Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#N)[C:3]=1[C:10]1[NH:19][C:18](=[O:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>[Zn].C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:10]1=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:18](=[O:20])[N:19]1[CH2:8]2
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)[nH]c1-c1c(F)cccc1C#N
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1c(F)cccc1C2
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 1.04 g of methyl 2-(2-fluoro-6-cyanophenyl)-1,6-dihydro-6-oxo-5-phenylnicotinate, 0.98 g of zinc powder and 30 ml of acetic acid was heated to boiling under reflux for 30 minutes. The mixture was filtered while hot and the filtrate was evaporated in a vacuum. The residue was stirred overnight in 30 ml of water, whereupon the resulting crystals were filtered off under suction and washed with methylene chloride. By chromatography on silica gel with methylene chloride/diethyl ether (9:1) there was obtained yellow crystals which were recrystallized from ethyl acetate. There was obtained 0.23 g of methyl 10-fluoro-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate with a m.p. of 134°-136°.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)=[O:13])=[C:4]1[CH3:23])[CH3:2].[C:24]([NH:27][C:28]1[CH:40]=[CH:39][C:31]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:32]([C:31]3[CH:39]=[CH:40][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:18])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CC(=O)Nc1ccc(Nc2ccccc2)cc1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Product: CCn1c(C)c(C2(N(c3ccccc3)c3ccc(NC(C)=O)cc3)OC(=O)c3ccccc32)c2ccccc21
Yield: 50.3 %

Procedure:
Following a procedure similar to that described in Example 1A but employing 4.5 g of 2-(1-ethyl-2-methyl-3-indolylcarbonyl)benzoic acid and 3.4 g of 4-acetamido-N-phenylaniline there was obtained 3.8 g of 3-(1-ethyl-2-methyl-3-indolyl)-3-[N-(4-acetamidophenyl)-N-phenylamino]phthalide, m.p. 93°-116° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a yellow-colored image.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2c1cccc(Cl)c1

Procedure:
The title compound was synthesized from methyl 4-(3-chlorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.179 g, 0.65 mmol) and lithium hydroxide (0.272 g, 6.5 mmol), according to General Procedure 7. A 1:1 mixture of THF and methanol (4 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound. 0.124 g. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.19 (ddt, J=12.73, 8.52, 6.46, 6.46 Hz, 1H), 2.69-2.97 (m, 3H), 4.17 (t, J=7.13 Hz, 1H), 6.53 (s, 1H), 7.11 (d, J=7.57 Hz, 1H), 7.13-7.18 (m, 2H), 7.20-7.26 (m, 1H); LCMS-MS (ESI−) 260.2 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])(O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:24])(=O)=O>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([Cl:24])([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC1(Cl)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.8 %

Procedure:
To a mixture of TEA (30 g, 296 mmol) and 1-benzhydryl-3-methyl-azetidin-3-ol (30 g, 118 mmol) in DCM (300 mL) at 0° C. was added a solution of methanesulfonyl chloride (20.49 g, 179 mmol) in DCM (15 mL) keeping the internal temperature below 5° C. The mixture was stirred at ambient temperature for 20 h and quenched by addition of water (50 mL). The organic phase was separated, dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0% EtOAc to 50% EtOAc in petroleum ether) to give 1-benzhydryl-3-chloro-3-methyl-azetidine (7 g, 22%): 1H NMR (CDCl3, 400 MHz): δ7.42-7.45 (m, 4H), 7.27-7.31 (m, 4H), 7.18-7.23 (m, 2H), 4.48 (s, 1H), 3.38-3.44 (m, 4H), 1.87 (s, 3H) and methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (16 g, 41%). 1H NMR (CDCl3, 400 MHz): δ7.40-7.37 (m, 4H), 7.20-7.28 (m, 4H), 7.16-7.20 (m, 2H), 4.42 (s, 1H), 3.33 (s, 4H), 3.02 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[CH:4].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26]>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.CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[C:4][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])/[C:14](=[O:19])[NH:15]2
Reactant: C#CC(N)(CC)CC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(N)(C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)CC

Procedure:
Using Method C above, 3-amino-3-ethyl-1-pentyne (37.6 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-4-[3-amino-3-ethyl-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 45 mg, 95%).
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([O:22]CC1C=CC=CC=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>CO.O.[Pd]>[NH:1]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
12 g of Boc-Tyr-(D)Ala-Gly-OBzl are dissolved in a mixture of methanol/H2O (9:1) and hydrogenated in the presence of Pd-C at normal pressure and room temperature. The mixture is fitered off from the catalyst, reduced in volume and crystallised from methanol/CH2CL2 /ether. Decomp. 110°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].[ClH:12].Cl[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:12])=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cl
Reactant: Cc1cc(C=NO)ccc1Br
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: Cc1cc(C(Cl)=NO)ccc1Br
Reaction time: 0.75 h

Procedure:
Into a solution of 82.0 g of 4-bromo-3-methylbenzaldoxim in 450 mL of tetrahydrofuran, 120.0 g of concentrated hydrochloric acid was dropped while stirring and ice-cooling the mixture over 45 minutes. Next, into the reaction mixture, 220 mL of 8% sodium hypochlorite aqueous solution was carefully dropped over 75 minutes so that the temperature of the reaction mixture does not exceed 5° C. After the completion of the dropping, the reaction mixture was stirred at 10° C. or less continuously for another 90 minutes. After the completion of the reaction, a nitrogen gas was blown into the reaction mixture for 45 minutes and the deposited insoluble matter was filtered off, followed by distilling off tetrahydrofuran under reduced pressure. The residual aqueous solution was extracted with 240.0 g of ethyl acetate and the organic phase was cleaned with water (240 mL×2). Subsequently, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure to obtain 93.5 g of the objective substance as a light yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2.Br[C:33]1[N:38]=[C:37]([C:39]([OH:41])=[O:40])[CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.[OH-].[Li+]>COCCOC.O.C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:33]2[N:38]=[C:37]([C:39]([OH:41])=[O:40])[CH:36]=[CH:35][CH:34]=2)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2
Reactant: O=C(O)c1cccc(Br)n1
Reactant: COc1ccc(B(O)O)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Temperature: 90 °C
Reaction time: 4 h
Yield: 76.9 %

Procedure:
A suspension of the [4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]boronic acid produced in Example 1-1 (2.41 g, 5.68 mmol), 6-bromopyridine-2-carboxylic acid (1.17 g, 5.68 mmol), sodium carbonate (2.41 g, 22.7 mmol), and tetrakis(triphenylphosphine) palladium(0) (0.33 g, 0.28 mmol) in 1,2-dimethoxyethane (48.2 ml) and water (21 ml) was prepared at room temperature, and the prepared suspension was then stirred at 90° C. for 4 hours. After air-cooling, a 10% aqueous solution of citric acid was added to the reaction solution, and the mixed solution was then extracted with dichloromethane three times. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then dissolved in THF (48 ml). Thereafter, an aqueous solution of lithium hydroxide monohydrate (524 mg, 12.5 mmol) was added to the solution obtained above, and the mixture thus obtained was then stirred at room temperature. Water was added to the reaction solution, and the resulting solution was then washed with diethyl ether. Thereafter, a 1 N aqueous solution of hydrochloric acid (12.5 ml) was added to the water layer, and the resultant was then extracted with dichloromethane four times. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=3:97 to 4:96, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (2.19 g, yield: 77%).
Reaction SMILES: [O:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]12([C:29](Cl)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([C:29]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:29]([C:19]45[CH2:28][CH:23]6[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]6)[CH2:26]4)[CH2:20]5)=[O:30])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][CH2:2][CH2:3]3)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2
Reactant: C1COCCOCCNCCOCCOCCN1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(N1CCOCCOCCN(C(=O)C23CC4CC(CC(C4)C2)C3)CCOCCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 2 from 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:9]=1)[NH2:6].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][S:27](Cl)(=[O:29])=[O:28])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][S:27]([NH:6][C:5]2[CH:7]=[C:8]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:29])=[O:28])=[CH:24][CH:25]=1
Reactant: COc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=S(=O)(Cl)Cc1ccc(F)cc1
Product: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 90.9 %

Procedure:
3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (822 mg, 3.29 mmol), was treated with (4-fluorophenyl)methanesulfonyl chloride (1.03 ml, 4.93 mmol) according to the method described in Preparation 15b to give 1.26 g (94% yield) of the title compound. Purity 97%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[CH:18]=1)=[CH:9][CH:8]=2.I[CH3:25]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH3:25])([CH3:23])[CH3:21])[CH:18]=1)=[CH:9][CH:8]=2
Reactant: CI
Reactant: CC(C)(O)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(C)(C)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
NaH (60%, 18 mg) was added to a solution of 1-(4-(3-chloroisoquinolin-6-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 22, 96 mg, 0.318 mmol) in THF (6 mL). After stirring for 15 minutes, iodomethane (0.1 mL, 0.57 mmol) was added. The resulting solution was stirred at 60° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with EtOAc, filtered and purified using Biotage silica gel column chromatography eluting with 25% EtOAc/cyclohexane to give the title compound as yellow oil (57 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12]>C1C=CC=CC=1>[C:2]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Cl:12])[CH:4]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(Cl)c1
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(Br)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 9 step (i) using 4-bromo-3-chlorobenzenesulfonyl chloride and benzene.
Reaction SMILES: [C:1]([C:3](=[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)SC)[C:4]([NH2:6])=[O:5])#[N:2].O.[NH2:21][NH2:22]>C(O)C>[NH2:2][C:1]1[NH:22][N:21]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(Nc1ccc(N(C)C)cc1)=C(C#N)C(N)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Temperature: 75 °C
Yield: 72 %

Procedure:
2-cyano-3-((4-(dimethylamino)phenyl)amino)-3-(methylthio)acrylamide (0.997 g) was suspended in 10 mL of ethanol and hydrazine hydrate (337 μL, 1.5 eq.) was added drop wise to the reaction. The reaction was then heated at 75° C. until the starting material was no longer present and confirmed via HPLC. Once starting material was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(dimethylamino)phenyl)amino)-1H-pyrazole-4-carboxamide as an off white to yellow powder. The product was allowed to dry under vacuum for 1 hr (900 mg, 72% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[N:13][N:12](CC3C=CN=CC=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[Se](=O)=[O:23]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccncc2)c1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnc2[nH]ncc2c1O

Procedure:
3 g of 4-hydroxy-1-(4-picolyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxylic acid ethyl ester (0.01 mol) is dissolved in 20 ml of acetic acid, 2.2 g of selenium dioxide (0.02 mol) and 2-3 drops of water are added. The mixture is refluxed for 30 minutes and then filtered off. 4-Hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester precipitates on cooling. Recrystallization from acetic acid yields 1.8 g (87%), m.p. 275°.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:22])=[C:16](F)[C:17]=3[O:19][CH3:20])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]2)[CH2:8][CH2:7]1>CN(C=O)C>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:22])=[C:16]([N:1]4[CH2:5][CH:4]=[CH:3][CH2:2]4)[C:17]=3[O:19][CH3:20])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1=CCNC1
Solvent: CN(C)C=O
Product: COc1c(N2CC=CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
3-Pyrroline (1 g; 14.5 mmol) and acid 52 (2.1 g; 7.2 mmol) in DMF (10 mL) were heated at 100° C. overnight. After cooling, the reaction mixture was filtered and washed with water. Acid 119 was isolated.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:18]=[C:17]([CH:19]=C)[CH:16]=[CH:15][C:14]=3[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:11]=2)[C:6]([CH3:29])([CH3:28])[CH2:5][C:4]1=[O:30])[CH3:2].CSC.B.[OH-:35].[Na+].OO>C1COCC1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:18]=[C:17]([CH2:19][OH:35])[CH:16]=[CH:15][C:14]=3[O:21][CH2:22][C:23]([F:24])([F:25])[F:26])[CH:11]=2)[C:6]([CH3:28])([CH3:29])[CH2:5][C:4]1=[O:30])[CH3:2]
Reactant: C=Cc1ccc(OCC(F)(F)F)c(-c2cc3c(cc2C)C(C)(C)CC(=O)N3CC)c1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(CO)ccc3OCC(F)(F)F)cc21
Reaction time: 8 h

Procedure:
To a solution of Compound 55A (0.24 mmol, 0.1 g) in 2 mL THF was added a solution of borane dimethylsulfide in THF (0.36 mmol, 0.03 mL) at 0° C. and the reaction mixture was stirred overnight. A solution of 2M NaOH (1 mL) was then added followed by a dropwise addition of hydrogen peroxide (30%, 1 mL). The solution was stirred at r.t. for 3 h. It was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The LCMS indicated the presence of the desired product (m/z found 436) and a byproduct where the amide carbonyl group was reduced to a methylene group (m/z found 422). The residue was purified by column chromatography (3:1 hexane/EtOAc followed by 1:1 hexane/EtOAc) to obtain 1-ethyl-7-[5-hydroxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,4,6-trimethyl-3,4-dihydro-1H-quinolin-2-one as a colorless oil (0.073 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:36][N:35]=[N:34][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 60 h
Yield: 0.4 %

Procedure:
A mixture of ethyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.21 g), sodium azide (1.3 g) and ammonium chloride (1.07 g) in DMF (8 ml) was stirred for 60 hours at 110-120° C. To the mixture was added water and the mixture was made acidic (pH 3-4) with 1N-HCl, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. To the concentrate was added ether, and resulting crude crystals were collected by filtration, followed by recrystallization from ethanol to afford colorless crystals (0.95 mg, 41%), m.p. 138-139° C.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH:7]=[CH2:8])[C:3]#[N:4].ClC1C=CC=C(C(OO)=[O:17])C=1.Cl>>[C:3]([CH:2]1[CH2:5][CH2:6][CH:7]([CH2:8][OH:17])[O:1]1)#[N:4]
Reactant: C=CCCC(O)C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Product: N#CC1CCC(CO)O1

Procedure:
The compounds of formula I wherein n is 0 are prepared by epoxidation-cyclization of novel cyanohydrins, i.e., 2-hydroxy-5-hexenenitrile or 2,5-dialkyl-2-hydroxy-5-hexenenitrile, of the formula ##STR3## wherein R1 and R2 are as defined for formula I, e.g., by epoxidation with m-chloroperbenzoic acid followed by treatment of the resulting epoxy cyanohydrin with hydrochloric acid to yield the novel 2-cyanotetrahydrofuran-5-methanol of the formula ##STR4## wherein R1 and R2 are as defined for formula I, and subsequent etherification e.g., with RCH2Cl. The 2-hydroxy-5-hexenenitriles are prepared by treating the corresponding unsaturated ketone with, acetic anhydride and potassium cyanide by the general procedure of R. Franks, R. Berry, and O. Shotwell, J. Am. Chem. Soc., 71, 3889 (1949). The unsaturated ketones are prepared by (1) reaction of an aldehyde with an unsaturated Grignard reagent followed by selective oxidation of the hydroxy group to a ketone, or (2) reaction of an allyl chloride with an alkanedione as described, for example, in F. Barbot, D. Mesnard, and L. Miginiac, Organic Preparations and Procedures International 10, 261 (1978).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:29])[C:18]3[C:13](=[CH:14][C:15]([O:30]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH3:28][O:27][C:24]1[N:25]=[CH:26][C:21]([C:20]2[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:10][CH:9]=3)[O:12][C:13]3[C:18]([C:19]=2[CH3:29])=[CH:17][CH:16]=[C:15]([OH:30])[CH:14]=3)=[CH:22][CH:23]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)cn1
Product: COc1ccc(C2=C(C)c3ccc(O)cc3OC2c2ccc(OCCN3CCCCC3)cc2)cn1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chromen-3-yl]-2-methoxy-pyridine and piperidine as the starting material.