Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13](O)=[O:14])=[CH:9][CH:8]=1)#[N:6]>>[C:5]([C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13]([Cl:3])=[O:14])=[CH:9][CH:8]=1)#[N:6]
Reactant: N#Cc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: N#Cc1ccc(C=CC(=O)Cl)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.2mol of p-cyanobenzaldehyde and 0.3mol of malonic acid were dissolved in 80ml of pyridine at room temperature, and 30 drops of piperidine were added thereto. The mixture was heated and stirred for 4 hours at about 100° C. After the reaction, the solution was poured slowly into dilute hydrochloric acid (250ml hydrochloric acid/250g water). Then, the resulting white precipitate was separated by filtering and washed with dilute hydrochloric acid and water, and was recrystallized by use of glacial acetic acid to obtain p-cyanocinnamic acid. 0.3mol of thionyl chloride was added to 0.1mol of the p-cyanocinnamic acid and the mixture was heated and stirred at about 80° C for 3 hours. An excess thionyl chloride was then removed under reduced pressure to obtain p-cyanocinnamic acid chloride.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([OH:33])([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH:23]=[CH:24]2)[CH:19]=[CH:18]3)[CH2:15][CH2:14]1)[CH3:12])[C:4]([F:7])([F:6])[F:5].[OH:36]O>>[F:1][C:2]([F:34])([F:35])[C:3]([OH:33])([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[C@@H:23]4[O:36][C@@H:24]42)[CH:19]=[CH:18]3)[CH2:15][CH2:14]1)[CH3:12])[C:4]([F:6])([F:5])[F:7]
Reactant: OO
Reactant: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C

Procedure:
treating the resulting 26,26,26,27,27,27-hexafluoro-25-hydroxycholest-1,4,6-trien-3-one with hydrogen peroxide to obtain 26,26,26,27,27,27-hexafluoro-25-hydroxy-1α,2α-epoxycholest-4,6-dien-3-one
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO.CCCCCC>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccccc1
Yield: 64.6 %

Procedure:
Preparation of example 24 from the title compound of Example 7 (hydrochloride) (23 mg, 0.082 mmol), benzoic acid (11 mg, 0.09 mmol), triethylamine (0.016 mL, 0.115 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (34 mg, 0.090 mmol) in CH2Cl2 (0.3 mL) and N,N-dimethylformamide (0.3 mL) was carried out analogously to Example 11. Silica gel chromatography (10:9:1 hexane:CH2Cl2:methanol followed by 8:5:2 CH2Cl2:hexane:methanol), also in an analogous manner, afforded the title compound (20 mg, 0.053 mmol) as a yellow powder in 64% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][N:32]=[N:31][CH:30]=1)CCC>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:34]=[CH:33][N:32]=[N:31][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnnc4)ncc3O2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (50 mg) and 4-(tributylstannyl)pyridazine (60 mg) in N,N-dimethylformamide (1 mL) is sparged with argon for 10 min and Pd(PPh3)3 (16 mg) is added. The resulting mixture is heated in an oil bath to 120° C. for 7 h. Ethyl acetate and water are added and the organic phase is separated, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 95:5→90:10). The crude product is triturated with diethyl ether, filtered off, and dried to give the title compound. LC (method 7): tR=1.35 min; Mass spectrum (ESI+): m/z=383 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH3:37].O>CN(C)C=O.C(OCC)(=O)C>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:36][CH3:37])=[O:16])[CH2:10][CH2:9]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)CC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A suspension of 23.6 g of N-triphenylmethyl-4-piperidineacetic acid, 16.9 g of potassium carbonate and 5.0 ml of ethyl bromide in 230 ml of dried N,N-dimethylformamide was stirred at 90° C. for 5 hours. After cooling, the reaction mixture was added with water and ethyl acetate, and the precipitated crystals were collected by filtration and washed with water to give 20.6 g of colorless crystals. Recrystallization from a mixture of methanol and tetrahydrofuran gave colorless crystals having the melting point of from 165 to 166° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].C(#N)C>O>[CH3:21][C:4]1[N:3]2[N:22]=[N:23][N:24]=[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]=1[CH3:20]
Reactant: CCOC(=O)CCCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCNc1c(C)c(C)n2nnnc2c1[N+](=O)[O-]
Yield: 98.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of ethyl 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butanoate (21.5 g, 68 mmol), sodium azide (8.90 g, 136 mmol), cerium(III) chloride heptahydrate (12.7 g, 34 mmol), and 9:1 acetonitrile:water (250 mL) was heated overnight at reflux. The hot reaction mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure, and the residue was triturated with ethyl acetate:hexanes and isolated by filtration to provide 21.5 g of ethyl 4-[(5,6-dimethyl-8-nitrotetraazolo[1,5-a]pyridin-7-yl)amino]butanoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19](O)=[O:20])=[N:11][C:12]3[N:13]([N:16]=[CH:17][CH:18]=3)[C:14]=2[F:15])=[C:4]([F:22])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:41]=[N:40]C=2C=1.NN.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:40][NH2:41])=[O:20])=[N:11][C:12]3[N:13]([N:16]=[CH:17][CH:18]=3)[C:14]=2[F:15])=[C:4]([F:22])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NNC(=O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Reaction time: 0.5 h

Procedure:
A mixture of 6-(4-bromo-2-fluorophenylamino)-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (1.00 equivalent), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMF is stirred for 30 minutes. Hydrazine (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After 3 hours, the reaction mixture is diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer is dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[C:22]([Cl:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[Cl:25])=[N:11][CH:12]=1.[CH3:26][O:27][C:28]([C:30]1[CH2:31][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:33][CH2:34][C:35]=1OS(C(F)(F)F)(=O)=O)=[O:29].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:26][O:27][C:28]([C:30]1[CH2:31][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:33][CH2:34][C:35]=1[C:7]1[CH:12]=[N:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[C:22]([Cl:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[Cl:25])=[CH:9][CH:8]=1)=[O:29]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(Br)cn2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
BuLi (1.6M in hexane, 39.3 mL, 45.2 mmol) was added to a sol. of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-pyridine (11.0 g, 28.3 mmol) in THF (700 mL) at −78° C. The mixture was stirred for 1 h, and ZnCl2 (0.71M in THF, 78.6 mL, 56.5 mmol) was added. This sol. was allowed to warm up to rt. A sol. of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957; 13.0 g, 34.5 mmol) in THF (30 mL) and Pd(PPh3)4 (814 mg, 0.704 mmol) were added. The mixture was stirred for 30 min at rt. Aq. sat. NH4Cl was added, and the mixture was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9→1:1) yielded the title compound (10.7 g, 70%). LC-MS: tR=1.16 min; ES+: 537.33.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH3:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([N:13]([CH3:12])[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNCc1ccccc1
Reactant: OC(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCC(O)c1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-1-phenylpropan-1-ol (2 g, 11.7 mmol), N-methylbenzylamine (2.12 g, 17.5 mmol), potassium iodide (2.6 g, 22 mmol), and potassium carbonate (3.2 g, 23.4 mmol) in dimethylformamide (120 mL) was stirred at 90° C. in a reacti-vial for 16 h. After this time the reaction was allowed to cool to room temperature. The reaction mixture was purified by an SCX-2 column eluting with Methanol followed by ammonia:methanol solution (7 N). The organics were then evaporated and the compound taken directly onto the next step without any further purification. (M+H+1 [256]); δH (300 MHz, CDCl3) 7.2-7.4 (10H, m, Ar), 4.9 (1H, t, CH—OH), 3.55 (1H, d, CH2-Ph), 3.45 (1H, d, CH2—PH), 2.8-3 (1H, m, CH2), 2.55-2.65 (1H, m, CH2), 2.25 (3H, s, CH3), 1.89-1.9 (2H, m, CH2), 1.6 (1H, brs, OH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[O:13]1[C:17]2[CH:18]=[CH:19]C=CC=2N=C1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:19][CH:18]3[CH2:17][O:13]3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: c1ccc2ocnc2c1
Reactant: Cc1ccc2ccc(O)cc2n1
Product: Cc1ccc2ccc(OCC3CO3)cc2n1

Procedure:
Compound 81 was prepared in the manner of compound 6 substituting 7-hydroxy-2-methyl-quinoline for compound 8 in part C-5 of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]1([CH2:18][CH2:19][CH2:20]O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:13]1([CH2:18][CH2:19][CH2:20][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=2[O:11][CH3:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OCCCC1CCCC1
Reactant: COc1cc(CC#N)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CC#N)ccc1OCCCC1CCCC1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
2-(4-Hydroxy-3-methoxyphenyl)acetonitrile (0.54 g, 3.31 mmol) in THF (10 mL) was treated with 3-cyclopentylpropan-1-ol (0.424 g, 3.31 mmol), triphenylphosphine (1.128 g, 4.3 mmol) and cooled in an ice bath to 0° C. DIAD (0.785 ml, 4 mmol) was added to the reaction mixture dropwise over the period of 5 min, and the reaction was left stirring slowly warming to room temperature over 18 hours. The reaction mixture was concentrated. Purification by flash chromatography (silica gel, 0-40% EtOAc/hexanes) afforded 0.871 g (96%) of 2-(4-(3-cyclopentylpropoxy)-3-methoxyphenyl)acetonitrile. MS (ESI) m/z 274 (M+H)+
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Temperature: 220 °C
Yield: 71 %

Procedure:
A mixture of 16.5 grams of 2-(4-methoxyphenyl)-6-methoxybenzothiophene and 50 grams of pyridine hydrochloride was prepared. The mixture was heated at 220° C. for six hours. The resulting mixture then was poured into an ice-water mixture. The mixture was filtered, and the collected solid was dried in air and recrystallized from methanol to obtain 10.5 grams of 2-(4-hydroxyphenyl)-6-hydroxybenzothiophene, melting point 305°-306° C.
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[C:10](OCC)=[O:11].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C(Cl)Cl>[N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[CH2:10][OH:11]
Reactant: CCOC(=O)c1cc2n(n1)CCOC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc2n(n1)CCOC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
To a solution of ethyl 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate (1.57 g, 8.0 mmol) in methylene chloride (30 ml) was added 24 ml of a 1.0 M solution of diisobutylaluminum hydride in methylene chloride at 0° C., under nitrogen. After stirring for 0.5 hr at 0° C., the mixture was warmed to room temperature for 2 hr. It was then treated with 30 ml of saturated ammonium chloride solution and extracted with ethyl acetate. The organic solution was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give 1.27 g of a colorless oil; MS (ESI) m/z 155.3 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[CH2:7][C:8]([Br:11])([F:10])[F:9])(=[O:3])[CH3:2].C([SnH](CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([Br:11])([F:9])[F:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(Br)CC(F)(F)Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1C
Product: CC(=O)OCCCC(F)(F)Br
Temperature: 120 °C
Reaction time: 18 h
Yield: 6.2 %

Procedure:
A solution of 8.6 grams (0.028 mole) of 2,4-dibromo-4,4-difluorobutyl acetate and 8.2 ml (0.028 mole) of tributyltin hydride in 15 ml of xylene was stirred, and 0.01 gram of 1,1'-azobisisobutyronitrile was added. The reaction mixture was warmed to 120° C. where it was stirred for 18 hours. The reaction mixture was distilled under reduced pressure, yielding 0.4 gram of 4-bromo-4,4-difluorobutyl acetate; b.p. 40°-55° C./1.8 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[CH2:12]([N:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:3]1[CH2:1][CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCBr
Reactant: CCc1nc(C)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCn1cc(C)nc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Hexyl-2-ethyl-4-methylimidazole was prepared in the following manner. All manipulations were performed under a nitrogen atmosphere. 2-Ethyl-4-methylimidazole (1.0 g) was dissolved in 10 mL THF. Sodium hydride (0.218 g) was added as a solid. An additional 10 mL of solvent was used to wash the hydride into the flask. There was a vigorous evolution of hydrogen. Mixture was stirred at room temperature overnight. 1-Bromohexane (1.568 mL) was added all at once. Mixture was stirred over weekend at room temperature and then refluxed for several hours. Reaction mixture was cooled and then filtered through Celite 545. Solvent was stripped under vacuum to yield viscous, yellow oil. Proton NMR spectrum (E102868-78) is consistent with indicated formulation and starting 1-bromohexane. This mixture was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)#[N:22].C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([C:21]#[N:22])[CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#Cc1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c1
Yield: 70.3 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 3-cyanobenzaldehyde (36.8 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 72.70 mg (63%) of the title compound. (300 MHz, DMSO-d6) 13.44 (s, 1H), 8.49 (s, 1H), 8.43 (d, J=8 Hz, 1H), 7.99 (s, 1H), 7.95 (d, J=8 Hz, 1H), 7.77 (m, 2H), 7.35 (d, J=9 Hz, 1H) 7.25 (s, 1H), 6.41 (m, 2H), 5.14 (t, J=17 Hz, 8.5 Hz, 1H), 2.91 (s, 1H), 2.81 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=405 (M+H), HPLC: 2.39 min. (G Method)
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)[CH3:4].[CH3:28][O:29][CH2:30][CH2:31][OH:32]>>[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:32][CH2:31][CH2:30][O:29][CH3:28])[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CCN1CCN(c2nc(-c3ccnc(Cl)c3)cc3ccccc23)CC1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: CCN1CCN(c2nc(-c3ccnc(OCCOC)c3)cc3ccccc23)CC1

Procedure:
60% oily sodium hydride (0.20 g) was added gradually to 2-methoxyethanol (50 ml), under ice-cooling. To the resulting solution was added 1-(4-ethylpiperazin-1-yl)-3-(2-chloropyridin-4-yl)isoquinoline (0.20 g) obtained in the previous Example, and the mixture was heated under reflux for 3 days. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purif ied water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol systemn), to give the title compound (0.12 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)[N:14]=[CH:13]1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)[N:14]=[CH:13]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(CN4CCOCC4)cc3c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
To a solution of methyl 4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzoate (0.62 g) in methanol (10 ml) and water (4 ml) was added 2N NaOH (2.35 ml) and stirred at room temperature for 4 hours. 1N HCl was added and the reaction was allowed to stand for 16 hours and then concentrated. The residue was dissolved in methanol (40 ml), inorganics removed by filtration. The filtrate concentrated to give 4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzoic acid as a solid (0.60 g). Mass Spectrum: M+H+ 380.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[C:22]([Cl:34])=[CH:21][N:20]=1>>[Cl:34][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 61 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine to yield 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-(2-methoxy-phenyl)-pyrimidine-2,4-diamine (2.93 mg, 61% yield) as a white powder. 1H-NMR (CDCl3) δ 8.44 (d, J=7.8 Hz, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.37 (s, 1H), 7.23 (m, 1H), 7.02 (m, 2H), 6.92 (m, 3H), 5.84 (m, 1H). 3.94 (s, 3H), 2.80 (m, 3H), 2.68 (m, 2H), 2.07 (m, 2H), 1.30 (m, 2H). LC/MS (ESI+)=474 (M+H). MP=191-193° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:8]2[C@@H:5]([C:6](=[O:20])[N:7]2CC2C=CC(OC)=C(OC)C=2)[N:4]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:3]1.O=C1[C@@H]2[C@@H](CCN2C(OCC2C=CC=CC=2)=O)N1>>[OH:1][C@@H:2]1[C@@H:8]2[C@@H:5]([C:6](=[O:20])[NH:7]2)[N:4]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:3]1
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@@H](O)CN3C(=O)OCc2ccccc2)cc1OC
Agent: O=C1N[C@@H]2CCN(C(=O)OCc3ccccc3)[C@H]12
Product: O=C1N[C@H]2[C@@H]1N(C(=O)OCc1ccccc1)C[C@@H]2O

Procedure:
Benzyl (1S,4S,5S)-4-hydroxy-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate was prepared from benzyl (1S,4S,5S)-4-hydroxy-6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (Example 1) in the same manner as described for benzyl (1S,5R)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (Example 1).