Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[NH:31]1[CH:35]=[CH:34][C:33]([CH:36]([OH:38])[CH3:37])=[N:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>C(#N)C.[Cu-]=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]([OH:38])[CH3:37])=[N:32]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC(O)c1cc[nH]n1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: CC(O)c1ccn(-c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)n1
Temperature: 200 °C

Procedure:
Under argon atmosphere, 150 mg (purity 62%, 0.18 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 2 ml of absolute acetonitrile, and 405 mg (3.62 mmol) of 1-(1H-pyrazol-3-yl)ethanol, 118 mg (0.36 mmol) of caesium carbonate, 5 mg (0.04 mmol) of copper(I) oxide and 20 mg (0.15 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was heated in the microwave for 1 h at 200° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 20 mg (24% of theor.) of the target compound was obtained.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11](OC(=O)CCCC(OCCC)=O)[CH2:12]C>>[CH2:11]([O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:10])=[O:9])[CH3:12]
Reactant: CCCOC(=O)CCCC(=O)OCCC
Reactant: O=C(O)CCCCC(=O)O
Product: CCOC(=O)CCCCC(=O)O

Procedure:
Hexane dioic acid monoethyl ester was prepared from hexane dioic acid through steps (a) and (b) discussed above in example 1, step 2 for the preparation of (III).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:13][S:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=2[N:16]=1.C(=O)([O-])[O-:27].[K+].[K+]>>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:13][S:14]([C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=2[N:16]=1)=[O:27]
Reactant: CCOC(=O)c1ccc(N)c(CSc2nc3cc(OC)ccc3[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(N)c(CS(=O)c2nc3cc(OC)ccc3[nH]2)c1

Procedure:
The title compound was prepared by the method of Example 3 using 557 mg of the title product of Example 72 instead of the title product of Example 2. The reaction mixture was passed three times through a column of potassium carbonate powder and concentrated in vacuo to dryness. Crystallization for acetonitrile gave 257 mg of the title compound. Anal. Calc'd. for C18H19N3O4S: C, 57.90; H, 5.13; N, 11.25; S, 8.59. Found: C, 57.63; H, 5.15; N, 11.32; S, 8.65.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH2:36])[NH:34][N:35]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH:36][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:18][CH:17]=3)[NH:34][N:35]=2)[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCCN(C)CC2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 20421.1 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide was prepared following the procedure as for Example 115, but starting from of methyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate (0.372 g, 1.5 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.371 g, 1.5 mmol) and 2M trimethylaluminium in toluene (1.875 ml, 3.75 mmol). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% 2.5M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness and the residual oil crystallised from DCM/diethyl ether to afford the title compound (0. 142 g, 20.42%) as a white solid. 1HNMR (500.13 MHz, DMSOd6+CD3COOD@373K) δ: 2.08-2.15 (2H, m), 2.69 (3H, s), 2.88 (4H, s), 3.11 (2H, t), 3.19-3.24 (2H, m), 3.56 (2H, t), 3.72 (3H, s), 3.74 (2H, t), 6.30 (1H, d), 3.32 (1H,s), 6.49 (2H, s), 6.79 (2H, d), 7.86 (2H, d). MS: m/z 464 (MH+).
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[S:20][CH2:21][CH2:22][N:23]=1>O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[S:20][CH2:21][CH2:22][N:23]=1
Reactant: NC1=NCCS1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(C3=NCCS3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde, (uridinedialdehyde), (2.4 g) was dissolved in water (10 ml). To the solution was added 2-amino-2-thiazoline (1.2 g). The mixture was stirred at ambient temperature overnight. An insoluble material was filtered off. The filtrate was evaporated in vacuo. The residue was triturated with acetone to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-thiazolin-2-yl)morpholin-2-yl]uracil (0.98 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:17]Cl>>[Cl:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: Cc1ccc(-c2nsc3ccccc23)cc1
Product: ClCc1ccc(-c2nsc3ccccc23)cc1
Yield: 80.2 %

Procedure:
225 g of 3-(4'-methylphenyl)-1,2-benzisothiazole are heated to 170° C. in a stirred apparatus and 100 g of chlorine are passed in over 2 hours whilst irradiating the mixture with a UV lamp. The end point of the reaction is determined by gas chromatography (disappearance of the starting material). The reaction mixture is then cooled and the product is filtered off and recrystallized from methanol. 208 g of 3-(4-chloromethylphenyl)-1,2-benzisothiazole, melting at 86°-89° C., are obtained; this yield corresponds to 80% of theory.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23](OC)=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1.[NH2-].[Li+]>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:22]([C:28]3[CH:29]=[CH:30][C:31]([S:34][CH3:35])=[CH:32][CH:33]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: C1CCNCC1
Reactant: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)cc2)c1=O
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2N2CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
To a slightly heterogeneous solution of piperidine (99.7 mg, 1.17 mmol) and toluene (8 mL) cooled to −78° C. was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). After stirring at −78° C. for 10 minutes, the cooling bath was removed and the mixture stirred an additional 1 hour at 23° C. The 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (400 mg, 1.17 mmol) was dissolved in portions in toluene (3×6–7 mL aliquots) with a heat gun and cooled to 0° C. prior to transfer via syringe to the lithium amide solution (cooled to −78° C.). The addition was made slowly along the interior wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23° C. as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated, and the ethyl acetate layer washed with additional water and brine and dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:2) to provide 440 mg (95%) of 2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4-piperidino-3(2H)-pyridazinone.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[C:5]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[C:4]([OH:19])[C:3]=1[C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[F:39])[C:33](Cl)=O>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[F:29][C:30]1[CH:31]=[C:32]([C:33]2[O:1][C:2]3[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[C:5]([CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])=[C:4]([OH:19])[C:3]=3[C:20](=[O:22])[CH:21]=2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=CCc1c(O)c(CC=C(C)C)c2oc(-c3ccc(F)c(F)c3)cc(=O)c2c1O
Temperature: 25 °C
Yield: 2.4 %

Procedure:
Under nitrogen atmosphere, 1-[2,4,6-trihydroxy-3,5-di(3-methyl-2-buten-1-yl)phenyl]ethanone (300 mg, 0.986 mmol), anhydrous potassium carbonate powder (817 mg, 5.91 mmol), TBAB (tetrabutyl ammonium bromide, 477 mg, 1.47 mmol) and 3,4-difluorobenzoyl chloride (348 mg, 1.97 mmol) were dissolved in toluene (30 mL), and refluxed for 6 hours. After cooling, toluene was removed, and then water (20 mL) was added. The aqueous solution was extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. A brown residue was obtained after removal of solvent. The residue was dissolved in a 5% potassium carbonate aqueous solution and heated to reflux for 2 hr. After cooling to ambient temperature, the mixture was acidified to pH 6 with 1N HCl solution, and extracted with dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate, and the solvent was removed. The crude product was purified by silica gel column chromatography (eluent:ethyl acetate/petroleum ether, 1:50) to give the desired compound (10 mg, yield 2.3%). 1H NMR (400 MHz, CDCl3): δ=12.92 (s, 1H), 7.73-7.68 (m, 1H), 7.64-7.61 (m, 1H), 7.35-7.25 (m, 114), 6.59 (s, 1H), 6.42 (s, 1H), 5.27-5.24 (m, 2H), 3.54 (d, 2H, J=6.8 Hz), 3.47 (d, 2H, J=6.8 Hz), 1.85 (s, 6H), 1.78 (s, 3H), 1.76 (s, 3H); LC-MS (ESI) m/z 427.8 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[Sn](C)(C)C.[CH2:11]([O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1)[CH3:12].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[CH2:11]([O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[Br:1])[CH:16]=1)[CH3:12]
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: C[Sn](C)(C)C1=C(Br)CCC1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(C2=C(Br)CCC2)c1
Yield: 31 %

Procedure:
(2-Bromo-cyclopent-1-enyl)trimethyl stannane (˜80% pure) (13.150 g, 43.7 mmol), ethyl-3-iodobenzoate (24.000 g, 87.4 mmol), triphenylarsine (4.000 g) and tris(dibenzylideneacetone)palladium (0) (1.500 g), were heated in dimethylformamide (20 mL) at 100° C., under nitrogen for 92 hours. The reaction mixture was then filtered through highflo, thoroughly washed with dichloromethane, reduced to an oil, and purified by chromatography with iso-hexane containing ether (2%–50%) to give the title compound (4.000 g, 28%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[S:20][C:21]([F:26])=[C:22]([CH2:24]Cl)[N:23]=1)([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[S:20][C:21]([F:26])=[C:22]([CH2:24][S:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[N:23]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCl)c(F)s1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(SCc2nc(NC(=O)OC(C)(C)C)sc2F)cc1
Reaction time: 1 h
Yield: 64 %

Procedure:
Sodium hydride (60%, 58 mg, 1.44 mmol) was added to a solution of 4-methoxythiophenol (0.19 mL, 1.56 mmol) in THF (5 mL). The resulting slurry was treated with a solution of Intermediate 105: (4-chloromethyl-5-fluoro-thiazol-2-yl)-carbamic acid tert-butyl ester (320 mg, 1.2 mmol) in THF (2 mL). After one hour, sat. ammonium chloride was added (1 mL) and THF was removed at reduced pressure. The residue was partitioned with water (5 mL) and diethyl ether (2×10 mL). The organic layer was concentrated an purified by silica gel chromatography (EtOAc/hexane) to afford [5-fluoro-4-(4-methoxy-phenylsulfanylmethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester as a colorless foam (285 mg, 64% yield).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH3:10])=[O:8])=[CH:20][CH:21]=1)#[N:2]
Reactant: COc1ccc(CN(C)C(=O)c2ccc(C#N)cc2)cc1
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(O)cc1)C(=O)c1ccc(C#N)cc1
Yield: 78.6 %

Procedure:
The procedure of Preparation Example 2 was repeated, except that 71 mg of 4-cyano-N-(4-methoxybenzyl)-N-methylbenzamide was used in place of 4′-methoxy-2-biphenylacetonitrile, and toluene was used in place of methylene chloride. The resulting crude product was purified by TLC (using a 4:1 mixture of chloroform and acetone as the developing solvent) to obtain 53 mg of 4-cyano-N-(4-hydroxybenzyl)-N-methylbenzamide.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:21]([NH:29][C:30]([O:32][C@H:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1)=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[NH:4][CH2:5][CH:6]([CH3:8])[CH3:7].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[OH:1][C@@H:2]([C@@H:21]([NH:29][C:30]([O:32][C@H:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1)=[O:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:3]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[NH:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CNC([C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCCOC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CNC([C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCCOC1)S(=O)(=O)c1ccc(N)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A mixture of 2(S)-hydroxy-3(S)-[3(S)-tetrahydropyranyloxycarbonyl]amino-1-(4-nitrobenzenesulfonyl)-1-isobutylamino-4-phenylbutane (36 mg, 0.067 mmol) and SnCl2.2H2O (77 mg, 0.34 mmol) in 1 mL of EtOAc was heated to 70° C. After 1 h the starting material disappeared and the solution was allowed to cool to room temperature. The mixture was poured into sat aq NaHCO3 solution (3 mL) and extracted with EtOAc (10 mL). The organic extract was dried over anhyd MgSO4 and concentrated under reduced pressure to give 30 mg of 2(S)-hydroxy-3(S)-[3(S)-tetrahydropyranyloxycarbonyl]amino-1-(4-aminobenzenesulfonyl)-1-isobutylamino-4-phenylbutane.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1C(O)=O)=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl[C:24](=[CH2:29])[C:25]([O:27][CH3:28])=[O:26].C(N(CC)CC)C>ClC(Cl)C>[C:24]1([C:25]([O:27][CH3:28])=[O:26])[CH:29]=[CH:1][N:3]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: C=C(Cl)C(=O)OC
Reactant: O=CN1CCCCC1C(=O)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccn2c1CCCC2

Procedure:
To a solution of 10 g of carboxylic acid obtained in Step A (63.6 mmol) in 65 mL of dichloroethane there are added in succession 13.4 g of tosyl chloride (70.4 mmol), 11.5 mL of methyl 2-chloroacrylate (113.5 mmol) and then, dropwise, 17.8 mL of N,N,N-triethylamine (127.2 mmol). The reaction mixture is then refluxed for 1.5 hours. It is then brought to ambient temperature, and then 5 mL of methyl 2-chloroacrylate (48.9 mmol) and, dropwise, 9 mL of N,N,N-triethylamine (64 mmol) are added. The whole is heated at reflux overnight.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)no1
Reaction time: 6 h
Yield: 54.2 %

Procedure:
To a solution of 161b (300 mg, 0.57 mmol) in methanol (10 mL) was added NaBH4 (108 mg, 2.85 mmol) at room temperature. After the reaction was stirred for 6 h, LCMS indicated the reaction was complete. It was then quenched with water (10 mL) and concentrated under reduced pressure. The resulting residue was extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (1:20 to 100% ethyl acetate) to afford 161c (164 mg, 54%) as a white solid. MS-ESI: [M+H]+ 530.8
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][NH:3][CH2:2]2.Br[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:3]2[CH2:4][CH:5]3[CH2:9][CH:1]([CH2:8][NH:7][CH2:6]3)[CH2:2]2)[CH:12]=1
Reactant: C1NCC2CNCC1C2
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: c1cncc(N2CC3CNCC(C3)C2)c1
Yield: 25 %

Procedure:
3,7-Diazabicyclo[3.3.1]nonane, prepared as described in (Garrison, G. L. et. al., J. Org. Chem. 58, 27, (1993) 7670), and 3-bromopyridine were processed as described in Example 1A. The proportions of reagents were changed from Example 1A to the following: Pd2(dba)3 (0.02 eq), BINAP (0.05 eq), and NaOt-Bu (1.7 eq). The title compound was obtained in 25% yield after purification by flash chromatography (silica gel; CHCl3:MeOH:NH4OH; 90:5:1). MS (DCI/NH3) m/z 204 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[C:8]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[N:7][C:6]=1[CH3:24])[CH3:2].[H][H]>[Pd].C(O)CCC>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([NH2:16])[C:8]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[N:7][C:6]=1[CH3:24])[CH3:2]
Reactant: [H][H]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(NCC(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCCCO
Product: CCCCNc1c(N)c(NCC(C)C)nc(C)c1C(=O)OCC

Procedure:
17.6 g. of butylamino-6-(2-methylpropyl)amino-2-methyl-5-nitronicotinic acid ethyl ester (0.05 mol.) are dissolved in 100 ml. of butyl alcohol. 200 mg. of palladium on charcoal are added and the mixture is hydrogenated at 80° until the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off and the mixture evaporated to dryness. The resulting oil, 5-amino-4-butylamino-6-(2-methylpropyl)amino-2-methylnicotinic acid ethyl ester, is used without further purification.
Reaction SMILES: C([N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:23][CH:24]([F:26])[F:25])[CH:10]=2)[C:5]1=[O:27])C=C.C(N(CC)CC)C.C(O)=O>O1CCOCC1>[F:26][CH:24]([F:25])[O:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:27])[NH:4][C:13]([C:14]#[N:15])=[C:12]2[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1
Reactant: C=CCn1c(C#N)c(-c2cccc(F)c2)c2cc(OC(F)F)ccc2c1=O
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1[nH]c(=O)c2ccc(OC(F)F)cc2c1-c1cccc(F)c1

Procedure:
To a solution of 2-allyl-6-(difluoromethoxy)-4-(3-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile in 10 mL dioxane were added triethylamine (0.363 mL) and formic acid (0.079 mL). The solution was sparged with argon for 10 min, then Pd(PPh3)4 was added, and the reaction was heated to 100 C for 2 h. The reaction was concentrated to dryness, then partitioned between CH2Cl2 and and 50% brine. The organic solution was dried (MgSO4) and concentrated to dry solid. Flash chromatography (5-45% EA/hex, 1% MeOH, 40 g silica) provided 110 mg of 6-(difluoromethoxy)-4-(3-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile. The material was approximately 80% pure and was used without further purification.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.B(F)(F)F>C1C=CC=CC=1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])(=[O:5])[C:2]1[CH:3]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1OC(=O)c2ccccc21
Agent: FB(F)F
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1ccccc1
Temperature: 20 °C
Yield: 177 %

Procedure:
7.4 g of phthalic anhydride and 3.9 of benzene were charged at ambient temperature into a stainless steel autoclave. The autoclave was cooled by liquid nitrogen and 10 g of HF and 37.4 g of BF3 were introduced. The autoclave was heated to 20° C. and the pressure raised to 47 bars. The temperature was maintained at 20° C. for 15 minutes and the product degassed under reduced pressure in order to recover the catalyst. After washing with cold water, 10 g of crude o-benzoyl benzoic acid were obtained titrating 74.4% and containing 0.5% of anthraquinone, thus a chemical yield of 66%. After purification by extraction with 600 cm3 of boiling water, then crystallization by cooling to 20° C., o-benzoyl benzoic acid titrating 98.4% was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[N:13]=2)=[CH:8][C:7]=1[Cl:26])[CH2:2][CH2:3][CH3:4].C(OC1C=C(C2ON=C(C3C=CC=C4C=3C=CN4)N=2)C=CC=1OCC)C>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH2:21][CH2:20]4)[N:13]=2)=[CH:8][C:7]=1[Cl:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Agent: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Product: CCCCOc1ccc(-c2nc(-c3ccc4c(c3)CCN4)no2)cc1Cl
Yield: 92 %

Procedure:
When the product of Step C was substituted for 5-(3,4-diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 34, Step C, the identical process afforded the title compound in 92% yield. 1H-NMR CDCl3) 0.97 (tr, 3H, J=8.34 Hz), 1.41-1.6 (m, 2H); 1.76-1.91 (m, 2H); 3.45 (tr, 2H, J=8.16 Hz; 3.63 (tr, 2H); 4.10 (tr, 2H, J=6.45 Hz); 6.75 (d, 1H, J=7.56 Hz); 7.06 (d, 1H, J=7.11 Hz); 7.18 (tr, 1H, J=7.77 Hz); 7.51 (broad d, 1H, J=7.8 Hz); 8.04 (dd, 1H, J=2.07-8.61 Hz); 8.21 (d, 1H, J=2.07 Hz).