Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][CH:28]1[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:5]([NH:26][CH:27]2[CH2:32][CH2:31][C@@H:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][C@@H:28]2[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=2)=[O:7])=[CH:8][CH:9]=[C:10]([O:12][CH3:13])[N:11]=1
Reactant: COc1ccc(C(=O)O)c(OC)n1
Reactant: CCOc1cc(C2CC(OC(C)=O)CCC2N)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc([C@H]2C[C@H](OC(C)=O)CCC2NC(=O)c2ccc(OC)nc2OC)ccc1OC
Temperature: 40 °C
Reaction time: 42 h
Yield: 102.6 %

Procedure:
555 mg of 2,6-dimethoxynicotinic acid and 581 mg of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are placed in a flask under nitrogen. 778 mg of acetic acid (1RS,3RS,4RS)-4-amino-3-(3-ethoxy-4-methoxyphenyl)cyclohexyl ester (compound B1) and 2 mg of 4-dimethylaminopyridine both as solution in dichloromethane are added and the solution stirred for 1 h at 40° C., than 42 h at room temperature. The reaction is quenched with 5 ml of water. After phase separation the organic layer is washed with 2.5 ml of saturated potassium hydrogencarbonate solution. After drying the organic layer with magnesium sulfate the solvent is removed to give 1.227 g of the crude title compound which are used for the following step without further purification.
Reaction SMILES: [F:1][C:2]1[C:11](S(C(F)(F)F)(=O)=O)=[C:10]([F:19])[C:9]([F:20])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>O1CCOCC1.CCOCC>[CH:21]([C:11]1[C:2]([F:1])=[C:3]([CH:8]=[C:9]([F:20])[C:10]=1[F:19])[C:4]([OH:6])=[O:5])=[CH2:22]
Reactant: COC(=O)c1cc(F)c(F)c(S(=O)(=O)C(F)(F)F)c1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 98 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
To a solution of 2,4,5-trifluoro-3-trifluoro methanesulfonyl benzoic acid, methyl ester (22.0 g, 0.065 mol) in dioxane (100 mL) was added tri-n-butyl vinyl tin (21.6 g, 0.068 mol), lithium chloride (16.7 g, 0.37 mL) 2,6-di-t-butyl-4-methylphenol (0.08 g) and palladium-tetra-triphenyl phosphine (1.1 g). The mixture was heated at 98° C. for 12 hours, cooled, diluted with ether and filtered through celite. The ether layer was concentrated and the resulting residue suspended in hexane and filtered. The filtrate was concentrated to a yellow oil which was immediately dissolved in methanol (250 mL) and 1N sodium hydroxide (150 mL). The mixture was stirred at room temperature for 4 hours, diluted with water and ether. The aqueous layer was acidified (pH~2) with 6N HCl and extracted with methylene chloride. The organic layer was dried and concentrated to provide the desired product 9.6 g, 77%); mp 108°-110° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:15][CH3:16])[NH:9][C:10](=[O:14])[C:11]=1[O:12][CH3:13])=[O:5])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:15][CH3:16])[N:9]([CH3:20])[C:10](=[O:14])[C:11]=1[O:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(SC)n(C)c(=O)c1OC
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A solution of 5-methoxy-2-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.442 g, 1.81 mmol) in dry N,N-dimethylformamide (5 ml) was treated at 10° C. with sodium hydride (0.080 g of a 60% dispersion in mineral oil, 2.0 mmol) and the resulting mixture was stirred for 10 min. Then iodomethane (0.123 ml, 2.0 mmol) was added and the mixture was stirred for another 1 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 9:1) gave 0.419 g (89% yield) of the title ester as white needles; mp 74.5–76° C. (ether-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.41 (3H, t, J=7.1 Hz, CH3), 2.62 (3H, s, SCH3), 3.55 (3H, s, NCH3), 3.95 (3H, s, OCH3), 4.43 (2H, q, J=7.1 Hz, CH2). Anal. Calcd for C10H14N2O4S: C 46.50, H 5.46; N, 10.85. Found: C 46.73; H, 5.21; N, 10.93.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([O:47]C)=[O:46])=[CH:41][C:40]=4[Cl:49])[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O.O1CCOCC1>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][C:40]=4[Cl:49])[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:52])([F:51])[F:1])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(F)c(-c2ccc(C(=O)O)cc2Cl)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 2 h

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-chloro-6′-fluoro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (84.5 mg, 0.11 mmol), lithium hydroxide monohydrate (46.2 mg, 1.1 mmol), water (1 mL) and 1,4-dioxane (2 mL) were stirred at room temperature. LCMS of aliquot at reaction time was 2 hrs indicated completion of reaction. Volatiles were removed under reduced pressure. Crude mixture was dissolved in MeCN and acidified by HCl (1N, aq.) to afford a clear solution. This solution was purified by a reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Corresponding fractions were pooled & evaporated in vacuo to afford a colorless glass. This glass was dissolved in DCM and washed with water. Organic extracts were combined, dried/Na2SO4, filtered and evaporated to afford the title compound. LCMS (ESI) calc.=749.10; found=750.06 (M+1)+. 1H NMR (CDCl3, 500 MHz, 1:1 mixture of atropisomers): δ 8.21 (dd, J=10, 2 Hz, 1H), 8.03 (dd, J=8, 2 Hz, 1H), 7.86 (s, 1H), 7.73-7.68 (m, 1.5H), 7.68-7.62 (m, 2.5H), 7.48 (t, J=7.5 Hz, 1H), 7.41 (dd, J=11, 8 Hz, 1H), 7.17 (dd, J=8.5, 2 Hz, 1H), 6.86 (dd, J=11, 3.5 Hz, 1H), 6.60 (d, J=8 Hz, 0.5H), 5.40 (d, J=8 Hz, 0.5H), 4.94 (t, J=15 Hz, 1H), 4.18 (d, J=16 Hz, 0.5H), 3.95 (d, J=16 Hz, 0.5H), 3.87 (s, 3H), 3.85-3.74 (m, 1H), 0.56 (d, J=6.5 Hz, 1.5H), 0.46 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20]([CH3:36])=[CH:21][C:22]([CH2:27][NH:28]C(=O)OC(C)(C)C)=[N:23][C:24]=2[O:25]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.Cl>O1CCCC1>[NH2:28][CH2:27][C:22]1[NH:23][C:24](=[O:25])[C:19]([CH2:18][NH:17][C:15]([C:4]2[C:5]3[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=[C:2]([Br:1])[CH:3]=2)=[O:16])=[C:20]([CH3:36])[CH:21]=1
Reactant: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(CN)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 80 °C
Yield: 82.3 %

Procedure:
To a stirred solution of tert-butyl ((5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (500 mg, 0.894 mmol) in Tetrahydrofuran (THF) (5 mL) was added 6N HCl (15 mL, 15.00 mmol). The reaction was stirred under N2 with heating at 80° C. for 18 hr. The reaction was cooled to RT and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-40 g, 0 to 10% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum. Dissolved with a small volume of CH2Cl2, scratched out by slowly adding hexanes, filtered, washed with hexanes and dried under vacuum to give the product N-((6-(aminomethyl)-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamide (328 mg, 0.736 mmol, 82% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.26 (t, J=5.1 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.0 Hz, 1H), 7.01 (d, J=1.5 Hz, 1H), 6.01 (s, 1H), 5.77 (s, 0H), 4.74 (quin, J=6.6 Hz, 1H), 4.32 (d, J=5.1 Hz, 2H), 3.46 (s, 2H), 2.25 (s, 3H), 2.14 (s, 3H), 1.39 (d, J=6.8 Hz, 6H). MS(ES)+ m/e 445.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:10]3[N:9]=2)[CH:7]=1.[F:27][C:28]([F:40])([F:39])[S:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>O1CCCC1>[CH2:19]([CH:18]([C:17]1[N:10]2[C:11]([C:12](=[O:14])[NH:13][C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:37]([NH:36][C:33]4[CH:34]=[CH:35][C:30]([S:29][C:28]([F:39])([F:27])[F:40])=[CH:31][CH:32]=4)=[O:38])[CH:3]=[CH:4][C:5]=3[O:24][CH2:25][CH3:26])=[N:9]2)=[C:15]([CH3:23])[N:16]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCOc1ccc(N)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(NC(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1

Procedure:
Analogously to the procedure of example 54, 230 mg (0.647 mmol) of the amino compound from example 48A are reacted with 284 mg (1.29 mmol) of 4-(trifluoromethylthio)phenyl isocyanate in 20 ml of tetrahydrofuran for 4 hours. The crude product is purified by silica gel chromatography using toluene and ethyl acetate as mobile phase.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[N:10]=[C:4]2[CH2:3]1.[C:12]([O:15][CH2:16][C:17]1[C:18]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27](Br)[C:26](=[O:30])[N:25]([CH3:31])[CH:24]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[C:12]([O:15][CH2:16][C:17]1[C:18]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27]([NH:11][C:9]2[N:10]=[C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[N:8]=2)[C:26](=[O:30])[N:25]([CH3:31])[CH:24]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCn2nc(N)nc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(-c2cc(Nc3nc4n(n3)CCN(C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 39.6 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 270f (100 mg, 0.65 mmol, 1.7 eq.), (4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl acetate 217a (200 mg, 0.38 mmol, 1.0 eq.), DMF (10 mL), and cesium carbonate (499 mg, 1.52 mmol, 4.0 eq.). After bubbling nitrogen through the resulting solution for 10 minutes, Xantphos (44 mg, 0.076 mmol, 0.20 eq.) and tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol, 0.10 eq.) were added. The reaction mixture was subjected to three cycles of vacuum/argon flush and heated at 100° C. for 16 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (50 mL) and water (10 mL). The aqueous layer was separated and extracted with ethyl acetate (3×20 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified on silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 270g (90 mg, 41%). MS-ESI: [M+H]+ 598.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]4=[CH:15][C:14]=3[NH:13][C:12]=2[CH:11]=[C:10]([OH:27])[CH:9]=1.[I-].[K+].Cl[C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>CN(C)C=O>[OH:7][C:8]1[CH:9]=[C:10]2[O:27][C:31]([CH3:35])([CH3:34])[CH:32]=[CH:33][C:11]2=[C:12]2[C:21]=1[C:20](=[O:22])[C:19]1[CH:18]=[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]3=[CH:15][C:14]=1[NH:13]2
Reactant: C#CC(C)(C)Cl
Reactant: O=c1c2cc3ccccc3cc2[nH]c2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2c(cc(O)c3c(=O)c4cc5ccccc5cc4[nH]c23)O1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 44.4 %

Procedure:
2 g of anhydrous potassium carbonate are added, under an inert atmosphere, to a solution of 2 g of the product of Step A in 50 ml of anhydrous dimethylformamide. After stirring for 15 minutes at 65° C., 2.4 g of anhydrous potassium iodide and 4.4 g of 3-chloro-3-methyl-1-butyne are added and the reaction mixture is maintained at 65° C. for 24 hours and then at 130° C. for 1 hour 30 minutes. After cooling, the solution is hydrolysed and then extracted with dichloromethane. The combined organic phases are washed with water and then with a 1M potassium hydroxide solution, dried over sodium sulphate and then evaporated. Chromatography over silica gel (cyclohexane/acetone: 90/10) yields 1.10 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O>O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]2[C:3]=1[CH2:12][CH2:13][CH2:14][C:15]2=[O:17]
Reactant: Cc1ccc(CCCC(=O)O)c(C)c1[N+](=O)[O-]
Solvent: O
Product: Cc1cc2c(c(C)c1[N+](=O)[O-])CCCC2=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
PPA (100 g) was warmed to 110° C. and 4-(2,4-dimethyl-3-nitrophenyl)butanoic acid (3.04 g, 12.8 mmol) was added. The resulting solid slowly turn to a brown solution. The reaction was stirred at 110° C. for 4 hours, then poured into 200 ml of water with strong stirring. The mixture was extracted with dichloromethane (×3), and the organic solution was dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by Biotage (hexane/EtOAc, 0-30%, 40 min) to give pure compounds as yellow solid (2 g, 71%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[CH:14]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.C1COCC1.CO.[Li+].[OH-].CC(O)=O>[Cl-].[Na+].O>[Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: COC(=O)CC1CCn2c1cc1c(Br)cc(F)cc12
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CC1CCn2c1cc1c(Br)cc(F)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (+/−)-methyl (8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (11 g) in a THF/MeOH (3:1) mixture at r.t. was added 1N LiOH (50 mL, aqueous solution). The reaction mixture was stirred at r.t. for 12 hours and AcOH (5 mL) and brine (100 mL) were added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated to provide the title compound as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].Cl>[OH-].[Na+].O>[C:1]([NH:4][C@H:5]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 0 %

Procedure:
A solution of 2-acetamido-3-(4-(trifluoromethyl)phenyl)propanoic acid (LXIII) (30 g, 109 mol) in 1 M NaOH (50 mL) and water (1 L) was adjusted to pH 7.6-7.8 before adding CoCl2 (300 mg, 2.3 mmol) and Acylase I (3 g) (from Aspergilus melleus). The reaction was stirred at room temperature under argon for 2 days at which time Marfey's test was performed and additional enzyme (1 g) was added and the reaction was stirred for an additional day. The mixture was acidified with 2 M HCl to pH 1 and extracted with EtOAc (3×) (the aqueous phase containing the L-enantiomer (LXIV) was saved). The combined organic extracts were washed with 2 M HCl (3×), brine (3×) and dried over MgSO4. The solvent was removed under reduced pressure and the residue was recrystallized from EtOAc/hexane, affording (R)-2-acetamido-3-(4-(trifluoromethyl)phenyl)propanoic acid (LXV) (10.2 g, 37 mmol, 68% yield).
Reaction SMILES: CC([S@@](N)=O)(C)C.ClC1C=C(CCC(=O)C)C=CC=1Cl.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][CH2:30]/[C:31](=[N:33]/[S@:34]([C:36]([CH3:39])([CH3:38])[CH3:37])=[O:35])/[CH3:32])[CH:25]=[CH:26][C:27]=1[Cl:28].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1.C(=O)=O.C(O[Ti](OCC)(OCC)OCC)C.CO>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][CH2:30][C@H:31]([NH:33][S@:34]([C:36]([CH3:37])([CH3:39])[CH3:38])=[O:35])[CH3:32])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: C/C(CCc1ccc(Cl)c(Cl)c1)=N\[S@@](=O)C(C)(C)C
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: CC(=O)CCc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[S@@](N)=O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](CCc1ccc(Cl)c(Cl)c1)N[S@@](=O)C(C)(C)C
Temperature: 75 °C
Reaction time: 72 h
Yield: 59.6 %

Procedure:
To a stirred solution of (S)-2-methylpropane-2-sulfinamide (373 mg, 3.08 mmol) and 4-(3,4-dichlorophenyl)butan-2-one (700 mg, 3.22 mmol) in THF (2 mL) at rt was added tetraethoxytitanium (1.22 mL, 5.86 mmol). The reaction mixture was heated at 75° C. overnight, and allowed to cool and stay at rt for 72 h. Another equivalent of Ti(OEt)4 (1.22 mL, 5.86 mmol) and (S)-2-methylpropane-2-sulfinamide (373 mg, 3.08 mmol) were added. The reaction mixture was heated at 75° C. overnight. The THF solution of (S,E)-N-(4-(3,4-dichlorophenyl)butan-2-ylidene)-2-methylpropane-2-sulfinamide (1033 mg, 3.23 mmol) was stirred in a round-bottomed flask under argon at −40 to −50° C. L-Selectride (2016 μL, 2.016 mmol) was added dropwise. The resulting mixture was then warmed up to 0° C. during a 1.5 h period and LC-MS showed the completion of the reaction. It was cooled in dry ice and MeOH was added dropwise until gas evolution stopped. The mixture was stirred at rt for 20 min. It was filtered through Celite® and rinsed with CH2Cl2 and the filtrate was washed with brine (2×) and dried over Na2SO4, filtered and concentrated. The residue was purified on ISCO flash chromatography (0-100% hexanes/EtOAc) to give (S)-N-((R)-4-(3,4-dichlorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (620 mg, 1.924 mmol, 59.6% yield) as slightly tan viscous oil (slow eluent) and an impure (S)-N-((S)-4-(3,4-dichlorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide. LC-MS (ESI) m/z 322.0 (M+H), RT=2.34 min (Method B).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCc1ccc(C=O)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 9.5 g. of p-n-hexylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 14.4 g. of a brownish oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-hexylbenzyliden)amino]benzonitrile which is obtained has a melting point of 32.2°-33.0° C. and a clearing point of 64.5° C. UV (ethanol): ε281 = 23500 (shoulder at 310 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:24]>CC(C)=O.[Ag]=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH2:13][C@H:12]1[CH2:21][O:22][CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: C[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: COC[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)OCc1ccccc1
Temperature: 57 °C
Yield: 67 %

Procedure:
To (2S,4R)-2-Hydroxymethyl-4-trimethylsilanyloxy-pyrrolidine-1-carboxylic acid benzyl ester in 10 mL of acetone was added iodomethane 0.86 mL (13.5 mmol), silver oxide 3.04 g (13.2 mmol) and the solution was warmed to 57° C. for 8 h. The mixture was cooled to 25° C., filtered through celite and concentrated. The residue was taken up in 50 mL of EtOAc and was washed with Sat. NaHCO3 (2×50 mL). The organic layer dried over Na2SO4 and concentrated. The residue was loaded onto 50 mL silica and eluted with Hexane:EtOAc (3:7). The purified fraction were concentrated to give 0.66 g (67%) of (2S,4R)-2-Methoxymethyl-4-trimethylsilanyloxy-pyrrolidine-1-carboxylic acid benzyl ester as clear oil. HPLC: Rt 3.43 min. (98.2% area). 1H NMR (CDCl3, 300 MHz) δ: 7.38-7.32 (5H, m), 4.70 (2H, s), 4.56-4.46 (2H, m), 4.18-4.13 (2H, m), 3.86 (1H, q, J=5.5 Hz), 3.07-3.02 (1H, m), 1.99-1.95 (1H, m), 1.61 (3H, bs), 1.57-1.52 (1H, m), 0.12 (9H, s). LCMS (ESI) (M+H+) m/z: 338.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2([OH:23])[CH2:19][CH:20]3[N:15]([CH3:14])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[CH:3][CH:4]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Product: CN1C2CCC1CC(O)(c1ccc(Cl)cc1)C2

Procedure:
The title compound was prepared from 4-bromochlorobenzene (15.4 g, 81 mmol), n-butyllithium in hexanes (31 mL 2.5 M; 78 mmol) and 8-methyl-8-azabicyclo[3.2.1]-octan-3-one (5 g, 36 mmol). Yield 5.7 g (63%) as a white solid, m.p. 186.3-187° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1.Cl.[CH3:18]O>>[ClH:1].[NH2:2][C:3]1([C:14]([O:16][CH3:18])=[O:15])[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1
Reactant: CO
Reactant: NC1(C(=O)O)CCc2c(F)cc(F)cc21
Agent: Cl
Product: COC(=O)C1(N)CCc2c(F)cc(F)cc21

Procedure:
A solution of 1-amino-4,6-difluoroindane-1-carboxylic acid hydrochloride (2.00 g, 15.5 mmol) in MeOH (100 mL) was saturated with HCl (g). The resulting mixture was heated at reflux for 20 h and concentrated in vacuo to provide the title compound. MS: m/z=228 (M+1).