Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])[CH:17]=[CH:16][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(O)(=O)C.[BH4-].[Na+]>O>[F:5][C:6]1[CH:19]=[C:18]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])[CH:17]=[CH:16][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
To a dimethyl sulfoxide (30.0 mL) solution of 2-(2-fluoro-4-((E)-2-nitro-vinyl)-phenoxymethyl)-pyridine (3.00 g, 10.9 mmol) described in Manufacturing Example 87-1-2 and acetic acid (3.00 mL) was added sodium borohydride (660 mg, 17.4 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 20 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was crystallized with a tetrahydrofuran-ethyl acetate-heptane system and filtered to obtain the title compound (1.50 g, 49.8%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CCOC(C)=O>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[C:3](/[CH:8]=[N:16]/[S@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ncccc1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C/c1ncccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-fluoropicolinaldehyde (300 g, 2400 mmol), copper sulfate (572 g, 3600 mmol) and (S)-2-methylpropane-2-sulfinamide (319 g, 2640 mmol) in DCM (3 L) in a 10 L 3-neck round bottom flask was stirred for 3 h at rt. The progress of the reaction was monitored by TLC (30% EtOAc in petroleum ether). After completion of reaction, the solid was filtered off and the filtrate was concentrated under vacuum. The initially obtained product was purified by column chromatography using silica (60-120 mesh) with 20% EtOAc in n-hexane as eluent to give the title compound sulfinamide as yellow oil. 1H-NMR (400 MHz, CDCl3): δ ppm 8.89 (s, 1H), 8.64 (s, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.46 (d, J=3.6 Hz, 1H), 1.29 (s, 9H). MS (ESI pos. ion) m/z: 155.0 (M-O and t-Bu).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([F:17])([F:16])[C:11]([O:13]CC)=[O:12])C1C=CC=CC=1.Cl.[CH3:26][CH2:27]O>[OH-].[OH-].[Pd+2]>[CH2:26]([CH:9]([NH2:8])[C:10]([F:16])([F:17])[C:11]([OH:13])=[O:12])[CH3:27]
Reactant: CCO
Reactant: CCOC(=O)C(F)(F)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: CCC(N)C(F)(F)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
To a solution of ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (517 mg, 1.55 mmol) in EtOH (1 mL) was added 0.5 N HCl (1 mL) and Pd(OH)2/C (20%, 50 mg). The reaction mixture was stirred at room temperature under H2 atmosphere for 3 days. The reaction mixture was filtered and the solid was rinsed with water and ether. The aqueous layer was separated from the ether layer and lyophilized to yield ethyl 3-amino-2,2-difluoropropanoic acid as a white solid (210 mg, 100% yield). 1H NMR (400 MHz, DMSO) ppm 3.27-3.46 (m, 2H), 8.06-8.64 (m, 3H).
Reaction SMILES: [O:1]=[C:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].C(N(CC)CC)C.[SH:25][C:26]1[CH:27]=[C:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:29]([OH:38])=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:31]=1>CO>[OH:38][C:29]1[C:28]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:27][C:26]([S:25][CH2:4][CH2:3][C:2]([N:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)=[O:1])=[CH:31][C:30]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Oc1c(-c2ccccc2)cc(S)cc1-c1ccccc1
Reactant: C=CC(=O)N1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CCSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1)N1CCN(Cc2ccccc2)CC1
Reaction time: 12 h
Yield: 29.5 %

Procedure:
Following the procedure of Example 4, 1-(1-oxo-2-propenyl-4-phenylmethyl)piperazine (Example 8) (2.30 g, 0.01 mole) was dissolved in methanol (150 ml) and triethylamine (1 ml) added to the solution. The solution was flushed with argon several times, 5'-mercapto [1,1':3',1"-terphenyl]-2'-ol (2.77 g, 0.01 mole) added and the reaction stirred for 12 hours. The solvent was removed and the product isolated by chromatography to yield 1.5 g of product after drying in vacuo.
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=S)[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:5]1[CH:4]2[CH2:3][CH2:2][CH2:1][CH:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CN
Reactant: S=C1Nc2ccccc2C2CCCC12
Product: CNC1=Nc2ccccc2C2CCCC12

Procedure:
1,2,3,3a,5,9b-Hexahydrocyclopenta[c]quinoline-4-thione (90 mg, 0.44 mmol) is stirred in 2 M methanolic methylamine solution (15 ml) for 24 hours at room temperature. After concentration by evaporation, the residue is purified on silica gel with dichloromethane-methanol: 90 mg (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20]2)=[CH:15][CH:14]=1.Cl([O-])=[O:29].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O.CC(=CC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:29])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20]2)=[CH:15][CH:14]=1
Reactant: COC(=O)N1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a solution of methyl 3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate (124 mg, 0.325 mmol) in acetonitrile (4 mL) and tert-butanol (4 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (327 mg, 3.59 mmol) and sodium phosphate monobasic dihydrate (761 mg, 4.875 mmol) in water (2 mL). After the resulting mixture was stirred for 2 hours at room temperature, additional sodium chlorite (435.5 mg, 4.79 mmol) and sodium phosphate monobasic dihydrate (1.014 g, 6.5 mmol) in water (2 mL) and 2-methyl-2-butene (1 mL) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo and the aqueous residue was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DMSO and purified via prep-HPLC to give 6-chloro-5-{4-[1-(methoxycarbonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylic acid (60 mg, 46%) as a white solid. The racemic mixture was separated by preparative chiral SFC to give 16 mg of peak 1 or Example 14A (>99% ee, ret time=4.73 minutes), and 17 mg of peak 2 or Example 14B (>93% ee, ret time=5.33 minutes) using ChiralPak AD-H Minigram-1, 60/40 CO2/MeOH 0.2% isopropylamine, 10 mL/min, 120 Bar. MS (ES+) 398.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.14 (br, 1H), 11.97 (s, 1H), 8.08 (d, 1H), 7.94 (s, 1H), 7.61 (s, 1H), 7.38 (m, 4H), 3.81 (m, 1H), 3.61 (s, 3H), 3.54 (m, 1H), 3.40 (m, 2H), 3.28 (m, 1H), 2.25 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][P:11]([CH2:16][C:17]([OH:19])=O)([O:13][CH2:14][CH3:15])=[O:12])[CH3:9].[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1)[N:27]=[CH:26][N:25]=[C:24]2[NH:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=1.O>CN(C)C=O>[Cl:44][C:39]1[CH:38]=[C:37]([NH:36][C:24]2[C:23]3[C:28](=[CH:29][C:30]([O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)=[C:21]([NH:20][C:17]([CH2:16][P:11]([O:10][CH2:8][CH3:9])([O:13][CH2:14][CH3:15])=[O:12])=[O:19])[CH:22]=3)[N:27]=[CH:26][N:25]=2)[CH:42]=[CH:41][C:40]=1[F:43]
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: CCOP(=O)(CC(=O)O)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.77 ml of triethylamine, 3.43 g of diethoxyphosphorylacetic acid, and 5.62 g of benzotriazol-1-yl-N-tetramethyluronium tetrafluoroborate are added successively to 5.00 g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxyquinazoline in 25 ml of N,N-dimethylformamide. The reaction mixture is stirred for one hour at ambient temperature; 250 ml of water is then added and the mixture is extracted with 250 ml of ethyl acetate/methanol (10:1). The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated by evaporation. The residue in the flask is crystallized by stirring with diethylether.
Reaction SMILES: C([O:8][C:9]1[CH:39]=[CH:38][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:37])[N:21]([NH:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2NC(C3C(=O)N(NC4CCCC4)C4C(C=3O)=CC=CC=4)=NS(=O)(=O)C=2C=1)C1C=CC=CC=1>>[CH:31]1([NH:30][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]([OH:29])=[C:19]([C:14]3[NH:13][C:12]4[CH:38]=[CH:39][C:9]([OH:8])=[CH:10][C:11]=4[S:16](=[O:17])(=[O:18])[N:15]=3)[C:20]2=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1NC1CCCCC1
Agent: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1NC1CCCC1
Product: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NC1CCCCC1

Procedure:
The title compound was prepared according to the procedure of Example 305C substituting the product of Example 306B for the product of Example 305B (39 mg, 42%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][CH2:35][OH:36]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:33][CH2:34][CH2:35][OH:36])=[CH:14][C:13]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OCc2ccccc2)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc(NCCCO)cc2F)c(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 68.3 %

Procedure:
4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (500 mg, 1.48 mmol), K2CO3 (1.23 g, 8.9 mmol) and 3-bromo-1-propanol (410 mg, 2.9 mmol) were taken in dry DMF (2 ml) in a microwave vial and was subjected to microwave at 180° C. for 2 h. The reaction mixture was filtered over celite and the residue washed thoroughly with ethyl acetate. The combined organic fractions including the filtrate were washed with water, brine, dried over Na2SO4 and concentrated. The crude obtained was combined with earlier crude products obtained from a 100 mg and 200 mg batches and purified together by column chromatography over silica gel using 40% ethylacetate in pet ether as eluant to get 400 mg (42.6%) of pure title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:37](OC(=O)C)(=O)[CH3:38]>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19]3[N:22]=[C:37]([CH3:38])[O:21][N:20]=3)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Cc1c(C(=N)NO)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)no1
Temperature: 110 °C
Reaction time: 5 h
Yield: 34.9 %

Procedure:
5-(N-Hydroxycarbamimidoyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (0.011 g, 0.021 mmol), acetic anhydride (0.02 g, 0.195 mmol), toluene (2 ml) and a magnetic stirrer bar were placed in a vial. The vial was sealed and was heated (110° C.) with stirring for 5 h. LC-MS confirmed the consumption of the starting material and the formation of a product with the expected MW. Evaporation and purification on preparative HPLC gave the title compound (0.004 g, 35%) as a white solid after freeze-drying the pure fractions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[S:17][C:11]=3[C:10]2=[O:26])[CH:6]=[CH:5][C:4]=1[O:27]C(=O)C(C)(C)C.C[O-].[Na+]>C(O)C>[OH:27][C:4]1[CH:5]=[CH:6][C:7]([N:9]2[CH2:14][CH2:13][C:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[S:17][C:11]=3[C:10]2=[O:26])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2nc3c(s2)C(=O)N(c2ccc(OC(=O)C(C)(C)C)c(OC)c2)CC3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(s2)C(=O)N(c2ccc(O)c(OC)c2)CC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
Dissolve 2,2-dimethyl-propionic acid 2-methoxy-4-[2-(4-methoxy-phenyl)-4-oxo-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-phenyl ester (749 mg, 1.61 mmol) in absolute ethanol (18 mL) and add NaOMe (183.1 mg, 6.44 mmol). Allow the reaction mixture to stir for 4 h at ambient temperature. Quench the reaction mixture with 1N HCl solution. to pH=7. Add a small amount of EtOAc (15 mL) and filter the solid precipitate via vacuum filtration to give the title compound as a yellow solid (430 mg, 70%). MS (ES+) 383.3 (M+1)+. 1H NMR (CDCl3): δ 7.95 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.94 (d, J=6.2 Hz, 1H), 6.93 (s, 1H), 6.80 (dd, J=8.8, 2.2 Hz, 1H), 4.07 (t, J=7.0. Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.28 (t, J=7.0 Hz, 2H).
Reaction SMILES: C(O)(=[O:15])CCCCCCCCCCCCC.OO.[CH3:19][C:20]1([CH3:42])[S:24][C@@H:23]2[C@H:25]([NH:28][C:29]([CH2:31][O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[C:26](=[O:27])[N:22]2[C@H:21]1[C:39]([OH:41])=[O:40].[K].P([O-])([O-])([O-])=O>C1(C)C=CC=CC=1.C(#N)C>[CH3:19][C:20]1([CH3:42])[S:24](=[O:15])[C@@H:23]2[C@H:25]([NH:28][C:29]([CH2:31][O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[C:26](=[O:27])[N:22]2[C@H:21]1[C:39]([OH:41])=[O:40]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: OO
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2S1=O
Reaction time: 5 h

Procedure:
To a mechanically stirred suspension of immobilized C. antarctica lipase (150 mg, according to example 1) in toluene (15 ml) and myristic acid (1 g, 4.6 mmol), was hydrogen peroxide (1.2 ml 60% (w/v), 21 mmol in all) added in four equal portions after 0, 2, 3 and 4 hours. Penicillin V-potassium salt (2.4 g, 6.2 mmol in all) was added in three equal portions after 2, 3 and 4 hours. The yields were determined by HPLC (Column: Supelco RP-18, 5 micro; Mobile phase: Acetonitrile 20% and pH 6.5 Phosphate buffer 80%; Flow: 1 ml/min. UV-detector). Full turnover was reached after 5 hours total reaction time.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:4]#[N:5].[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].CC(N1CCCC1)(C)C(N)C1C=CC=CC=1>C(OCCCC)CCC.C1COCC1.CO>[NH2:5][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([N:2]([CH3:10])[CH3:1])([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCC(C#N)(CC)N(C)C
Reactant: [Li]c1ccccc1
Agent: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCOCCCC
Product: CCC(CC)(C(N)c1ccccc1)N(C)C
Yield: 88 %

Procedure:
The title compound (11.12 g, 88%) was prepared from 2-(dimethylamino)-2-ethylbutanenitrile D19 (8.05 g, 0.0575 mol) and phenyllithium in dibutylether (64 ml of a 1.8M solution; 0.115 mol) in THF (350 ml), followed by reaction with sodium borohydride (3.9 g, 0.103 mol) in methanol (300 ml) in a similar manner to that described in D5. 1H NMR (CDCl3) δ: 0.72 (3H, t, J=7.6 Hz), 0.97 (3H, t, J=7.6 Hz), 1.40-1.68 (4H, m), 1.70 (2H, br, m), 2.43 (6H, s), 4.09 (1H, s), 7.19-7.43 (5H, m).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:37]=[CH:36][CH:35]=[CH:34][C:13]3=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)([C:26]#[N:27])[CH2:22][CH2:21]3)[CH:15]=2)[N:10]=[CH:9]1.Cl.ClC1C=C(C=CC=1)C(OO)=[O:44].C(#N)C>C1COCC1.O>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:37]=[CH:36][CH:35]=[CH:34][C:13]3=[C:14]([CH2:19][N+:20]3([O-:44])[CH2:25][CH2:24][C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)([C:26]#[N:27])[CH2:22][CH2:21]3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: N#CC1(c2ccccn2)CCN(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: N#CC1(c2ccccn2)CC[N+]([O-])(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)CC1
Reaction time: 1 h

Procedure:
To a solution 1-({3-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)-4-pyridin-2-ylpiperidine-4-carbonitrile (Example 2, 9.0 mg, 0.018 mmol) in 1.5 mL of THF and 0.018 mL HCl (1 M in dioxane, 0.18 mL, 0.18 mmol) was added m-chloroperoxybenzoic acid (3.2 mg, 0.18 mmol). After 1 h, acetonitrile (1 mL) was added. After 15 h, additional m-chloroperbenzoic acid (1.6 mg, 0.090 mmol) was added. After 30 min, the reaction was treated with water and extracted 3× with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via preparative TLC eluting with 10% methanol in dichloromethane to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 510.2505 for [M+H]+ [Cal'd for C30H32N5O3, [M+H]+=510.2500]: 1H NMR (400 MHz, CDCl3) δ 9.05 (d, J=8.4 Hz, 1H), 8.61 (d, J=4.9 Hz, 1H), 8.54 (d, J=8.5 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 7.95-7.92 (m, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75-7.71 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 4.65 (br s, 1H), 4.05 (br s, 1H), 3.95-3.85 (m, 2H), 3.84-3.82 (m, 2H), 3.68-3.49 (m, 1H), 3.21-3.14 (m, 1H), 2.26-1.71 (m, 6H), 1.68-0.83 (m, 6H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][N:9]([CH3:18])[C:8]=1[CH3:19].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1>O1CCCC1>[F:30][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][N:9]([CH3:18])[C:8]=1[CH3:19]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Cc1c(Br)c(-c2ccccc2)cn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(F)c(-c2ccccc2)cn1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
n-Butyllithium (2.06 mL, 1.6M solution, 3.30 mmol) was added to a solution of 3-bromo-1,2-dimethyl-4-phenyl-pyrrole (550 mg, 2.20 mmol) in tetrahydrofuran (10 mL) at −78° C. and the reaction mixture was stirred at −78° C. for 30 min. A solution of n-fluorodibenzene sulfonamide (901 mg, 2.86 mmol) in tetrahydrofuran (8 mL) was added to the reaction mixture at −78° C. and the reaction mixture was stirred at this temperature for another 1 h. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h after which time the reaction mixture was quenched with dilute HCl and evaporated to dryness. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by preparative HPLC afforded 3-fluoro-1,2-dimethyl-4-phenyl-pyrrole (160 mg, 39%) as a solid.
Reaction SMILES: O[C:2]1([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.C(O)(=O)C.O>C(O)C.[Zn]>[F:10][C:9]([F:11])([F:12])[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: O=C1C=CC(O)(C(F)(F)F)C=C1
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of 200 mg (1.1 mmol) of 4-hydroxy-4-trifluoromethyl-2,5-cyclohexadien-1-one in 1 mL of absolute ethanol was treated successively with 147 mg (2.2 mmol) of zinc dust and 1 mL of a solution of 80% acetic acid--20% water. The mixture was heated to reflux for one hour, allowed to cool to room temperature, and poured into 20 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of diethyl ether. Combination, extraction with one 10 mL portion of 10% Na2CO3, drying (MgSO4), and concentration of the ether layers afforded a residue which was subjected to PTLC (one 2 mm silica gel plate eluted with dichloromethane), giving 151 mg (83% yield) of 4-trifluoromethylphenol.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2C(OC(C)(C)C)=O)=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>>[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][NH:23]2)=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84.7 %

Procedure:
Cooled TFA (5.0 mL) was added to tert-butyl (R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (526 mg, 1.11 mmol), and the mixture was stirred at room temperature for 2 min. The reaction mixture was poured into ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane) to give (R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (350.3 mg, 0.940 mmol, 84%) as a white solid.