Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH:19]=[CH:18][O:17][C:16]4=[O:20])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@H:4]([CH2:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)[O:3]1>C(O)C>[NH2:22][CH2:21][C@H:4]1[C@H:5]2[N:6]([C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH:19]=[CH:18][O:17][C:16]4=[O:20])=[CH:11][C:8]=3[O:9][CH2:10]2)[C:2](=[O:1])[O:3]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1OC(=O)N2c3ccc(-n4ccoc4=O)cc3OC[C@@H]12
Solvent: CCO
Product: NC[C@@H]1OC(=O)N2c3ccc(-n4ccoc4=O)cc3OC[C@@H]12

Procedure:
Using compound 2-(((3S,3aS)-1-oxo-7-(2-oxooxazol-3-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)isoindolin-1,3-dione (0.26 g, 0.586 mmol), and methylamine alcohol (0.15 g, 4.686 mmol) as starting materials, ethanol as solvent, preparation following the method as described in Example 1(e) afforded a crude product, which was directly subjected to the next step of reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.O.O.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:11]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(C(C)(C)C#N)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of methyl 2-chloro-3-(1-cyano-1-methylethyl)benzoate (1.67 g, 7.02 mmol) in tetrahydrofuran (24 mL)/methanol (8 mL)/water (8 mL) was added lithium hydroxide-monohydrate (501 mg, 11.9 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and 6N hydrochloric acid (2.8 mL) was added dropwise to the residue. The precipitate was collected by filtration, and washed with water to give the title compound (1.43 g, 91%) as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCNCC1)OCc1ccccc1
Reaction time: 0.75 h
Yield: 104.9 %

Procedure:
To a solution of 4-benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (20.4 g, crude from previous step) in dichloromethane (100 mL) at 23° C. was added trifluoroacetic acid (40 mL). After stirring for 45 min the reaction mixture was concentrated. The residue was dissolved in water (100 mL) then basified to pH 11 via addition of solid potassium carbonate. The resulting solution was extracted with dichloromethane (2×150 mL). The organic extracts were extremely cloudy; they were dried (Na2SO4), filtered and concentrated. The residue was dissolved/suspended in chloroform (70 mL) and the observed particulates were removed via filtration through a glass frit. The solution was concentrated to give 15 g of brown oil. This material was used without purification in the subsequent step.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][C:17](=[O:21])[NH:18]3)=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1>C1COCC1>[O:21]=[C:17]1[CH2:16][C:15]2[C:19](=[CH:20][C:12]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[CH:23][CH:22]=3)=[O:11])=[CH:13][CH:14]=2)[NH:18]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A dry 100 mL flask was charged with acetyl chloride (0.408 g, 5.20 mmol) and THF (40 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.00 g, 3.96 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The brown solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the N-[4-(2-Oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide as a tan solid (1.16 g, 3.94 mmol, 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:23])=[CH:4][CH:3]=1.[Sn](Cl)Cl>CO.Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[N:10]=2)=[CH:14][CH:15]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(F)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(F)cc3)[nH]2)cc1

Procedure:
5-(4-Fluorophenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide obtained in Example 57 is suspended in methanol and ice-cooled. To the suspension is added a solution of tin(II) chloride 6 hydrate in 6 M hydrochloric acid solution and the mixture is reacted and treated in the same manner as in Example 48 to give 2-(4-aminophenyl)-5-(4-fluorophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[NH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[Cl:24])=[CH:21][CH:20]=[CH:19][CH:18]=2>ClCCl>[Cl:24][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH:13][C:1](=[O:4])[CH2:2][CH3:3]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cnc2ccccc2c1Cl
Reaction time: 8 h

Procedure:
Propionyl chloride (6.32 mL, 1.3 eq) and triethylamine (11.69 mL, 1.5 eq) were added sequentially to a solution of 3-amino-4-chloroquinoline (10.0 g, 1.0 eq) in dichloromethane (200 mL). The reaction mixture was stirred overnight and then quenched with aqueous saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2% methanol in dichloromethane) to provide 5.8 g of N-(4-chloroquinolin-3-yl)propionamide.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.I[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccccc2C1=O
Yield: 35 %

Procedure:
Using analogous reaction conditions as described in Example 1, 3,4-dihydro-2H-isoquinolin-1-one (I-23b: 150 mg, 1.0204 mmol) was reacted with 3-iodo-4-methyl-pyridine (223.4 mg, 1.0204 mmol), 1,4-dioxane (3 mL), copper iodide (19.4 mg, 0.1020 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (48.1 mL, 0.3061 mmol) and potassium phosphate (540.8 mg, 2.551 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 85 mg of the product (35% yield).
Reaction SMILES: [CH2:1]([C@:3]1([OH:38])[C:35]2[CH:34]=[C:33]3[N:9]([CH2:10][C:11]4[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([F:31])=[C:18]5[CH2:23][CH2:22][CH:21]([NH:24]C(=O)C(F)(F)F)[C:20]=4[C:19]=35)[C:8](=[O:36])[C:7]=2[CH2:6][O:5][C:4]1=[O:37])[CH3:2].[ClH:39]>>[ClH:39].[NH2:24][CH:21]1[C:20]2=[C:11]3[CH2:10][N:9]4[C:33](=[CH:34][C:35]5[C@:3]([CH2:1][CH3:2])([OH:38])[C:4](=[O:37])[O:5][CH2:6][C:7]=5[C:8]4=[O:36])[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([F:31])=[C:18]([C:19]=32)[CH2:23][CH2:22]1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(F)c3c1c2C(NC(=O)C(F)(F)F)CC3
Agent: Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(F)c3c1c2C(N)CC3

Procedure:
30 ml of 1N hydrochloric acid was added to 95 mg of the compound prepared in (11) above, and the mixture was heated under reflux for 1 hour. The solvent was evaporated and 30 ml of water was added to remove insoluble substances by filtration. The filtrate was purified with HPLC (CAPCELL PAK C18) using a mixture of acetonitrile-water-1N hydrochloric acid (20:80:1) to obtain 6.2 mg of Isomer A and 5.9 mg Isomer B of the title compound.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[C:10](=[O:18])[N:9]([CH3:19])[CH2:8][C:7]=12)#[CH:2].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[C:36]1(=[O:40])[CH2:39][CH2:38][CH2:37]1>O1CCCC1.CCCCCC.O>[F:17][C:15]1[CH:14]=[CH:13][C:12]2[N:6]3[CH:5]=[N:4][C:3]([C:1]#[C:2][C:36]4([OH:40])[CH2:39][CH2:38][CH2:37]4)=[C:7]3[CH2:8][N:9]([CH3:19])[C:10](=[O:18])[C:11]=2[CH:16]=1
Reactant: C#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1Cc2c(C#CC3(O)CCC3)ncn2-c2ccc(F)cc2C1=O
Reaction time: 2 h

Procedure:
3.83 g (15 mmol) of 3-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was suspended in 30 ml of tetrahydrofuran and treated dropwise within 30 minutes at a maximum of -5° with 20 ml (30 mmol) of 1.6M butyllithium in hexane. After stirring for two hours in an ice-bath the mixture was cooled to -70° and 5 ml of hexamethylphosphoric acid triamide and 2 g (28 mmol) of cyclobutanone was added thereto in succession. The mixture was left to come to room temperature within 5 hours, stirred overnight and poured into 300 ml of water. After acidification with 4N hydrochloric acid the mixture was extracted five times with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and crystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-[ (1-hydroxycyclobutyl)-ethynyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 177°-179°.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:20])=[C:4]2[CH2:8][CH2:9][C@@H:10]([CH3:11])[C:3]=12
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.1 %

Procedure:
To a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidine (2.5 g, 14.8 mmol) in CHCl3 (60 mL) was added MCPBA (8.30 g, 37.0 mmol) in three portions. The mixture was stirred at room temperature for 2 days. The mixture was cooled to 0° C. and to this was added dropwise Na2S2O3 (10 g) in water (60 mL), followed by Na2CO3 (6 g) in water (20 mL). The reaction mixture was stirred for 20 minutes. The aqueous phase was extracted with CHCl3 (2×200 mL), and the combined organic phases were concentrated at low temperature (<25° C.). The residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) to give (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidine-oxide (1.45 g, 53%). 1H NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H), 3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:21])=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:13]=1)=[O:11].Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[C:15]([O:21][S:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=2)(=[O:34])=[O:33])=[C:14]([CH:22]([CH3:23])[CH3:24])[CH:13]=1)=[O:11]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 46.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197 g, 0.831 mmol). Purification on Dynamax C18 (90% CH3CN/H2O) gave 0.20 g (47%) of the title compound as a yellow solid, mp 90-95° C. 1H NMR (DMSO-d6) δ1.06 (d, 12H), 1.85 (s, 3H), 2.19 (s, 3H), 3.07 (septet, 2H), 3.91 (s, 2H), 7.14-7.16 (m, 2H), 7.29 (dt, 1H), 7.44 (d, 1H), 7.47-7.52 (m, 4H), 8.05 (d, 1H), IR (KBr) 3400, 2950, 1690, 1380 and 1190 cm−1. mass spectrum (−ESI) m/z 667/669 (M−H). Anal. Calcd. for C33H33BrO8S: C, 59.19; H, 4.97; N, 0.00. Found: C, 58.82; H, 5.13; N, 0.13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(N(CC)CC)C.[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:18][CH2:17][C:16]([OH:20])=[O:19]
Reactant: Fc1ccccc1S
Reactant: C=CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCSc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluorothiophenol (5.0 g, 39 mmol) was dissolved in tetrahydrofuran (50 ml) under a nitrogen atmosphere. Triethylamine (3.94 g, 5.33 ml, 85.8 mmol) was added. Acrylic acid (2.81 g, 2.67 ml, 39 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction solution over 2 h at room temperature. The mixture was stirred at room temperature overnight. 1M Hydrochloric acid (50 ml) was added and the phases were separated. The aqueous phase was washed with ethyl acetate (2×50 ml). The combined organic phases were dried over magnesium sulphate, filtered and concentrated under vacuum. A yellow oil was obtained which solidified upon storage at room temperature. The solid was triturated with hexane, filtered and dried under vacuum. The title compound was isolated as an off-white solid (4.19 g, 20.9 mmol, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:12]=1.[F:24][C:25]([F:30])([F:29])[CH:26]1[O:28][CH2:27]1>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])[CH:12]=1)[CH2:27][CH:26]([OH:28])[C:25]([F:30])([F:29])[F:24]
Reactant: FC(F)(F)C1CO1
Reactant: Fc1ccc(F)c(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cc(F)ccc1F)C(F)(F)F
Temperature: 50 °C
Yield: 83.5 %

Procedure:
EX-661 B) The N-(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amine (2.22 g, 6.67 mmol) product from EX-661A and 1,1,1-trifluoro-2,3-epoxypropane (1.12 g, 10 mmol) were dissolved in 1.5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.21 g, 0.33 mmol) was added, and the stirred solution was warmed to 50° C. for 2 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:10) to give 2.49 g (84%) of the desired 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. for C18H14F9NO2: 448.0959 [M+H]+, found: 448.0940.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].C(=O)=O>CO>[CH3:8][S@@:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)=O)cc3)nc2)CC1
Agent: O=C=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc([S@](C)=O)cc3)nc2)CC1
Yield: 34.1 %

Procedure:
The racemic sulfoxide 1-methylethyl 4-[({6-[4-(methylsulfinyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (Example 173, 370 mg) was subjected to Chiral HPLC [column: Chiralpak AS-H, column mobile phase: 65% CO2: 35% MeOH (1 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separation to give two (R and S) enantiomers. The title compound (99 mg) was isolated as an off-white solid with Tr of 7.24 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17](=O)([O:23]C(C)(C)C)[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 5-amino-2-methoxypyridine (8.00 g, 64.4 mmol) and triethylamine (11.7 mL, 83.8 mmol) in dioxane (32 mL) at 0° C. was added a solution of di-tert-butyl carbonate in dioxane (20 mL). The reaction mixture was allowed to warm to RT, stirred for 16 h. After concentration in vacuo, the residue was dissolved in 65 mL of EtOAc and 32 mL of a saturated aqueous NaHCO3 solution and stirred at RT for 2 h. The layers were separated. The organic layer was washed with water and dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[C:3]([OH:5])=[O:4].[CH3:13]O>S(=O)(=O)(O)O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[C:3]([O:5][CH3:13])=[O:4]
Reactant: CO
Reactant: Cc1ccccc1C(O)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccccc1C

Procedure:
A solution of (RS)-a-hydroxy-(2-methylphenyl)acetic acid (3.6 g) in methanol (80 ml) containing 2 drops of concentrated sulphuric acid was heated at reflux for 2 hours. The reaction mixture was concentrated and the residual oil partitioned between ethyl acetate and water. The organic phase was washed with water, dried over magnesium sulphate and evaporated to give the title compound (2.5 g) as a colourless oil.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[H][H]>CC(O)C>[CH3:3][O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11]
Reactant: COC1CCCCC1=O
Reactant: [H][H]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@H]1CCCC[C@H]1O
Temperature: 50 °C
Reaction time: 19 h

Procedure:
In a 100 ml autoclave were charged 1.5 ml of a 0.2M solution of potassium hydroxide (0.30 mmol) in 2-propanol, 4.2 mg (0.02 mmol) of (1S,2S)-diphenylethylenediamine, 1.28 g (10.0 mmol) of 2-methoxycyclohexanone, 10.1 mg (0.01 mmol) of Ir(COD)[(S)-BINAP]BF4, and 8.5 ml of 2-propanol in a nitrogen atmosphere, and hydrogen was introduced therein to 50 atm. The mixture was stirred at 50° C. for 19 hours and cooled to room temperature. The disappearance of the starting material was confirmed by gas chromatography. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure to obtain (1R,2S)-2-methoxycyclohexanol. The optical purity of the product was found to be 78% d.e. and 31% e.e. by gas chromatography.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[CH:14]=[N:13][S:12][N:11]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:10]1[CH:14]=[N:13][S:12][N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1cnsn1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1cnsn1
Yield: 94.3 %

Procedure:
Ethyl 2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (anti isomer) (3.0 g.) was treated with 1 N aqueous solution of sodium hydroxide (16.8 ml.) according to a similar manner to that of Example 1(a)(5) to give 2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (anti isomer) (2.46 g.), mp 110° to 111° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:12]([C:22]1[NH:23][CH:24]=[C:25]([CH3:28])[C:26]=1[CH3:27])=[CH:13][C:14]=2[S:15][CH2:16][CH2:17][NH:18]C(=O)O.C(OC(=O)NCCSC1C=C(C2NC=C(C)C=2C)C2C(=O)NC3C=2C=1C(F)=CC=3)(C)(C)C.[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62].[OH-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[NH2:18][CH2:17][CH2:16][S:15][C:14]1[CH:13]=[C:12]([C:22]2[NH:23][CH:24]=[C:25]([CH3:28])[C:26]=2[CH3:27])[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3
Reactant: Cc1c[nH]c(-c2cc(SCCNC(=O)O)c3c(F)ccc4c3c2C(=O)N4)c1C
Agent: Cc1c[nH]c(-c2cc(SCCNC(=O)OC(C)(C)C)c3c(F)ccc4c3c2C(=O)N4)c1C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c(-c2cc(SCCN)c3c(F)ccc4c3c2C(=O)N4)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of [2-[6-fluoro-2-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tent-butyl ester (from Example 49 above) (66 mg, 0.145 mmol) in CH2Cl2 (5 mL) was added TFA (Aldrich, 2.5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Aqueous ammonium hydroxide (4 mL) and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by RP-HPLC (C-18, eluted with 1% acetonitrile/0.05% TFA in H2O) to give 5-(2-amino-ethylsulfanyl)-6-fluoro-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one trifluoroacetic acid salt as a yellow-green solid. (Yield 20 mg, 29.4%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:49][CH2:50][CH2:51][OH:52])[C:20]([O:22][C@H:23]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]4[CH2:48][CH2:47]4)[CH:35]=3)[CH2:24][C:25]3[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=3[Cl:33])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:53](Cl)(=[O:55])[CH3:54]>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:49][CH2:50][CH2:51][O:52][C:53](=[O:55])[CH3:54])[C:20]([O:22][C@H:23]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]4[CH2:47][CH2:48]4)[CH:35]=3)[CH2:24][C:25]3[C:26]([Cl:33])=[CH:27][N+:28]([O-:32])=[CH:29][C:30]=3[Cl:31])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: O=C(N[C@H](CCCO)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: CC(=O)OCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of 4-((S)-2-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-hydroxypentanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)-3,5-dichloropyridine 1-oxide (268 mg, 0.354 mmol) in DCM (5 mL), acetyl chloride (54 μl, 0.757 mmol) and TEA (108 μl, 0.775 mmol) were added. The mixture was stirred at RT for 3 hours. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1 M and brine. The organic phase was dried over Na2SO4 and the solvent was evaporated, to yield 284 mg of the title compound.