethyl 7-bromoheptanoate (300 mg, 1.44 mmol) in ethanol (7.0 ml), and the mixture was heated under reflux for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was then purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give ethyl 7-ethoxyheptanoate (102.4 mg, 40%).
Reaction SMILES: N1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2N=CC=C3)C=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:39]1[CH:43]=[C:42]([C:44]2[C:45]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:46][O:47][C:48]=2[CH3:49])[N:41]=[CH:40]1.IC1C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:49][C:48]1[O:47][N:46]=[C:45]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:44]=1[C:42]1[N:41]=[CH:40][N:39]([C:5]2[CH:14]=[CH:13][CH:8]=[CH:7][CH:6]=2)[CH:43]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Ic1ccccc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Temperature: 120 °C
Yield: 13.6 %

Procedure:
To a mixture of copper(I) trifluoromethanesulfonate benzene complex (12.3 mg, 0.22 mmol), 1,10-phenanthroline (79.5 mg, 0.44 mmol), dibenzylideneacetone (5.2 mg, 0.22 mmol) and cesium carbonate (144 mg, 0.44 mmol) was added a suspension of 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (149 mg, 0.6 mmol) in toluene (2 mL) followed by iodobenzene (90 mg, 0.44 mmol) and the resulting mixture heated at 120° C. for 2 days. After cooling to room temperature the resulting mixture was poured into aqueous ammonium chloride (saturated) and extracted with ethyl acetate. The organic extracts were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:1) afforded the title compound (18 mg, 13%) which was obtained as a light brown gum. MS: m/e=302.1 [M+H]+.
Reaction SMILES: [CH:1]([C@@:3]1([CH3:10])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1)=O.[Cl-].[CH3:12][O:13][C:14]1[C:39]([CH3:40])=[C:38]([CH3:41])[C:37]([O:42][CH3:43])=[C:36]([CH3:44])[C:15]=1[CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[CH3:43][O:42][C:37]1[C:38]([CH3:41])=[C:39]([CH3:40])[C:14]([O:13][CH3:12])=[C:15]([CH3:16])[C:36]=1[CH:44]=[CH:1][C@@:3]1([CH3:10])[CH2:7][O:6][C:5]([CH3:8])([CH3:9])[O:4]1
Reactant: CC1(C)OC[C@](C)(C=O)O1
Reactant: COc1c(C)c(C)c(OC)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: COc1c(C)c(C)c(OC)c(C=C[C@@]2(C)COC(C)(C)O2)c1C
Yield: 62.8 %

Procedure:
1.84 g of (R)-4-formyl-2,2,4-trimethyl-1,3-dioxolan, 11.0 g of 2,5-dimethoxy-3,4,6-trimethylbenzyl-triphenylphosphonium chloride and 3.3 g of finely ground anhydrous potassium carbonate were heated at reflux for 30 hours in 25 ml of dry acetonitrile (dried over phosphorus pentoxide and distilled over potassium carbonate) in the presence of 55 mg of 18-crown-6 (1,4,7,10,13,16-Hexa-oxo-cyclooctadecane) the suspension being vigorously stirred. Thereupon, the brown suspension was chromatographed on 400 g of silica gel with toluene-methyl acetate-pentane (20:3:3 parts by volume) as the elution agent. After bulb-tube distillation at 170° (bath temperature)/0.2 mmHg, there were obtained 2.57 g of (S)-4-(2,5-dimethoxy-3,4,6-trimethyl-styryl)-2,2,4-trimethyl-1,3-dioxolan as a colorless viscous oil; [α]D20 =+17.9° (c=2.1 in chloroform).
Reaction SMILES: [SH:1][CH2:2][CH:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[C:17](=O)([O-])[O-:18].[K+].[K+].O.C1N=CN(C(N2C=NC=C2)=O)C=1>C(#N)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:7]2[C@H:3]([C:4]([OH:6])=[O:5])[CH2:2][S:1][C:17]2=[O:18])=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CNC(CS)C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)O)cc1
Temperature: 40 °C

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with 3-mercapto-2-(4-methoxybenzylamino)-propionic acid (400.0 g, 1.66 mol), potassium carbonate (480.0 g, 3.47 mol) and 2.80 L of water. The mixture was heated at 40° C. with stirring until it became homogeneous and was then cooled to 20-25° C. A solution of N,N-carbonyldiimidazole (400.0 g, 222.47 mol) in 2.8 L of acetonitrile was added while maintaining an internal reaction temperature of less than 30° C. The reaction was monitored by HPLC and was complete upon the disappearance of starting material. The acetonitrile was removed by distillation at 40° C. and 80-100 torr. Iso-propyl acetate (200 mL) was added and the pH of the mixture was adjusted to 2 with 150 mL of 3M H2SO4. The biphasic mixture was filtered, separated and the organic layer azeotropically dried by distillation at atmospheric pressure. The final measured water content was less than 0.5%. The resulting solution was further diluted with 1.8 L of iso-propyl acetate and used in the next example. 1H NMR (300 MHz, DMSO) δ 7.15 (d, 8.3 Hz, 2H), 6.88 (d, 8.3 Hz, 2H), 4.52 (AB, JAB=15.5 Hz, ΔvAB=238.4 Hz, 2H), 4.31-4.24 (m, 1H), 3.71 (s, 3H), 3.67-3.59 (m, 1H), 3.36-3.28 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8].[OH-].[Na+]>C1COCC1>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1ccc(F)cc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCc1ccc(F)cc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-fluorobenzoic acid (2.0 g, 8.4 mmol) from Step 1 above in THF (25 mL) at 0° C. was added BH3.THF complex (25 mL of a 1.0 M solution in THF, 25 mmol). The mixture was stirred at 0° C. for 30 min and then at ambient temperature for 6 h. Aqueous NaOH (20 mL of a 4 N solution, 80 mmol) was added and the solvents were removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and water (2×50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 2-(2,2,2-trifluoroethoxy)-4-fluorobenzyl alcohol as an oil (HPLC retention time=7.3 min (method A)).
Reaction SMILES: C(C(=O)C([O-])=O)C.COC1C=CC(NN)=CC=1.C1C(=O)N(Cl)C(=O)C1.[CH2:26]1[CH2:32][C:30](=[O:31])[NH:29][CH2:28][CH2:27]1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(OC(=O)C)C>[N:39]1([C:32]2[C:30](=[O:31])[NH:29][CH2:28][CH2:27][CH:26]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: C1COCCN1
Reactant: O=C1CCCCN1
Agent: CCC(=O)C(=O)[O-]
Agent: COc1ccc(NN)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1NCCC=C1N1CCOCC1

Procedure:
Condensation of ethylglyoxalate with 4-methoxyphenyl hydrazine and chlorination with NCS afforded (4-Methoxy-phenyl)-chlorohydrazono]-acetic acid ethyl ester. Separately d-valerolactam was dichlorinated with PCl5 and treated with morpholine at reflux to afford 3-Morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one. [3+2] cycloaddition of the chlorohydrazone with the morpholine dihydropyridinone obtained above in refluxing toluene and triethylamine afforded the key intermediate 1-(4-Methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. Alkylation (with 4-bromo-butyrylacetate) followed by deprotection of the acetate group as outlined outlined in Example 32, and amidation of the ester with ammonia afforded the desired compound. Mass Spec 357.3(M−H)−.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][N:8]1[C:27](=[S:28])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=4)[S:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:29])C.CCCCCC>C(O)(C(F)(F)F)=O.O.C(OCC)(=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[S:15][C:16]3[CH:17]=[C:10]4[C:9](=[O:29])[N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[C:27](=[S:28])[N:11]4[C:12]=3[CH:13]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CCOC(=O)CCCN1C(=O)c2cc3sc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: O=C(O)CCCN1C(=O)c2cc3sc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Temperature: 70 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
Compound 31 (20 mg, 0.046 mmol) was dissolved in a mixture of TFA and water (4:1, 2 ml) and the resulting solution was heated at 70° C. for 5 hours, while monitoring the reaction progress by TLC using a 6:4 hexane:ethyl acetate mixture as eluent. The mixture was cooled to room temperature and left intact for one hour. The formed precipitate was thereafter filtered and washed with small portions of ethanol. The crude residue was recrystallized from ethanol to give pure Compound 32 (10 mg, 56% yield).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:10][F:11])=[CH:4][N:3]=1.O.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].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>[Cl:8][C:7]1[C:2]([C:13]#[N:14])=[N:3][CH:4]=[C:5]([O:9][CH2:10][F:11])[CH:6]=1
Reactant: FCOc1cnc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ncc(OCF)cc1Cl
Temperature: 145 °C

Procedure:
To a solution of 2,3-dichloro-5-fluoromethoxy-pyridine (1.18 g, 6.02 mmol) in dry DMF (14.00 ml) were added Zinc cyanide (0.341 g, 2.90 mmol) and Zinc powder (3.94 mg, 0.060 mmol). The suspension was flushed with Argon (3×). Then tetrakis(triphenylphosphine)palladium(0) (0.570 g, 0.494 mmol) was added. The reaction was heated to 145° C. for 2 h. Water was added and the aqueous layer was extracted twice with Et2O. The combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 7:3) to provide the title compound as yellow oil (515 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:19][C@@H:18]([C:20](=[O:36])[NH:21][C@:22]3([C:27](=[O:35])[NH:28][S:29]([CH:32]4[CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:24][C@H:23]3[CH:25]=[CH2:26])[NH:17][CH2:16]1)=[O:13])[CH2:7]2.[C:37]([O:41][C:42]([C@@H:44]([CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)[C:45](O)=[O:46])=[O:43])([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.O>[CH:32]1([S:29]([NH:28][C:27]([C@@:22]2([NH:21][C:20]([C@H:18]3[N:17]([C:45](=[O:46])[C@@H:44]([C:42]([O:41][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:43])[CH:48]4[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]4)[CH2:16][C@H:15]([O:14][C:12]([N:6]4[CH2:5][C:4]5[C:8](=[CH:9][CH:10]=[CH:11][C:3]=5[Cl:2])[CH2:7]4)=[O:13])[CH2:19]3)=[O:36])[CH2:24][C@H:23]2[CH:25]=[CH2:26])=[O:35])(=[O:31])=[O:30])[CH2:33][CH2:34]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)[C@@H](C(=O)OC(C)(C)C)C1CCCCC1)C(=O)NS(=O)(=O)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A 25 mL round-bottomed flask was charged with (3R,5S)-5-(((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate hydrochloride (0.500 g, 0.894 mmol), (S)-2-(tert-butoxycarbonyl)-2-cyclohexylacetic acid (276 mg, 1.07 mmol) and HATU (408 mg, 1.07 mmol) in dry DMF (9 mL). The solution was cooled on an ice-water bath and treated with DIEA (0.467 mL, 2.68 mmol) by dropwise addition. The mixture was stirred at 0° C. for 1 h, then allowed to warm up and stirred at room temperature for 16 h. The mixture was diluted with water (50 mL) and the pH adjusted to 3 with 1N HCl, the mixture was extracted with Et2O (3×20 mL). The combined organic extracts were then washed with 1N HCl (3×20 mL), water (3×20 mL) and brine (3×20 mL). The organic extract was then dried over MgSO4, filtered and concentrated. The crude material was the purified by chromatography (Biotage) eluting with 1-3% MeOH—CH2Cl2 to give the product as a white foam, (394 mg, 59%). MS m/e 662 (M+−Boc).
Reaction SMILES: S(=Cl)=O.[F:4][C:5]1[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[CH2:18]([CH:20]([CH2:23][CH3:24])[CH2:21]O)[CH3:19]>N1C=CC=CC=1>[F:4][C:5]1[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:21][CH:20]([CH2:23][CH3:24])[CH2:18][CH3:19])=[O:8]
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Reactant: CCC(CC)CO
Solvent: c1ccncc1
Product: CCC(CC)COC(=O)c1ccc(OC(C)=O)cc1F

Procedure:
Thionyl chlorine in an amount of 60 ml (milliliter) was added to 11.9 g (0.06 mol) of 2-fluoro-4-acetoxybenzoic acid, and the mixture was allowed to react under reflux for 7 hours. Then, excess thionyl chloride was distilled off, and then 10 ml of pyridine and 3.7 g (0.0402 mol) of 2-ethyl-1-butanol were dropwise added.
Reaction SMILES: [Na].Cl[C:3]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH3:16][OH:17]>>[CH3:16][O:17][C:3]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCc1cc(C(=O)OC)c(Cl)nc1C
Reactant: CO
Agent: [Na]
Product: CCc1cc(C(=O)OC)c(OC)nc1C
Yield: 73 %

Procedure:
To a solution of sodium metal (0.55 g, 24 mmol) dissolved in anhydrous methanol (15 mL), under a nitrogen atmosphere, was added a solution of methyl 2-chloro-5-ethyl-6-methylnicotinate (3.18 g, 14.9 mmol) in dry methanol (5 mL). This solution was refluxed and monitored by tlc (thin layer chromatogram) until the starting material had been consumed (about 24 hours). The cooled mixture was diluted with diethyl ether (50 mL), washed with water, saturated aqueous NaHCO3, dried (Na2SO4), filtered and the solvent evaporated to yield 2.28 g (73%) of pure product as a light yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7](S(C2C=CC(C)=CC=2)(=O)=O)[NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:2]=1>[I-].C[N+]1C(C)=C(CCO)SC=1>[O:16]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:7]([NH:8][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC(=O)c2ccccc2)c2ccncc2)cc1
Agent: Cc1c(CCO)sc[n+]1C
Agent: [I-]
Product: O=C(NC(C(=O)c1ccccc1)c1ccncc1)c1ccccc1
Temperature: 45 °C

Procedure:
A flask containing a mixture of N-(pyridin-4-yl(tosyl)methyl)benzamide, 66 (10.0 g), and 3,4-dimethyl-5-(2-hydroxyethyl)-thiazolium iodide (1.1 g) is flushed with nitrogen for 15 min. Dichloromethane (150 mL) and benzaldehyde are added and the solution heated to 45° C., then triethylamine (42 mL) is added. After heating for 16 h, the solution is cooled to room temperature and saturated aqueous sodium hydrogen carbonate is added. The layers are separated, the aqueous phase extracted with additional dichloromethane, and the combined organic layers are washed with brine. Drying (magnesium sulfate), filtration, concentration and chromatography furnished the title compound, 67 (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7]1.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([NH:21][NH2:22])=[O:14])[CH2:8][CH2:7]1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2cccc(Cl)c2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2cccc(Cl)c2)CC1

Procedure:
Synthesized according to General Procedure C: 6{8} (6.78 g, 22.8 mmol, 1 equiv.), anhydrous hydrazine (2.9 mL, 91.4 mmol, 4 equiv.), ethanol (31.4 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{8} (5.04 g, 78%) as a light yellow oil. 1H-NMR (500 MHz, CDCl3): δ 8.15 (br s, 1H), 7.27 (br s, 1H) 7.21-7.12 (m, 3H), 3.82 (br s, 2H) 3.42 (s, 2H), 3.03 (s, 2H), 2.49 (br s, 4H), 2.41 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 140.0, 134.0, 129.3, 128.8, 127.1, 126.9, 62.0, 60.4, 53.4, 52.8.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[CH3:12][CH:13]([C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](OCC)=[O:15].C(O)(C(F)(F)F)=O.O>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14](=[O:15])[CH:13]([CH3:12])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:11]1
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2Cl)C(=O)C1C
Temperature: 75 °C

Procedure:
2,4-dichlorophenylhydrazine hydrochloride(12.6 g) is dissolved in 100 ml of toluene and this solution is placed under nitrogen; after stirring, 10 g of diethyl 2-methyl-3-oxosuccinate are added and the mixture is then heated and 5 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 30 ml of water. The mixture is separated by settling out, the aqueous phase is discarded and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 10 ml of toluene and the expected product then crystallizes, m=10.2 g.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1.C(OC=C)(=O)C>C(OC(C)C)(C)C>[OH:1][CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(CO)c3ccccc32)cc1
Solvent: CC(C)OC(C)C
Solvent: C=COC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CO)c3ccccc32)cc1
Reaction time: 1.5 h

Procedure:
5-Hydroxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (9.94 g) is dissolved in diisopropyl ether (150 ml), and thereto are added with stirring vinyl acetate (7.75 g) and Lipase QL (8%) (0.80 g) at -2° C. The mixture is stirred at -2° C. to 1° C. for 1.5 hour. The Lipase QL is removed by filtration on celite, and the filtrate is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:1→1:1) to give (5S)-5-hydroxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (hereinafter, referred to as Compound C) (4.54 g) and (5R)-5-acetyloxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (hereinafter, referred to as Compound D) (5.63 g).