Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[BH4-].[F:3][C:4]([F:17])([F:16])[CH:5]([C:12]([F:15])([F:14])[F:13])[CH:6]([C:8](OC)=[O:9])[NH2:7].Cl>C1COCC1>[F:3][C:4]([F:16])([F:17])[CH:5]([C:12]([F:13])([F:14])[F:15])[CH:6]([NH2:7])[CH2:8][OH:9]
Reactant: COC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.9 %

Procedure:
A solution of LiBH4 (2M THF, 19.66 mL, 39.33 mmol) was added to a solution of methyl 4,4,4,4′,4′,4′-hexafluoro-dl-valinate (2.35 g, 9.83 mmol) in THF (80 mL) at 0° C. The reaction was allowed to warm to 25° C. After 19 h, the reaction was cooled to 0° C. and 2M HCl was added to the reaction mixture very carefully until pH<2. The organic solvent was removed in vacuo and the aqueous layer was neutralized with sat NaHCO3 until pH=7. The aqueous layer was extracted with EtOAc (2×50 mL) and the organic extracts were dried over Na2SO4 and concentrated to provide 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propyl amine as a yellow oil (1.7 g, 82% yield). The crude oil was of sufficient purity to utilize in the subsequent reaction. Mass Spectrum (−ESI): 210 [M−H]−.
Reaction SMILES: CS[CH:3]1[CH2:12][CH:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH2:10]2)[C:5](=O)[C:4]1=[CH:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[CH3:28][NH:29][NH2:30].O>C(O)C>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][N:15]([C:14]2[C:4]3[CH2:3][CH2:12][C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]=3[N:29]([CH3:28])[N:30]=2)[CH2:20][CH2:19]1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: CNN
Reactant: CSC1CC2CC=CC=C2C(=O)C1=CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: O
Product: Cn1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2c1-c1ccccc1CC2
Yield: 11 %

Procedure:
2-(Methylthio(4-(tert-butyloxycarbonyl)piperazin 1-yl)methylene-4,5-dihydro-2H-naphthalen-1-one (3.2 g, 8.2 mmol) and methylhydrazine (5 ml) were kept in ethanol (30 ml) for four days. Water (150 ml) was added, and the mixture extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine, dried (MgSO4), evaporated in vacuo, and purified by flash chromatography, eluting with hexane:ethyl acetate (4:1 v/v) to give 3-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-4,5-dihydro-1-methyl-1H-benzo[g]indazole (342 mg, 11%) as a colourless oil; 1H NMR (360 MHz, CDCl3) δ 1.52 (9H, s, tBu), 2.67 (2H, t, J=7.3 Hz, CCH2CH2C), 2.94 (2H, t, J=7.3 Hz, CCH2CH2C), 3.15 (4H, t, J=5.1 Hz, NCH2), 3.61 (4H, t, J=5.1 Hz, NCH2), 4.15 (3H, s, Me), 7.22-7.34 (3H, m, ArH), 7.55 (1H, d, J=7.7 Hz, H-9). Iradiation at δ 4.15 gave a positive nOe to the doublet at δ 7.55, and the reverse; and 3-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-4,5-dihydro-2-methyl-2H-benzo[g]indazole (561 mg, 19%) as a white solid δ (360 MHz, CDCl3) 1.54 (9H, s, tBu), 2.86 (2H, t, J=7.8 Hz, CCH2CH2C), 2.95 (2H, t, J=7.8 Hz, CCH2CH2C), 3.08 (4H, t, J=4.9 Hz, NCH2), 3.60 (4H, t, J=4.9 Hz, NCH2), 7.20-7.30 (3H, m, ArH), 7.83 (1H, d, J=7.5 Hz, H-9).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:29]>C(#N)C.CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[N:13]([CH3:29])[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Product: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3n2C)CC1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A solution of 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 51, 260 mg) in anhydrous acetonitrile (10 mL) is treated with 60% sodium hydride (47 mg) for 1 h at room temperature. The mixture is then cooled to 0° C. and iodomethane (36 μL) is introduced. After stirring for 15 h, dilution with water and extraction with ethyl acetate, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5) to afford the pure base that is then converted into its dioxalate salt in acetone to give 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole, dioxalate, melting at 76° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])C>O1CCCC1.O>[C:12]1(=[O:13])[N:8]([CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[C:9](=[O:14])[CH:10]=[CH:11]1
Reactant: CCOC(CCCN1C(=O)C=CC1=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: O=CCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Maleimidobutyraldehyde diethylacetal (2 g, 8.29 mmol) in tetrahydrofuran (20 ml) and water (0.5 ml) was stirred under argon and DOWEX 50X8 ion exchange resin (H+, 2 g, ® Dow Chemical Co.) was added. After 12 hours stirring at room temperature, the solvent was decanted, dried (MgSO4) and evaporated in vacuo to afford 4-maleimidobutyraldehyde (formula III) as a yellow oil which rapidly solidified on standing (1.38 g, 99%); TLC Rf=0.4, ethyl acetate/hexane 1:1. The 4-maleimidobutyraldehyde turned out to be extremely unstable, so that it was necessary to do all work-up at low temperatures (0° C.) and under complete exclusion of oxygen (inert atmosphere).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([O:16]C)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][O:5][C:6]=1[CH3:7].[Li+].[OH-].Cl>CO>[Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COC(=O)[C@H](CC(C)C)Nc1noc(C)c1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(N[C@@H](CC(C)C)C(=O)O)c1Br
Temperature: 0 °C

Procedure:
A methanol solution (25 mL) of methyl N-(4-bromo-5-methylisoxazol-3-yl)leucinate (602 mg, 1.97 mmol) and 2 M LiOH (10 ml, 20 mmol) was stirred for 50 minutes at room temperature. Ice water and aq. 10% HCl was added and the product was extracted with ethyl acetate (3×), dried over Na2SO4 and concentrated in vacuo to afford N-(4-bromo-5-methylisoxazol-3-yl)leucine which was used as is in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7]CCO.[CH2:11]([O:13][C:14](=[O:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]S(C)(=O)=O)[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:7][CH2:6][CH2:5][O:4][CH3:3])[CH3:12]
Reactant: COCCOCCO
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
NaH (88 mg of a 60% dispersion in oil, 2.2 mmol) was suspended in anhydrous toluene (3 ml) under N2 and chilled to 0° C. Monodispersed diethylene glycol monomethyl ether (0.26 ml, 0.26 g, 2.2 mmol) that had been dried via azeotropic distillation with toluene was added. The reaction mixture was allowed to warm to room temperature and stirred for four hours, during which time the cloudy grey suspension became clear and yellow and then turned brown. Mesylate 5 (0.50 g, 1.0 mmol) in 2.5 ml dry toluene was added. After stirring at room temperature over night, the reaction was quenched by the addition of 2 ml of methanol and the resultant solution was filtered through silica gel. The filtrate was concentrated in vacuo and the FAB MS: m/e 499 (M+H), 521 (M+Na). Additional purification by preparatory chromatography (silica gel, 19/3 chloroform/methanol) provided the monodispersed compound 6 as a clear yellow oil (0.302 g 57%). FAB MS: m/e 527 (M+H), 549 (M+Na).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([SH:16])[CH:11]=[C:12]([Cl:15])[C:13]=1[OH:14].[F:17][C:18]([F:31])([F:30])[CH2:19]OS(C1C=CC=CC=1)(=O)=O.Cl>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([S:16][CH2:19][C:18]([F:31])([F:30])[F:17])[CH:11]=[C:12]([Cl:15])[C:13]=1[OH:14]
Reactant: O=S(=O)(OCC(F)(F)F)c1ccccc1
Reactant: Oc1c(Cl)cc(S)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1c(Cl)cc(SCC(F)(F)F)cc1Cl
Reaction time: 6 h
Yield: 71.1 %

Procedure:
64 g of potassium carbonate were added to a solution of 41.9 g of 3,5-dichloro-4hydroxy-benzenethiol in 200 ml of N,N-dimethylformamide under nitrogen atmosphere. To the stirred mixture were dropped at 30° to 40° C. 55 g of 2,2,2-trifluoroethyl-benzenesulfonate. The whole was stirred at 60° to 70° C. for 6 hours, cooled, mixed with 1.5 l of water, and acidified to pH 2 by dropwise addition of hydrochloric acid. A resulted oil was extracted with toluene and the toluene extract was washed with water. The washed toluene extracted was stirred with 160 ml of a 25% aqueous potassium hydroxide solution, and a water layer was separated. Then the separated water layer was acidified to pH 2 by adding hydrochloric acid. A resulted oil was extracted with toluene. The toluene extract was washed with water, dried over anhydrous sodium sulphate, and evaporated to give a residue. The residue was distilled under reduced pressure to give 42.3 g of 2,6 -dichloro-4-(2,2,2-trifluoroethylthio)-phenol which boiled at 85° to 88° C./1 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[C:17]3[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][S:12][CH2:11][CH2:10]2)[CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[C:17]3[C:23]([C:24](=[O:29])[C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH:6]=[C:7]([N:9]2[CH2:10][CH2:11][S:12](=[O:38])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc(N2CCSCC2)c1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc(N2CCS(=O)CC2)c1
Yield: 73.3 %

Procedure:
To a solution of 1-[2-(3-methoxy-5-thiomorpholin-4-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (80 mg, 0.195 mmol) in methylene chloride (5 ml) and methanol (5 drops) was added m-CPBA (44 mg, 0.195 mmol). After 1 hour the crude material was loaded onto 2 preparative TLC plates, eluting with 10% methanol in methylene chloride. The product band was collected to afford 61 mg of 1-{2-[3-methoxy-5-(1-oxo-1lambda*4*-thiomorpholin-4-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one as a light yellow-brown solid. MP 259-260° C., M+H=427.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>ClCCl>[O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([N:24]1[CH2:25][CH2:26][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:28][CH2:29]1)=[O:22]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.31 g, 1 mmol), tert-butyl piperidin-4-ylcarbamate (CAS 73874-95-0, 0.2 g, 1 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.38 g, 1 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (0.7 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with sequentially with 20 mL of 1 N HCl, water, 20 ml, of 1 N NaOH, and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.33 (m, 8H), 7.21 (m, 2H), 4.45 (m, 2H), 4.03 (m, 1H), 3.77 (m, 1H), 3.49 (m, 2H), 3.11 (m, 1H), 2.79 (m, 1H), 2.63 (m, 2H), 1.97 (m, 2H), 1.83 (m, 2H), 1.45 (m, 9H), 1.32 (m, 2H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17]([NH2:20])(=[O:19])=[O:18].[CH:22]1([C:28]2[C:29]3[CH:30]=[CH:31][C:32]([C:50](O)=[O:51])=[CH:33][C:34]=3[N:35]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][C:38]4[CH:44]=[C:45]([O:48][CH3:49])[CH:46]=[CH:47][C:37]=4[C:36]=23)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17]([NH:20][C:50]([C:32]1[CH:31]=[CH:30][C:29]2[C:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:36]3[C:37]4[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:38]=4[CH2:39][N:40]([CH3:43])[CH2:41][CH2:42][N:35]3[C:34]=2[CH:33]=1)=[O:51])(=[O:19])=[O:18]
Reactant: COC(=O)CS(N)(=O)=O
Reactant: COc1ccc2c(c1)CN(C)CCn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C)Cc1cc(OC)ccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
1.6 eq of 1-ethyl-(3-dimethylaminopropyl)carbodiimide HCl salt was added to a mixture of 2.7 eq of DMAP, 1.6 eq of methyl(aminosulfonyl)acetate and the hydrochloride salt of 14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]-benzodiazocine-11-carboxylic acid (from Example 4) in DCM (0.02 M). The reaction was stirred at RT overnight before being partitioned between aqueous HCl (1 N) and EtOAc. The organics were washed with saturated aqueous NaHCO3, water and brine before being dried over Na2SO4, filtered and concentrated in vacuo. The crude was then purified by RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 30×50 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (18%).
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[CH:30]=[O:31])=[CH:24][CH:23]=1>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:30](=[O:31])[CH:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: Cc1ccc(/C=C/C=O)cc1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: Cc1ccc(CC2C(=O)Oc3[nH]c(-c4cc(F)ccc4F)nc3C2c2ccccc2)cc1
Yield: 82 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(p-tolyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 7 as an off-white solid (106 mg, 82%). Analytical data for 7: 1H NMR (500 MHz, CDCl3) δ 9.35 (d, J=8.1 Hz, 1H), 7.89 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.38-7.29 (m, 3H), 7.13 (d, J=7.7 Hz, 2H), 7.05 (ddd, J=11.4, 8.9, 4.1 Hz, 1H), 7.02-6.94 (m, 5H), 4.08 (d, J=6.8 Hz, 1H), 3.58 (ddd, J=10.2, 6.8, 4.5 Hz, 1H), 3.32 (dd, J=14.8, 4.5 Hz, 1H), 2.39 (dd, J=14.9, 10.2 Hz, 1H), 2.35 (s, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.0, 159.1 (d, JCF=243.8 Hz), 155.4 (d, JCF=240.9 Hz), 148.9, 137.1, 136.34, 136.30, 134.7, 129.3, 129.2, 128.9, 128.3, 128.0, 118.4 (dd, JCF=12.8, 9.1 Hz), 117.1 (dd, JCF=25.7, 8.8 Hz), 116.5 (dd, JCF=24.7, 9.6 Hz), 114.5 (dd, JCF=26.8, 3.7 Hz), 111.1 (d, JCF=4.0 Hz), 47.4, 38.3, 32.2, 21.1; IR (film) cm−1 3029, 2923, 1768, 1618, 1529, 1482, 1463, 1452, 1351, 1240, 1172, 1118, 1102, 811, 766, 736, 700; LRMS (ESI): Mass calcd for [M+H]+ C26H21F2N2O2: 431.2. found 431.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 4% IPA/2% MeOH/hexanes; 0.7 mL/min, 280 nm), Rt1 (major)=34.4, Rt2 (minor)=43.7 min; er=99:1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH:16]=[O:17])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:18]([O:21][CH:22]=[CH2:23])(=[O:20])[CH3:19]>C(OCC)C>[C:18]([O:21][CH:22]1[C:5]2([CH:16]=[O:17])[C:6]3[C:11]([CH:12]([C:13]4[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=42)[CH2:23]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:20])[CH3:19]
Reactant: O=Cc1c2ccccc2cc2ccc(Cl)cc12
Reactant: C=COC(C)=O
Solvent: CCOCC
Product: CC(=O)OC1CC2c3ccccc3C1(C=O)c1cc(Cl)ccc12
Temperature: 200 °C
Yield: 463.8 %

Procedure:
A mixture of 2-chloro-9-formylanthracene (described in example 1b) (100.0 g, 0.415 mol) and vinyl acetate (400 ml, 374 g, 4.34 mol) was placed in a stainless steel bomb (PARR) and heated at 200° C. (sand bath temp.) for 24 h, then cooled. The reaction mixture was concentrated on the rotary evaporator to remove the excess vinyl acetate, leaving the crude product as a tan crystalline solid. The crude product from several batches, which consumed 670.0 g (2.78 mol) of the 2-chloro-9-formylanthracene, was pooled. Trituration with diethyl ether (1.0 L) gave an off-white crystalline solid which was collected by filtration, washed with diethyl ether (2×300 ml), then vacuum dried to afford 629.0 g (69.1%) of the title compound (mp 145°-153° C.). 1H NMR (CDCl3) 10.58 (s) and 10.64 (s, 1H), 7.63 (m) and 7.76 (d, J=1.5 Hz, 1H), 7.15-7.36 (m, 6H), 5.46 (m, 1H), 4.29 (s, 1H), 2.55 (m, 1H), 1.88 (s) and 1.91 (s, 1H), 1.55 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]#[N:12].[C:13]([O:16][C:17]1[CH:25]=[C:24]([NH:26][C:27]([CH3:29])=[O:28])[C:23]([Cl:30])=[CH:22][C:18]=1[C:19](Cl)=[O:20])(=[O:15])[CH3:14]>C(Cl)(Cl)Cl>[C:11]([CH2:10][NH:9][C:19](=[O:20])[C:18]1[CH:22]=[C:23]([Cl:30])[C:24]([NH:26][C:27]([CH3:29])=[O:28])=[CH:25][C:17]=1[O:16][C:13](=[O:15])[CH3:14])#[N:12]
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)Cl)cc1Cl
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(C)=O)c(C(=O)NCC#N)cc1Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
104 g of triethylamine and 890 cc of chloroform were introduced into a 3 liter balloon flask provided with a sealed agitator, a reflux condenser and a thermometer. The solution obtained was cooled to 5° C. 51 g of amino acetonitrile hydrochloride was then gradually added, with the temperature being maintained at between 5° and 10° C. Thereafter over a period of 30 minutes and at a temperature of between 0° and 5° C., 143 g of 2-acetoxy 4-acetamino 5-chlorobenzoyl chloride in finely divided form was added. A dark-coloured solution resulted, which was agitated, first, for a period of 2 hours at 10° C. and, thereafter, for 2 hours at ambient temperature.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=O)=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (93 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=C(C#N)[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:18][C:19]([OH:21])=[O:20]>CO>[CH3:1][C:2]1[N:7]=[C:18]([C:19]([OH:21])=[O:20])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(-c2ccccn2)c(C#N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2ccccn2)c(C(=O)O)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
6′-Methyl-[2,3′-bipyridine]-2′-carbonitrile (0.87 g, 4.46 mmol) and NaOH (1.87 g, 46.8 mmol) were dissolved in methanol (3 mL) and stirred at reflux overnight. The reaction was cooled to rt, diluted with more methanol (5 ml), and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% DCM/EtOAc) to yield the title compound as a clear oil (0.9 g, 94%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]([O-])=[O:23])[S:21][C:14]=12.[Li+]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:22]([C:20]2[S:21][C:14]3[C:15](=[N:16][CH:17]=[CH:18][C:13]=3[Cl:12])[CH:19]=2)=[O:23])[CH2:4][CH2:3]1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CN1CCN(CCCNC(=O)c2cc3nccc(Cl)c3s2)CC1

Procedure:
The title compound was prepared from 3-(4-methylpiperazin-1-yl)-propylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 353/355 (MH+); HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccccc1F
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1cccnc1Cl
Temperature: 90 °C

Procedure:
A 50 mL round bottom flask was charged with 2-chloropyridin-3-ol (2.5 g, 19 mmol), 2-fluorobenzonitrile (2.6 g, 21 mmol) and potassium carbonate (6.7 g, 48 mmol) in DMF (10 mL) and heated at 90° C. for 1.5 days. Water was added water, and the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 10-20% ethyl acetate in hexanes as eluent to afford the title compound as an off white solid (2.1 g, 47% yield).