Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[C:16]([F:17])=[C:15]2[C:10]([C:11](=O)[CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:14]2)=[CH:9][CH:8]=1>C(#N)C>[Br:3][C:11]1[C:10]2[C:15](=[C:16]([F:17])[C:7]([Cl:6])=[CH:8][CH:9]=2)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1
Reactant: O=c1cc(-c2ccccc2)[nH]c2c(F)c(Cl)ccc12
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: Fc1c(Cl)ccc2c(Br)cc(-c3ccccc3)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Phosphorus oxybromide (19 g, 0.066 mole), 7-chloro-8-fluoro-2-phenyl-1H-quinolin-4-one (6.2 g, 0.022 mole) and acetonitrile (40 mL) were combined in a 150 mL pressure bottle with a magnetic stir bar. The flask was heated at 100° C. and stirred overnight. Heat was removed, and an ice-water bath was installed. After 10 minutes, the bottle was opened, and water (60 mL) was added to the cooled stirring reaction. The quenching was exothermic to ca. 50° C. After stirring 10 minutes, a nice, filterable solid had formed, however, the reaction was extracted with 100 mL, then 3×50 mL methylene chloride. The extracts were combined, washed with saturated sodium bicarbonate solution (100 mL), and suction filtered through a small pad of silica gel, rinsing with methylene chloride. The filtrate was concentrated in vacuo, and put under high vacuum at 45° C. for 1 h to afford the crude product, which was recrystallized from 100 mL of ethanol, suction filtered to collect, and washed with ethanol. The purified product was vacuum oven dried for 1 h at 45° C. to afford the title compound as a white solid. A second crop was taken. The mother liquor was concentrated then chromatographed on silica gel with hexanes/methylene chloride 1:1 and combined with the second crop to afford additional material; 1H NMR (CDCl3, 400 MHz) δ 7.49-7.55 (m, 4H), 7.87-7.90 (dd, 1H, J=1.7 Hz & J=8.9 Hz), 8.15-8.18 (dd, 2H, J=1.5 Hz & J=7.9 Hz), 8.21 (s, 1H); HPLC tR=4.15 min (OpenLynx, nonpolar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:30][CH2:29][CH:28]([O:27][C:26]5[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=5)[CH2:33][CH2:32]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Oc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-fluoro-phenoxy)-piperidine (Table No.1, SM 5) in ethanol essentially as described above in Example 21. Purity by LC/MS=88%, [M+H]+=481.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.[NH:21]1[CH:25]=[CH:24][CH:23]=[N:22]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: c1cn[nH]c1
Reactant: Fc1ccc(C2=NOC(COc3ccon3)C2)cc1F
Product: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1-n1cccn1

Procedure:
(5RS)-3-(3,4-Difluorophenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (140 mg, 0.5 mM) was treated with pyrazole using essentially the conditions of Example 5. Crude product was chromatographed on a S g silica Mega Bond Elut® column, eluting with a gradient from 0–25% ethyl acetate in dichloromethane. Relevant fractions were combined to give the desired product (37 mg). MS ESP): 329 (MH+) for C16H13FN4O3
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].Cl>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:10][C:5]=2[O:4][C:3]1=[O:11]
Reactant: O=C(Cl)CCCl
Reactant: Cn1c(=O)oc2ccccc21
Agent: Cl
Product: Cn1c(=O)oc2cc(C(=O)CCCl)ccc21
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
The flask is equipped with a reflux condenser and taken to an oil bath at a temperature in the region of 40°-45° C. 0.04 mole of 3-methylbenzoxazolinone and 0.44 mole of 3-chloropropionic acid chloride are introduced. The mixture is heated to a temperature in the region of 75° C. for 2 hours 30 minutes. After cooling, the reaction mixture is poured into 300 g of ice, acidified with concentrated hydrochloric acid and stirred for 1 hour 30 minutes. The precipitate obtained is drained, washed with water and dried. The product is recrystallized in ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10](C)([O-])C.[K+].C(I)C>C(O)C>[CH2:9]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH3:10]
Reactant: Nc1ccccc1S
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: CCO
Product: CCSc1ccccc1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.8 %

Procedure:
2-Aminothiophenol (5.0 g, 40 mmol, Lancaster Synthesis Inc., Windham, N.H.) was stirred in dry ethanol (100 mL) and cooled in an ice bath. Potassium t-butoxide (4.5 g, 40 mmol) was added portionwise over 15 minutes and the mixture was stirred for an additional 45 minutes. Ethyl iodide (3.3 mL, 41 mmol) was added dropwise over 15 minutes and the mixture was allowed to warm to room temperature and stirred for 45 minutes. The mixture was filtered and the filtrate evaporated to dryness in vacuo. The resulting residue was treated with dichloromethane (100 mL) and filtered and the resulting filtrate was evaporated to dryness in vacuo to give 2-(ethylthio)aniline (5.2 g).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([CH2:22][C:23]#[N:24])[CH:19]=[CH:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-:26].[K+].[K+].OO.O>CS(C)=O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([CH2:22][C:23]([NH2:24])=[O:26])[CH:19]=[CH:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Cc1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Reaction time: 72 h
Yield: 70.1 %

Procedure:
To a solution of (3-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (58.3 mg) obtained in Example 128 in DMSO (5 mL) were added potassium carbonate (30.4 mg) and 30% aqueous hydrogen peroxide (0.056 mL), and the mixture was stirred for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (43.2 mg).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.Br[CH2:40][CH2:41][F:42].[H-].[Na+].[Br-].FC(F)(F)C(O)=O>CN(C=O)C>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:40][CH2:41][F:42])[CH2:30][CH2:31]2)[CH3:32])=[O:24])[C@:10]([CH2:9][OH:8])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=1
Reactant: FCCBr
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)C1CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 60 mg (0.11 mmol) of amine 7-2 in DMF at 0° C. was added 13 μL (0.17 mmol) of 1-bromo-2-fluoroethane and 8 mg (0.17 mmol) of NaH (60% dispersion in oil). After warming to room temperature, another portion of NaH and the bromide were added, and the reaction was allowed to stir overnight. LC-MS indicated still 25% unreacted 7-2, so the mixture was heated to 60° C. for several hours. After cooling to room temperature, ˜500 μL of trifluoroacetic acid was added and the mixture was stirred for 1 h. The reaction was partitioned between EtOAc and 15% aqueous Na2CO3, the layers were separated, the organic phase was washed with saturated NaHCO3, water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 12-1 as a white solid. Data for 12-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6-4.4 (m, 4H), 4.0 (m, 1H), 3.75 (m, 1H), 3.1 (m, 2H), 2.9 (s, 3H), 2.75-2.65 (m, 2H), 2.2 (m, 2H), 1.9 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H30F3N3O2: 474.2363. Found: 474.2355. Resolution of the enantiomers was carried out chromatographically using a Chiralpak AD© 10×50 cm column with 30% isopropanol in hexanes (with 0.1% diethylamine) at 150 ml/min. Analytical HPLC analysis of the eluent on a 4×250 mm Chiralpak AD® column with 30% isopropanol in hexanes (with 0.1% diethylamine) at 1 ml/min indicated that inactive enantiomer has Rt=6.3 min and the active enantiomer has Rt=7.5 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[Cl:26][C:27]1[C:28]([O:42][CH3:43])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:21])([F:22])[O:20][C:16]=5[CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[N:7]=2)[CH:30]=[N:29][C:28]=1[O:42][CH3:43]
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1Cl
Temperature: 80 °C
Yield: 27.4 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in 1,2-dimethoxyethane (2 mL) was added 3-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reaction mixture was heated to 80° C. in an oil bath overnight. The reaction mixture was diluted with dichloromethane (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (26 mg, 27%). ESI-MS m/z calc. 473.86. found 474.3 (M+1)+. Retention time 2.27 minutes.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[O:26]1CCCC1>>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][CH2:2][CH2:3][OH:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5 g, 12.5 mmol) in tetrahydrofuran (60 mL) was added BH3 THF (25 mL, 1 mol/L, 25 mmol) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then NaOH (3 mol/L, 10 mL) and H2O2 (15 mL) were added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by column chromatography to give (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (2.5 g, 40%). 1H NMR: (400 MHz, CDCl3): δ=1.48 (t, 3H), 1.53 (m, 1H), 1.73 (m, 1H), 1.93-1.98 (m, 2H), 2.17-2.28 (m, 3H), 3.57 (t, 2H), 5.59 (m, 1H), 6.72 (m, 2H), 7.20 (m, 2H), 7.25-7.37 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:29])[O:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]([NH:21][S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:6]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[N:25]1([S:22]([NH:21][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[N:10]=[C:5]([O:4][C@H:3]([CH3:29])[CH2:2][NH:1][C:36](=[O:38])[CH3:37])[CH:6]=2)(=[O:23])=[O:24])[CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CN)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-[6-((2)-2-amino-1-methylethoxy)-2-[[(2,3-Difluorophenyl)methyl]thio]pyrimidin-4-yl]azetidine-1-sulfonamide (the title product of Example 42) (0.05 g) in dichloromethane (10 mL) was added pyridine (0.02 mL), followed by acetic anhydride (0.02 mL). The mixture was stirred overnight at room temperature. Pyridine (0.02 mL) and acetic anhydride (0.02 mL) were added and the reaction mixture was stirred for a further 2 h. Pyridine (1.0 mL) and acetic anhydride (0.50 mL) were added and the reaction mixture was stirred for a further 2 h. The reaction mixture was diluted with dichloromethane, washed with aqueous citric acid, H2O, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 40% EtOAc in isohexane as eluent. The isolated product was further purified by reverse phase HPLC eluting with acetonitrile/aq. 0.1% ammonium acetate mixtures to give the title compound as a white solid. Yield: 55 mg.
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6]1)([CH3:3])[CH3:2].[F:23][C:24]([F:39])([F:38])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:37])[CH2:33][C:34](O)=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:34](=[O:35])[CH2:33][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([F:38])([F:23])[F:39])=[O:37])[C@H:7]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CC(=O)Nc2ccccc2C(F)(F)F)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 14 h

Procedure:
A solution of (1R*,3R*,4S*)-N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)cyclohexane-1,4-diamine (47.4 mg, 0.11 mmol, see example 25b) in DMF (2 mL) was charged sequentially with N-(2-trifluoromethyl-phenyl)-malonamic acid (29.5 mg, 0.12 mmol), BOP (72 mg, 0.16 mmol), and N-methyl morpholine (60 uL, 0.54 mmol). The solution was stirred for 14 h and the reaction was partitioned between water and EtOAc. The organic phase was washed with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by RP-HPLC to afford the desired product as a white powder (presumed mono-TFA salt). MS found: (M+H)+=554.32.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][N:23]([CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:32])[CH3:31])[CH:25]=1>C(OC(=O)C)(=O)C>[CH3:31][N:30]([CH3:32])[C:26]1[CH:25]=[C:24]([N:23]([CH3:33])[CH3:22])[CH:29]=[CH:28][C:27]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:17])[O:16]1
Reactant: Cc1[nH]c2ccccc2c1C(=O)c1ccccc1C(=O)O
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: Cc1[nH]c2ccccc2c1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
A mixture of 8.37 g (0.03 mole) of 2-[(2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 8.37 g (0.05 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 10 ml of acetic anhydride was interacted at 50° C. as described in part B of Example 8 above to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(2-methyl-3-indolyl)phthalide (Formula III: Ro =R1 =R2 =R3 =R6 =Y1 =H; R=R5 =CH3 ; R4 =N(CH3)2). After purification by slurrying in a benzene and ligroin mixture, the collected and dried product melted at 183°-186° C. The product had mass spectrum with a m/e peak at 425 (M+). Both the infrared and nuclear magnetic resonance spectra were consistent with this structure. A toluene solution of the product spotted on a phenolic resin coated paper developed an intense grape-colored image.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH:13](O)[N:14]=1.S(Cl)(Cl)=O.Cl.[CH2:28]([O:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][NH2:35])[CH3:29]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH:13]([NH:35][CH2:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])[N:14]=1
Reactant: Cc1c2c(cn1C)N(C)C(=O)C(O)N=C2c1ccccc1Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNC1N=C(c2ccccc2Cl)c2c(cn(C)c2C)N(C)C1=O
Reaction time: 24 h
Yield: 70.3 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1,7-dihydro-3-hydroxy-1,6,7-trimethyl-pyrrolo[3,4-e][1,4]diazepin-2(3H)-one (6.3 g, 0.0198 mole) and thionyl chloride (18 mole) is allowed to stand at room temperature for one night. The 3-chloro derivative which forms is precipitated by the addition of ethyl ether, recovered by filtration and washed on filter with ethyl ether. The obtained intermediate is dissolved in chloroform (100 ml) and triethylamine (8 g) and γ-aminobutyric acid ethyl ester hydrochloride (6.4 g, 0.0382 mole) are gradually added to the obtained solution. The reaction mixture is allowed to stand, at room temperature for one day, then chloroform is evaporated, the residue is taken up with water acidified with HCl and the undissolved oil is extracted with chloroform. The chloroform solution is neutralized by washing with aqueous NaHCO3, dried over Na2SO4, filtered and concentrated to dryness yielding 6 g of an oily residue.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:21](OC)(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:29]=[C:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[S:24][C:1]([C:3]2[CH:8]=[C:7]([CH:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 61 %

Procedure:
tert-Butyl 2-(2-cyano-4-pyridyl)-1-pyrrolidinecarboxylate (1.6 g, 6.0 mmol) and methyl thiosalicylate (3.0 g, 18.3 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.5 g, 63%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][C@H:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH:11]1[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cnc(CN[C@@H]2CCCc3cccnc32)c(C)c1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)C1CCCc2cccnc21

Procedure:
(R)-(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.40 g, 1.50 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.40 g, 1.57 mmol) and K2CO3 (0.58 g, 4.50 mmol) in CH3CN (10 mL) were reacted according to General Procedure A. The crude 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8yl)-amino]-methyl}-benzoic acid methyl ester was isolated as an orange-brown oil (0.68 g, 100%) and used without purification in the next step of the synthesis.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:18][CH2:19][CH2:20][OH:21]>C(Cl)Cl>[Br:18][CH2:19][CH2:20][O:21][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCOC1CCCCO1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
12 ml of dihydropyran and 20 mg of paratoluenesulphonic acid are added to a solution of 3.7 ml of 2-bromoethanol dissolved in 100 ml of methylene chloride. After stirring for 3 hours at 20° C., the reaction medium is washed with water and then with saturated aqueous sodium chloride, and evaporated to dryness. The residue is distilled at 90° C. at a pressure of 0.5 mbar.