Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.1 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (10 g, 0.0543 mol) and N,N-diisopropylethylamine (14.2 mL, 0.0814 mol) in dry dichloromethane (200 mL) at 0° C. under nitrogen was added dropwise a solution of 4-bromobenzenesulfonyl chloride (10.4 g, 0.0407 mol) in dry dichloromethane (80 mL) over 10 minutes. The ice bath was removed and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was then washed with 1 M hydrochloric acid (2×250 mL), 0.5 M sodium hydroxide (250 mL) and water (250 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a purple syrup (17.91 g). Purification by flash chromatography using a solvent gradient of 5 to 10% ethyl acetate in hexane afforded a tan solid (3.21 g) that was recrystallized from ethyl acetate/hexane to afford the title compound (2.55 g, 16%) as a tan crystalline solid, m.p. 128-129° C.
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[SH:13][C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)(=O)C>[S:13]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])([OH:3])(=[O:2])=[O:1]
Reactant: CCOC(=O)C1=C(S)CCCC1
Reactant: O
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCCC1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 145.8 %

Procedure:
Sodium peroxyborate tetrahydrate (74.3 g) was admixed with acetic acid (400 ml) and heated to 50 to 55° C. and then a solution of ethyl 2-mercapto-1-cyclohexene-1-carboxylate (30.0 g) in acetic acid (50 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (660 ml) and stirred at room temperature for 1 hour and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (50 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (500 ml) and stirred at room temperature for 2 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (1000 ml) and the powder which precipitated was isolated by filtration to obtain ethyl 2-sulfo-1-cyclohexene-1-carboxylate as a white powder (55 g) containing inorganic substances. This was treated dropwise with thionyl chloride (150 ml) at 0° C. over 1 hour and then stirred at 80 to 85° C. for 20 hours. The mixture was evaporated under reduced pressure to dryness and the residue was partitioned between ethyl acetate (300 ml) and a dilute brine (400 ml) and the aqueous layer was extracted with ethyl acetate (200 ml). The ethyl acetate layers were combined and washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a residue, which was purified by flash chromatography on silica gel column (eluent: ethyl acetate/hexane=1/8→ethyl acetate/hexane=1/5) to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (21.5 g) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.CCCCCC.[NH2:19]C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[NH:19])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Nc1ccccc1
Reactant: Cc1[nH]c2ccccc2c1C=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ccccc2c1C=N
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 110.6 %

Procedure:
2-methylindole-3-carboxaldehyde (10 g, 0.06 mol) was mixed with hexane (40 ml), to which aniline (9.6 ml, 0.11 mol) was added and stirred at 70° C. for 3.5 hours under reflux. Then, toluene (20 ml) was added and dissolved. The mixture was then submitted to silica gel column chromatography. The column was eluted by a developing solvent of hexane/ethyl acetate=3/1 and a fraction containing the desired product was concentrated by distilling off the solvent, to obtain 10.5 g (yield: 75%) of 2-methylindole-3-carboxaldehyde imine. 1H-NMR spectra (chemical shift, ppm: in CDCl3): 2.63 (3H, s), 7.15-7.42 (8H, m), 8.19 (1H, s), 8.45-8.48 (1H, m), 8.69 (1H, s).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17]>>[N+:1]([C:19]1[CH:20]=[CH:21][C:13]([O:12][C:11]([F:10])([F:23])[F:22])=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1[N+](=O)[O-]

Procedure:
29.7 ml of nitric acid were added dropwise to 76.5 ml of concentrated sulfuric acid, while cooling and stirring, and 9.0 g (43.7 mmol) of 3-trifluoromethoxybenzoic acid were then added. The reaction mixture was heated at 50°-55° C. for 1 hour and, after cooling, was poured onto ice, and the residue was filtered off with suction to give, after drying, 8.8 g of product, melting point 90°-93° C. (sintering at 85° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=O.BrC1C=C2C(C=CN2C)=CC=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.O>[OH:2][CH2:3][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cn1ccc2ccc(Br)cc21
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2ccc(CO)cc21
Temperature: 25 °C

Procedure:
To a solution of 6-methoxycarbonyl-1-methylindole (prepared by the method of Example 1(b), but using 6-bromo-1-methylindole in place of 6-bromo-1-ethylindole, 5g) in tetrahydrofuran (30 ml) at −70° C. under a nitrogen atmosphere, was added diisobutyl aluminium hydride (66 ml of a 1.0M solution in tetrahydrofuran) dropwise with stirring. The solution was stirred at −70° C. for 15 mins then warmed to room temperature for 2 hours. The mixture was diluted with water (100 ml) and partitioned between ethyl acetate and aqueous sodium hydroxide. The aqueous layer was re-extracted with ethyl acetate and combined organic extracts were dried (MgSO4) and evaporated to give crude product which was purified by flash column chromatography using 80% ethyl acetate/20% hexane eluant to give the subtitle compound as a clear oil which solidified on standing (4.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.[BrH:19].BrBr>C(O)(=O)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[Br:19]
Reactant: Br
Reactant: CSc1ccc(CC(=O)c2ccccc2F)cc1
Agent: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Reaction time: 0.83 h

Procedure:
A 100 mL three necked round bottomed flask equipped with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel was charged with 1-(2-fluorophenyl)-2-(4-methylthiophenyl)ethanone from Step 2, (4.36 g, 16.7 mmol), acetic acid (30 mL) and 33% HBr in acetic acid (0.5 mL). The solution was stirred and treated with bromine (17 mL, 16.8 mmol, 1.0M in acetic acid) from the addition funnel at such a rate that the bromine color was discharged rapidly, ca, 15 min. After an additional 50 minutes at room temperature, the solution was concentrated in vacuo to give a brown oil. The crude haloketone was dissolved in dichloromethane and washed with 1N NaHSO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone as an oil that solidified upon standing (4.83 g, 85%): mp 58°-63° C. 1H NMR (CDCl3) 300 MHz 7.87 (td, J=7.6, 1.8Hz, 1H), 7.52 (m, 1H), 7.39 (d, J=8.3Hz, 2H), 7.27-7.03 (m, 4H), 6.34 (s, 1H), 2.45 (s, 3H). 19F NMR (CDCl3) -108.51 (m). Mass spectrum M+ =338.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH:48]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:49]1[CH:54]=[CH:53][C:52]([P:55]([CH2:60][CH2:61][CH3:62])(=[O:59])[O:56][CH2:57][CH3:58])=[CH:51][CH:50]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][CH:48]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:49]2[CH:50]=[CH:51][C:52]([P:55]([CH2:60][CH2:61][CH3:62])(=[O:59])[O:56][CH2:57][CH3:58])=[CH:53][CH:54]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCCP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid (8-b, 526 mg, 2.56 mmol) in MeCN (10 ml) was added Et3N (645 mg, 6.39 mmol), then added HATU (1068 mg, 2.81 mmol). After 5 mins, ethyl 4-(amino(phenyl)methyl)phenyl(propyl)phosphinate, 16-e, (810 mg, 2.56 mmol) was added and the resulting mixture was stirred at rt for 2 hours. The mixture was then evaporated and the residue was diluted with ethyl acetate followed by washing with brine. The organic layer was dried and concentrated under vacuo to give the title compound, 16-f, (crude product, 2.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27].C(N(CC)CC)C>O1CCCC1>[Cl:22][CH2:23][CH2:24][NH:25][C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1)=[O:27]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCCl)ccc21
Reaction time: 8 h

Procedure:
4.2 g (0.015 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are heated at reflux for 3 hours in 80 ml of absolute tetrahydrofuran with 3.5 ml of chloroethylisocyanate and a catalytic amount of triethylamine. The mixture is left to stand at room temperature overnight. The solution is concentrated on a steam-bath and the residue is crystallised from ethyl acetate. There is obtained 1-(2-chloroethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea which melts at 240° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:26])=[CH:23][CH:22]=1)[CH3:20])=[O:17]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44, 250 mg, 0.60 mmol), methanesulfonamide (60 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (139 mg, 0.73 mmol) and dimethylaminopyridiene (78 mg, 0.63 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The solution was washed with 1M hydrochloric acid, water, and brine, dried over sodium sulfate, and evaporated. The residue was purified by flush column chromatography on silica gel eluting with dichloromethane/methanol (40/1) to afford 292 mg (98%) of the title compound: 1H-NMR (CDCl3) δ 8.52 (1H, d, J=2.8 Hz), 8.14 (1H, d, J=2.8 Hz), 8.16–8.02 (1H, m), 7.81 (2H, d, J=8.3 Hz), 7.46 (2H, d, J=8.3 Hz), 7.23–7.10 (4H, m), 5.44–5.28 (1H, m), 3.41 (3H, s), 1.59 (3H, d, J=7.0 Hz); MS (ESI) m/z 492 (M+H)+, 490 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[CH:7]=O.[Br-].[CH2:12]([O:14][C:15]([CH:17]=[C:18]([CH3:44])[CH:19]=[CH:20][CH:21]=[C:22]([CH3:43])[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16])[CH3:13].[Na].C(O)C>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:16])[CH:17]=[C:18]([CH3:44])[CH:19]=[CH:20][CH:21]=[C:22]([CH3:43])[CH:23]=[CH:7][C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[CH3:1])[CH3:13]
Reactant: Cc1sc(C)c(C=O)c1C
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)sc(C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.9 G. of 2,4,5-trimethyl-3-thiophenecarboxaldehyde and 6.75 g. of (7-ethoxycarbonyl-2,6-dimethyl-2,4,6-heptatrienyl)triphenylphosphonium bromide are dissolved in 50 ml of dry dimethylformamide. The solution is treated at 10° C. dropwise with a solution of 0.29 g. of sodium in 8 ml. of ethanol. The mixture is subsequently stirred for 4 hours at room temperature, then introduced into 100 ml. of methanol/water 60:40 parts by volume and thoroughly extracted with hexane. The hexane extract is washed with methanol/water (60:40 parts by volume, then with water, dried over sodium sulfate and evaporated. There is obtained 3,7-dimethyl-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester, which melts after recrystallization from hexane at 88°-89° C.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>CC(O)C>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:18][CH2:19][CH2:20][S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1SCCCCl
Reactant: Oc1ccc(CCc2ccncc2)cc1
Agent: [Na]
Solvent: CC(C)O
Product: O=C(O)c1ccccc1SCCCOc1ccc(CCc2ccncc2)cc1
Yield: 18.4 %

Procedure:
To the solution of 1.3 g (58 mmol) sodium in 100 ml ethanol one adds 5.7 g (29 mmol) 4-[2-(4-pyridinyl)-ethyl]-phenol, stirs for 10 min at room temperature, adds thereto 6.7 g (29 mmol) 2-(3-chloropropylthio)-benzoic acid and heats under reflux for 12 h. One allows to cool, filters, evaporates the filtrate, takes up in water, washes with ether, adjusts the aqueous phase to pH 5 and extracts with dichloromethane. After chromatography of the extract on silica gel and trituration with ligroin, one isolates 2.1 g of title compound (19% of theory) of the m.p. 151°-153° C.
Reaction SMILES: Cl[O-].[F:3][C:4]([F:16])([F:15])[CH2:5][N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][C:9](=[O:14])[CH2:10]2.Cl.C(OCC)C.[C-:23]#[N:24].[K+]>O>[C:23]([C:9]1([OH:14])[CH2:8][CH:7]2[N:6]([CH2:5][C:4]([F:3])([F:15])[F:16])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1)#[N:24]
Reactant: O=C1CC2CCC(C1)N2CC(F)(F)F
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Agent: [O-]Cl
Solvent: CCOCC
Solvent: O
Product: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A 500 ml 3-necked round bottom flask was equipped with an overhead paddle stirrer, thermometer and hypochorite scrubber. 8-(2,2,2-Trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (10.82 g, 50 mmol) was charged to the reaction flask followed by hydrochloric acid (5M, 100 ml) and the mixture was cooled to 0° C. Diethyl ether (70.8 g, 955 mmol) was added and the mixture stirred for 5 minutes. Potassium cyanide (36.9 g, 550 mmol) was added to the stirred reaction mixture portionwise over 0.5 hour. After complete addition the resultant pink mixture was stirred for 3 hour at about 3° C. The pH of the mixture was adjusted to 5.8 using hydrochloric acid (5M), water (50 ml) was added and the pH re-adjusted from 7 to 5.8. The organic layer was separated off and the aqueous phase was extracted with diethyl ether (2×100 ml). The ether extracts were combined, washed with highly dilute (pH 5.6) hydrochloric acid to leave a solution of 3-cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane in diethyl ether (303 ml).
Reaction SMILES: [OH:1][C@@:2]([C@H:9]1[CH2:13][N:12]([C@H](C2C=CC(OC)=CC=2)C)[C:11](=[O:24])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]>C(O)(C(F)(F)F)=O.CC(O)C>[OH:1][C@@:2]([C@H:9]1[CH2:13][NH:12][C:11](=[O:24])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]
Reactant: COc1ccc([C@H](C)N2C[C@H]([C@](C)(O)c3nccs3)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: C[C@@](O)(c1nccs1)[C@H]1CNC(=O)C1
Temperature: 25 °C

Procedure:
A solution of (4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one (3.6 g, 10.4 mmol) in TFA (10 mL) was heated to 70° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with IPA (30 mL), and stirred until the color dissipated. The reaction mixture was then absorbed on silica gel and purified by silica gel chromatography to afford (4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidin-2-one. MS ESI calc'd. for C9H13N2O2S [M+H]+ 213. found 213. 1H NMR (600 MHz, DMSO-d6) δ 7.68 (d, J=3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.39 (s, 1H), 6.10 (s, 1H), 3.25 (t, J=9.2 Hz, 1H), 3.19 (dd, J=9.6, 7.4 Hz, 1H), 2.91-2.81 (m, 1H), 2.20 (dd, J=16.7, 8.6 Hz, 1H), 1.77 (dd, J=16.7, 9.6 Hz, 1H), 1.43 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:41])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]4[CH2:32][O:31]C(C)(C)[O:29]4)[C:21]([C:35]([CH3:40])([CH2:37][CH2:38][OH:39])[CH3:36])=[CH:20]5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.FC1(F)OC2C=CC(C3(C(NC4C=C5C(=CC=4F)NC(C(C)(CCO)C)=C5)=O)CC3)=CC=2O1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[F:41][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])[C:21]([C:35]([CH3:36])([CH2:37][CH2:38][OH:39])[CH3:40])=[CH:20]5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CCO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Agent: CC(C)(CCO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(CCO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1C[C@@H](O)CO
Temperature: 80 °C
Yield: 31 %

Procedure:
To a solution of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide containing some 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (315 mg, 0.55 mmol) in methanol (3 mL) and water (0.3 mL) was added p-TsOH.H2O (21 mg, 0.11 mmol). The mixture was heated at 80° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with saturated. NaHCO3 solution and brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (20-80% ethyl acetate-hexanes) to provide (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (92 mg, 31%). ESI-MS m/z calc. 534.2. found 535.5 (M+1)+. Retention time 1.72 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.53 (d, J=1.0 Hz, 1H), 7.43-7.31 (m, 4H), 6.17 (s, 1H), 4.97-4.92 (m, 2H), 4.41 (dd, J=2.4, 15.0 Hz, 1H), 4.23 (t, J=5.0 Hz, 1H), 4.08 (dd, J=8.6, 15.1 Hz, 1H), 3.87 (s, 1H), 3.48-3.44 (m, 1H), 3.41-3.33 (m, 1H), 3.20 (dd, J=7.4, 12.7 Hz, 2H), 1.94-1.90 (m, 2H), 1.48-1.45 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H) and 1.15-1.12 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([F:14])([F:13])[F:12])[N+:5]=1[O-:15].[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>OS(O)(=O)=O>[N+:18]([C:8]1[CH:7]=[C:6]([CH2:10][C:11]([F:14])([F:12])[F:13])[N+:5]([O-:15])=[C:4]([CH2:3][C:2]([F:1])([F:16])[F:17])[CH:9]=1)([O-:20])=[O:19]
Reactant: [O-][n+]1c(CC(F)(F)F)cccc1CC(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(CC(F)(F)F)[n+]([O-])c(CC(F)(F)F)c1
Temperature: 0 °C

Procedure:
2,6-Bis-(2,2,2-trifluoro-ethyl)-pyridine 1-oxide (2.65 g, 10.22 mmol) was dissolved in H2SO4 (4 mL) and cooled to 0° C. HNO3 (3.2 mL) was added slowly and after the addition was complete the reaction mixture was heated to 90° C. for 2 hours. The mixture was poured into ice, made basic with 15% NaOH and extracted with CH2Cl2. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a red oil (2.72 g, 81%). 1H NMR (400 MHz, CDCl3): δ 3.95 (t, J=10.1 Hz, 4H), 8.31 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH3:11]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: N
Product: NC(=O)c1ccc(Br)cc1
Yield: 89.8 %

Procedure:
On an ice water bath, 108 g (0.49 mol) of 4-bromobenzoic acid chloride was added drop-wise over 30 minutes to 330 cm3 (4.9 mol) of concentrated aqueous ammonia while vigorously stirring. The resultant crystals were filtered out, washed with water and recrystallized from acetone to yield 88 g (0.44 mol) of 4-bromobenzoic acid amide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:22][CH2:23][CH2:24][C:25](Cl)=[O:26].Cl>O>[Br:22][CH2:23][CH2:24][C:25]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:26]
Reactant: O=C(Cl)CCBr
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a stirred solution of 22.5 g of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid and 21.2 g of sodium carbonate in 200 ml of water, cooled by an ice-water bath, 18.8 g of 3-bromopropanoyl chloride is added dropwise. The resulting mixture is continuously stirred for 2 hr at room temperature, acidified with 2 N aqueous hydrochloric acid solution, and extracted with 300 ml of ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate. After removal of ethyl acetate in vacuo, 100 ml of chloroform is added to the residue and the separated crystals are filtered to give 24.3 g (70%) of the product. The product is recrystallized from methanol to yield the titled compound: mp 109°-115° C.; IR (nujol) 3330, 1709, 1629, 1594, 1229, 1198, 1029 cm-1.