Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[C:4]([C:9]([CH3:15])=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[NH4+].O>CO.[Fe]>[NH2:12][C:10]1[C:9]([CH3:15])=[C:4]([C:3]([F:16])=[C:2]([Br:1])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)c([N+](=O)[O-])cc(Br)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C)c(N)cc(Br)c1F
Temperature: 70 °C
Yield: 102.3 %

Procedure:
To a solution of methyl 3-bromo-2-fluoro-6-methyl-5-nitrobenzoate (2.43 g, 8.32 mmol) in Methanol (80 ml) at room temperature was added ammonium chloride (4.37 g, 83.2 mmol) followed by deionized Water (40 ml). The mixture was heated to 70° C. in air before the addition of iron (2.79 g, 49.92 mmol). The reaction turned brown over the 2.5 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (80 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3 (aq) (50 ml) and EtOAc (150 ml). The phases were separated and the organic phase was washed with saturated NaHCO3 (aq) (50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 2.23 g (95%, 77% corrected yields) of methyl 3-amino-5-bromo-6-fluoro-2-methylbenzoate as a yellow oil. The material was taken through the next step without further purification. LC-MS 81%, 1.87 min (3 minute LC-MS method), m/z=261.9/263.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 6.89 (d, J=6.0 Hz, 1H), 3.94 (s, 3H), 3.60 (s, 2H), 2.08 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH3:10]O>>[CH3:10][O:8][C:7]([C@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][NH:5]1)=[O:9]
Reactant: CO
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Product: COC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 0 °C

Procedure:
Cis-4-Hydroxy-D-proline (15 g, 115 mmol) was suspended in 150 mL anhydrous methanol under an argon atmosphere, then cooled to 0° C. before bubbling in HCl gas for 15 minutes. The solution gradually became homogenous. The argon and HCl gas lines were removed and the solution was refluxed for 4 h. The solution was cooled and then concentrated under reduced pressure. The crude material was redissolved in 100 mL methanol and diethyl ether was added until a precipitate formed. The precipitate was filtered off, washed with diethyl ether, and dried in vacuo overnight to reveal 1 (20 g, 95%) as a white solid. MS: APCI (AP+): 146 (M)+.
Reaction SMILES: C1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:12]C=O)=CN=1.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:12][C:11]#[C:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: O=CC=Cc1cncc2ccccc12
Reactant: Nc1nc2c(s1)CCNCC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc2c(s1)CCN(CC#Cc1ccccc1)CC2

Procedure:
Prepared from 3-(4-isoquinolinyl)acrolein and 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine by reductive amination with sodium cyanoborohydride (in methanol in the presence of I equivalent of glacial acetic acid). The crude product is purified by column chromatography on silica gel (acetone/methanol/conc. ammonia =50:12:0.5). At first the title compound (A) is eluted. Yield: 4% of theory, Melting point: 205°-208° C. (ether).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:10][CH2:11]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
Representative sulfonation (Step 1A): To a stirred solution of 1-(3-(trifluoromethyl)phenyl)piperazine (300 mg, 1.3 mmol) and 4-methylbenzene-1-sulfonyl chloride (248 mg, 1.3 mmol) in anhydrous dichloromethane (3 mL) was added diisopropylethylamine (0.27 mL, 1.6 mmol). The mixture was stirred overnight. Reaction was complete as determined by TLC. The reaction mixture was purified with flash column chromatography to yield 1-(4-methylphenylsulfonyl)-4-[3-(trifluoromethyl)phenyl]piperazine in 81% yield (405 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[CH3:11][O-:12].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:11])[CH:9]=1)[C:5]#[N:6]
Reactant: C[O-]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)cc(C#N)c1
Yield: 35.5 %

Procedure:
In a 250 ml round bottom flask equipped with stir bar added 3,5-Difluorobenzonitrile (4.2 g, 30.4 mmol), sodium methoxide (10.4 ml, 45.6 mmol, 25% methanol) and dimethylformamide (40 ml). Stirred the resulting reaction mixture at room temperature, overnight. The reaction mixture was concentrated in-vacuo and residue was dissolved in dichloromethane (200 ml). The organic phase was washed sequentially with water (150 ml) and brine (150 ml), dried (sodium sulfate) and concentrated in-vacuo. The crude residue was purified on silica gel using 10% diethyl ether in hexanes to isolate 3-Fluoro-5-methoxybenzonitrile (1.63 g) as a white solid.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30]Cl)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[CH2:1]([S:8][CH2:30][C:25]1[C:22]2[CH2:23][CH2:24][N:18]([C:16]([O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:17])[CH2:19][CH2:20][C:21]=2[CH:28]=[CH:27][C:26]=1[Cl:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSCc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.9 %

Procedure:
Dissolve benzylmercaptan (230 mg, 1.84 mmol) in anhydrous DMF (5 mL). Add sodium hydride (100 mg, 2.5 mmol, 60% dispersion in mineral oil) and stir the mixture for 10 min. Add then a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (550 mg, 1.67 mmol) in anhydrous DMF (1 mL). Stir under nitrogen at room temperature overnight. Pour reaction mixture into water (150 mL) and extract with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate in vacuo to afford crude 6-benzylthiomethyl-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (1.13 g) suitable for use without additional purification.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C[Si]([C:15]#[N:16])(C)C.[I-].[CH3:18][CH2:19][O:20]CC>>[CH2:19]([O:20][C:15]([C:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[NH:16])[CH3:18]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCc2ccccc21
Reactant: CCOCC
Agent: [I-]
Product: CCOC(=N)C1(O)CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 100 ml ethereal solution of 1-indanone (20.0 g, 0.152 mol) (Aldrich), trimethylsilyl cyanide (21.9 g, 0.22 mol) (Silar), and zine iodide (0.200 g, 0.001 mol) was kept at 20° C. for four days then diluted with 250 ml ether and washed with 5% sodium bicarbonate (2×100 ml). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to a residue of the desired trimethylsilyl cyanohydrin and was used directly in the next step. This oily residue was dissolved in 100 ml ethanol and perfused with anhydrous hydrogen chloride while cooling at 0° C. After a 30 minute perfusion period the flask was stoppered and allowed to come to room temperature overnight. The mixture was poured into 200 ml of ice water and extracted with ethyl acetate (2×100 ml). The aqueous phase was layered with ethyl acetate, cooled to 0° and basified with 6 N sodium hydroxide. The separated basic layer was extracted with (2×100 ml) ethyl acetate. The three ethyl acetate portions were pooled, dried over magnesium sulfate, filtered, and evaporated in vacuo to an oily solid residue, 3.59 g (12%). Crystallization from hexane gave a solid which slowly melted at room temperature.
Reaction SMILES: O[C@H:2]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(C)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl>[N:47]([C@@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:25](=[CH:30][CH:31]=1)[C:26](=[O:29])[O:27][CH2:28]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1)=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1=C(N2CCC3(CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=C(N2CCC3(CCN(C[C@@H](N=[N+]=[N-])c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 35 °C
Reaction time: 20 h

Procedure:
To a suspension of 8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 7, 300 mg, 0.68 mmol) and diphenylphosphoryl azide (578 mg, 1.36 mmol) in a mixed solvent of toluene and dichloromethane (v:v, 10:1, 11 mL) was added DBU (310 mg, 1.36 mmol). The reaction mixture was stirred at 35° C. for 20 h. The solvent was removed by evaporation and the residue was purified by flash column chromatography (0-100% ethyl acetate in petroleum ether gradient) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 5.20 (s, 2H), 5.18 (s, 2H), 4.94 (dd, J=4.0 Hz, 9.2 Hz, 1H), 3.94 (t, J=6.8 Hz, 2H), 2.88-2.85 (m, 2H), 2.72-2.67 (m, 1H), 2.54-2.50 (m, 1H), 2.42-2.39 (m, 1H), 2.33-2.27 (m, 4H), 2.04 (t, J=6.8 Hz, 2H), 1.95 (s, 3H), 1.94-1.87 (m, 2H), 1.51-1.47 (m, 2H); MS-ESI (m/z): 466 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[CH:20]=1)=O>C(O)C>[Cl:25][C:21]1[CH:20]=[C:19]([C:17](=[O:16])[CH:8]([C:9]#[N:10])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:24]=[CH:23][N:22]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: N#CCc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C(=O)c1ccnc(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Fluorophenylacetonitrile (11.13 g, 82 mmol) was dissolved in absolute ethanol (100 ml) and sodium ethoxide (21 wt % in EtOH) (46 ml, 123 mmol) was added in one portion. The resulting brown solution was stirred for 10 min. at room temperature. A solution of 2-chloropyridine-4-carboxylic acid methyl ester (14.1 g, 82 mmol) in absolute ethanol (100 ml) was then added to the reaction over 3-5 min. The reaction mixture was then refluxed for 2 h during which time the color turned to dark brown. The reaction mixture was concentrated in vacuo and water (100 ml) was added to the resulting residue. The pH of the reaction mixture was adjusted to 3 using 10% hydrochloric acid. The product was extracted with ethyl acetate and the combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo to yield 1-(2-chloropyridin-4-yl)-2-cyano-2-(4-fluorophenyl)ethanone as a dark brown solid which was used without further purification (22.0 g).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].ClCCCl.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:20]=[C:21]([CH2:25][C:26](Cl)=[O:27])[CH:22]=[CH:23][CH:24]=1>O>[F:17][C:18]([F:29])([F:30])[C:19]1[CH:20]=[C:21]([CH2:25][C:26]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(C(=O)Cc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anisole (32.4 g) and aluminium trichloride (36.0 g) are added to 1,2-dichloroethane (240 ml). The mixture is cooled to -5° and (3-trifluoromethylphenyl)-acetyl chloride (66.8 g) is slowly added. The mixture is stirred for 11/2 hours and poured into a mixture of crushed ice (400 g) and water (150 ml). After heating to room temperature, the compound is extracted with ether (3×200 ml). The combined organic phases are washed with a 2% aqueous solution of sodium hydroxide (200 ml and with water (3×200 ml), dried over magnesium sulphate and the solvents are removed in vacuo. The residue is recrystallised from hexane. The product is dried in vacuo to constant weight to yield 2-(3-trifluoromethylphenyl)-1-(4-methoxyphenyl)-ethanone, m.p. 94°-95°.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([CH:29]1[CH2:38][CH2:37][C:32]2[N:33]=[C:34]([NH2:36])[S:35][C:31]=2[CH2:30]1)=[O:28])C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:36][C:34]3[S:35][C:31]4[CH2:30][CH:29]([C:27]([O:26][CH3:24])=[O:28])[CH2:38][CH2:37][C:32]=4[N:33]=3)=[O:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCc2nc(N)sc2C1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C1CCc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2C1
Yield: 41.1 %

Procedure:
The compound of example A6 was obtained by similar method described in example A1 using 2-(4-cyclopropanesulfonyl-phenyl)-2-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 4, 0.340 g, 1.0 mmol), 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester (Preparation 49; 0.286 g, 1.0 mmol), HOBt (0.162 g, 1.2 mmol), and EDCl (0.229 g, 1.2 mmol), N-methyl morpholine (0.36 g, 3.58 mmol) in DMF (6 mL) to provide the title compound (0.22 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:17]([OH:19])=[O:18].[CH:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:34]=[C:35]([C:36]([O:38][CH3:39])=[O:37])[C:28]=12)=O>C(Cl)Cl>[C:43]([O:42][C:40]([N:33]1[C:29]2=[N:30][CH:31]=[CH:32][C:27]([CH2:25][NH:15][C@H:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:17]([OH:19])=[O:18])=[C:28]2[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: NC(CC(F)(F)F)C(=O)O
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(F)(F)F)C(=O)O)c12
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol), 2-amino-4,4,4-trifluorobutanoic acid (51.6 mg, 0.329 mmol) and DCM (2 mL). The reaction mixture was stirred for 30 min after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture was concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C19H22F3N3O6, 446; found, 446.5.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([C:35]#[CH:36])[NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:34])/[CH:19]=[CH:20]\[CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])C.CCO.O>O1CCCC1>[NH:24]1[CH2:23][CH2:22][CH:21](/[CH:20]=[CH:19]\[C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([NH:9][C@H:8]([C:35]#[CH:36])[CH2:7][C:6]([OH:37])=[O:5])=[O:11])[CH2:13]2)=[O:34])[CH2:26][CH2:25]1
Reactant: C#C[C@H](CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)/C=C\C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)/C=C\C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
1N aqueous LiOH (3.0 ml) was added to a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(Z)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine ethyl ester (1.0 g) in tetrahydrofuran (5 ml)-EtOH (5 ml) at 0° C. The reaction mixture was stirred for 2 hours at room temperature, then water was added, and the whole was washed with diethyl ether. The aqueous layer was made acidic with 20% aqueous KHSO4, and extracted with ethyl acetate. The organic layer was dried over MgSO4, evaporated in vacuo. The residue was dissolved in ethyl acetate (10 ml) and 4N HCl in ethyl acetate (5.1 ml) was added. The reaction mixture was stirred for 2 hours and diethyl ether was added. The precipitates were collected with filtration and dissolved with water. The solution was neutralized with saturated aqueous NaHCO3 and purified by HP-20 resin eluting with isopropanol/water=(0-30%) to give N-[(R)-1-[3-(4-piperidyl)-(Z)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (0.5 g, 67.8%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:13]1[CH2:24][OH:25])([CH3:9])[CH3:8].C(N(CC)CC)C>>[CH3:9][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@@H:13]1[CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:6])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (3.85 mL, 39.29 mmol) was added to an ice cold methylene chloride solution of 1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl) (dimethyl)silyl]oxy}-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (6.05 g, 26.19 mmol) and triethylamine (7.28 mL, 52.38 mmol). The reaction was warmed to room temperature, stirred for 16 hours then concentrated under reduced pressure. The crude material was dissolved in ethyl acetate and washed with saturated NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to give the title compound as a yellow oil. (4.69 g, 11.4 mmol). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.1 (s, 6 H) 0.8 (s, 9 H) 1.4 (m, 9 H) 1.7 (m, 1 H) 2.0 (m, 1 H) 3.2 (s, 3 H) 3.3 (m, 2 H) 3.7 (m, 1 H) 4.0 (m, 1 H) 4.2 (m, 1 H) 4.3 (m, 0.1 H). ES+=410.16.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH3:27]I>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:27])[C@H:10]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1NCCc1ccccc1
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(Cc2ccccc2)C[C@H]1NCCc1ccccc1
Temperature: 0 °C

Procedure:
17.3 g (58 mmol) of crude trans-1-benzyl-3-benzylmethylamino-4-hydroxy-pyrrolidine in 80 ml of absolute tetrahydrofuran are added dropwise to 2.8 g (93.3 mmol) of 80% strength sodium hydride in 40 ml of absolute tetrahydrofuran and the mixture is heated under reflux at the same time. When the evolution of hydrogen has ended, 8.7 g (61 mmol) of methyl iodide are added dropwise and the mixture is then heated under reflux overnight. It is poured into ice-water and extracted with toluene, the extracts are dried with K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH2:20]O)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.S(Cl)([Cl:26])=O>C(Cl)Cl>[Cl:26][CH2:20][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=1
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(Oc2ccc(CCl)cc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.7 %

Procedure:
To a suspension of (3-(trifluoromethyl)-4-{[3-(trifluoromethyl)phenyl]oxy}phenyl) methanol (300 mg, 0.892 mmol) in DCM (4 mL) was added thionyl chloride (0.130 mL, 1.784 mmol) dropwise under nitrogen. The mixture was stirred at room temperature for 2 h. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water, adjusted pH about 7 and extracted with DCM. The organic layer was separated and concentrated to afford the crude title compound (430 mg, 0.970 mmol, 109% yield) which can be used in next step directly.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:25])[NH:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH:13]=1)[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].CO.O.[Li+].[OH-]>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:25])[NH:15][CH:16]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH3:17])[CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(=O)O)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of methyl 3-acetyl-5-((1-(4-fluorophenyl)ethyl)-carbamoyl)benzoate (302 mg, 0.88 mmol) in a mixture of THF (1.2 mL), MeOH (2.4 mL) and H2O (6.0 mL), was added LiOH (63.3 mg, 2.64 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The aqueous layer was washed with ethyl acetate twice and acidified with 1N HCl solution to pH around 2˜3. The aqueous layer was extracted with ethyl acetate 3 times and the combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the title compound which was ready for next step without further purification (278 mg, 96% yield): HPLC retention time: 1.718 min (method A). MS (ESI) (M+H)+ 329.00.