Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[Cl:23]N1C(=O)CCC1=O.C(OCC)(=O)C.O>CN(C)C=O>[Cl:23][C:20]1[N:12]2[C:13]3[S:17][C:16]([CH2:18][CH3:19])=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]2=[N:22][N:21]=1
Reactant: CCc1cc2c(s1)-n1cnnc1CN=C2c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(s1)-n1c(Cl)nnc1CN=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
4-(2-Chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (10.0 g) and N-chlorosuccinimide (4.55 g) were dissolved in dimethylformamide (50 ml), and the mixture was stirred at room temperature overnight. Ethyl acetate and water were added thereto. The organic layer was washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 1.8 g of 9-chloro-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine.
Reaction SMILES: CO[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10].[Cl-].[NH4+:23]>C(O)C>[NH:23]=[C:6]1[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:3][CH2:8][NH:7]1
Reactant: COC1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCO
Product: N=C1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1

Procedure:
The mixture of 5-methoxy-4-p-nitrobenzyloxycarbonyl-1,2,3,6-tetrahydropyrazine (5.7 g) and ammonium chloride (1.6 g) in dry ethanol (100 mL) was heated to reflux for 4 hours. The reaction mixture was then concentrated under reduced pressure. Dichloromethane (100 mL) was added to the residue and extracted with water (3×50 mL) then the combined aqueous layer was washed with dichloromethane. The aqueous layer was neutralized with 10% potassium carbonate aqueous solution and then extracted with dichloromethane (8×50 mL). The combined organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the title compound was obtained as a white solid. Yield: 4.9 g, 91.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:25]=[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH2:11][N:35]2[CH2:34][CH2:33][CH:32]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][C:26]3=[O:25])[CH2:37][CH2:36]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCCCN1C1CCNCC1
Product: CCN1C(=O)c2ccccc2C1C(CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 137.4 %

Procedure:
A solution of 3-(3,4-dichlorophenyl)-3-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.476 g) was treated with 4-(2-oxopiperidino)piperidine (0.945 g) as described in Example 8. The resulting material was not purified by chromatography but was transformed into the hydrochloride to give title compound (0.51 g); mp 135°-140° C. (dec); MS: m/z=558(M+1); NMR(CD3OD): 1.22 (m,3), 2.2 (m,12), 3.0 (m,11), 4.5 (m, 1), 5.04 (d,1, J=3.85), 7.27 (m,7). Analysis for C29H35Cl2N3O2. HCl.H2O: Calculated: C, 59.74; H, 6.56; N, 7.20; Found: C, 59.77; H, 6.33; N, 6.83.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([OH:26])[CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[OH:26])[CH:10]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]=1[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=1
Reactant: COc1nc2ccc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc2ccc(C(O)C3CCNCC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methyl)piperidine-1-carboxylate (110 mg, 0.19 mmol, Intermediate 11: step a) in DCM (5 mL) was added TFA (75 μL, 0.97 mmol). The resulting solution was stirred at room temperature for 2 hours. TFA (75 μL, 0.97 mmol) was added and the mixture stirred at room temperature overnight. Then the reaction was diluted with DCM, cooled to 0° C., and the pH adjusted to ˜pH 8 by the addition of 3 N aqueous NaOH dropwise. The layers were separated and the organics dried (MgSO4), filtered and concentrated to dryness to afford the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14](O)[CH2:15]C=C)=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.CSC.[C:31](=[O:34])([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][CH:31]=[O:34])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: C=CCC(O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CSC
Solvent: CO
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=CC=O
Reaction time: 2 h
Yield: 96.1 %

Procedure:
N-[4-(4-fluorophenyl)-5-(1-hydroxybut-3-enyl)-6-isopropyl-pyrimidin-2-yl]-N-methylmethanesulfonamide (4 g, 10.2 mmol) is diluted in 102 mL methanol. O3 gas is bubbled through the solution at −15° C. to −10° C. for 60 min. Reaction solution is bubbled through with Argon for 2 min to remove the excess of O3. Dimethylsulfide (1.5 ml, 20.3 mmol) is added to the solution, maintaining stirring for 2 hours. To the reaction mixture, potassium carbonate (2.8 g, 20.3 mmol) is added at room temperature. The progress of the reaction is monitored by TLC. Upon completion of the reaction, 150 ml sodium bicarbonate (aq.) is added and methanol is distilled off under reduced pressure. The residue is extracted with ethyl acetate (2×300 mL) and washed with DM water (100 mL) and brine (150 mL). The organic solvent is distilled off under reduced pressure to give 3.7 g (95%) of N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methyl-methanesulfonamide The product is recrystallized from 20% ethylacetate:cyclohexane at 0° C. to 5° C. to afford 2.4 g (67%) of N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methyl-methanesulfonamide as an oily white-yellow solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:16]2[NH:17][C:18]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:19][N:20]=2)[CH2:14][OH:15])OCC[O:4]1)[CH3:2].C(Cl)Cl.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>>[F:37][C:36]([F:39])([F:38])[C:34]([O-:40])=[O:35].[OH:15][CH2:14][CH:13]([C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)=[CH:19][NH+:20]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3](=[O:4])[CH2:1][CH3:2]
Reactant: CCC1(CCCCCC(CO)c2ncc(-c3ccc4ccccc4c3)[nH]2)OCCO1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)CCCCCC(CO)c1[nH]c(-c2ccc3ccccc3c2)c[nH+]1
Product: O=C([O-])C(F)(F)F
Reaction time: 2 h

Procedure:
The alcohol C1 was dissolved in DCM/TFA (8:2, 0.03 M solution) and the solution was stirred for 2 hr and then the solvents were removed under reduced pressure and the crude was purified by preparative RP-HPLC (column: C18), using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents. The desired fractions were lyophilized to yield a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 14.41 (1H, bs), 8.40 (1H, s), 8.22 (1H, s), 8.15-8.06 (1H, m), 8.03-7.92 (3H, m), 7.70-7.54 (2H, m), 3.70 (2H, d, J=5.9 Hz), 3.32-3.19 (1H, m), 2.47-2.32 (4H, m), 1.88-1.72 (2H, m), 1.56-1.40 (2H, m), 1.35-1.15 (4H, m), 0.92 (3H, t, J=7.2 Hz). MS (ES) C23H28N2O2 requires: 364, found: 365 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CSc1cccc2c(Cl)cc(C)nc12
Product: CSc1cccc2c(NCc3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methylsulfanylquinoline and 4-chlorobenzylamine.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:39])[CH2:37][CH3:38]
Reactant: CCC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: CCC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(OC)cc(N5CCN(C)CC5)c4o3)cc2)CC1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)amide (Example 43) and commercially available propionyl chloride (Aldrich) via the parallel synthesis described above. MS-base peak at m/z=534 by positive ion CI.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(C(C)C)CC)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.5 g, 1.3 mmol), diisopropylethylamine (0.5 mL, 2.9 mmol), and anhydrous dichloromethane (17 mL). Cool to 0° C. using an ice bath. Add methanesulfonyl chloride (201 mg, 1.36 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.26 (silica gel, ethyl acetate).
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:13][C:14]([C:17]3[S:18][CH:19]=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=3[CH3:22])=[N:15][N:16]=2)=[CH:7][C:6]=1[CH3:27])C=C.C[N+]1([O-])CC[O:32]CC1.[C:36]([OH:40])([CH3:39])([CH3:38])C>CC(C)=O.O.O=[Os](=O)(=O)=O>[CH2:23]([C:20]1[C:21]([CH3:22])=[C:17]([C:14]2[O:13][C:12]([C:8]3[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:38][CH:36]([OH:40])[CH2:39][OH:32])=[C:6]([CH3:27])[CH:7]=3)=[N:16][N:15]=2)[S:18][CH:19]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: C=CCOc1c(C)cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc1C
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CO
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 2-(4-allyloxy-3,5-dimethyl-phenyl)-5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazole (181 mg crude, 0.4 mmol) in a mixture of acetone and water (15:1.5 mL) are added N-methylmorpholine-N-oxide (250 mg, 1.85 mmol) and, subsequently, 2.5% OsO4 in tert.-butanol (0.1 mL). The mixture is stirred at rt for 36 h. The mixture is quenched into diethyl ether (75 mL) and washed with 1M aq. NaOH (50 mL), 1M aq. HCl (30 mL) and brine (20 mL). The organic phase is dried (Na2SO4), filtered and evaporated. The residue is purified by TLC (SiO2, EA-heptane) to give 118 mg of 3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol as a white powder; LC-MS: tR=1.00 min, [M+1]+=417.28; 1H NMR (D6-DMSO): δ, 7.70 (s, 2 H) 7.51 (s, 1 H), 4.96 (d, J=5.0 Hz, 1 H), 4.63 (t, J=5.6 Hz, 1 H), 3.68-3.89 (m, 3 H), 3.47 (t, J=5.6 Hz, 2 H), 2.51 (s, 3 H), 2.45 (m, 2 H), 2.33 (s, 6 H), 1.85 (m, 1 H), 0.90 (d, J=6.7 Hz, 6 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.[CH3:12][Mg+].[Br-]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]([OH:10])[CH3:12])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)nc(N)nc1Cl
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A fine suspension of 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (3.0 g, 15 mmol); (Seela, F.; Stecker, H. Helv. Chim. Acta 1986, 69, 1602) in THF was cooled to −78° C. A 3M solution of MeMgBr in THF (25 mL, 75 mmol, 5 equiv.) was added over 3 h, keeping the internal temperature at −78° C. The mixture was stirred for a further 0.5 h, quenched with 100 ml H2O, and neutralized with aw. HCl. Extraction (EtOAc) gave 1-(2-amino-4,6-dichloro-pyrimidin-5-yl)-ethanol as a pale yellow solid (2.5 g, 76%) which was used without further purification.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([O-:19])=[O:18]>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[N+:17]([O-:19])=[O:18])[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)-hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene was treated dropwise simultaneously with a solution of sodium hydroxide (1.24 g of 50% aqueous solution) in 5 ml of water and 2-nitrobenzoyl chloride (0.96 g). The resulting mixture was stirred at 23° C. overnight. Water was added and the mixture was extracted with ether. A second extraction was performed with methylene chloride and the combined organic extracts were dried over magnesium sulfate. Evaporation afforded 0.4 g of N'-t-butyl-N-(2-pyridinecarbonyl)-N'-(2-nitrobenzoyl)hydrazine as a yellow solid. m.p. 137-140° C.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:7][O:6]1)[CH2:2][CH:3]=[CH2:4].[CH2:8]=[CH:9][CH2:10][CH2:11]CC>>[CH2:1]([CH:5]1[CH2:7][O:6]1)[CH2:2]/[CH:3]=[CH:4]/[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CCCCC
Reactant: C=CCCC1CO1
Product: CCCC/C=C/CCC1CO1

Procedure:
2-(But-3-enyl)oxirane (1.000 g, 10.2 mmol) and hex-1-ene (9.12 g, 102 mmol) were stirred at room temperature for 24 hr in a sealed scintillation vial with Zhan Catalyst-1 (0.057 g, 0.086 mmol). Solvent was removed under reduced pressure and the residue purified by column chromatography (0–10% EtOAc/n-hexane/silica) to give (±)-(E)-2-(oct-3-enyl)oxirane as a colorless oil. 1H NMR (CDCl3): δ 5.5–5.4 (m, 2H), 3.0–2.9 (m, 1H), 2.8–2.7 (m, 1H), 2.5–2.45 (m, 1H), 2.2–2.1 (m, 2H), 1.99 (q, 2H, J=5.7), 1.65–1.55 (m, 2H), 1.35–1.25 (m, 4H), 0.95–0.85 (m, 3H). Contains ca 20% (Z)-2-(oct-3-enyl)oxirane.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60]O.C(Cl)[Cl:63]>>[ClH:63].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH3:54])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: ClCCl
Reactant: COCCOCCO
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCOCCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
Diethyl azodicarboxylate (236 μl, 1.5 mmol) was added dropwise to a mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (182 mg, 0.5 mmol), (prepared as described for the starting material in Example 48), triphenylphosphine (393 mg, 1.5 mmol) and 2-(2-methoxyethoxy)ethanol (84 μl, 0.7 mmol) in methylene chloride (7 ml) under nitrogen. The mixture was stirred for 4 hours at ambient temperature, the reaction mixture was purified by pouring it directly on to a column of silica and eluting with ethyl acetate/petroleum ether (9/1 followed by 10/0). The purified product was triturated with ether and collected by filtration. The solid was dissolved in methylene chloride/methanol and 2M ethereal hydrogen chloride (1 ml) was added. The mixture was concentrated by evaporation and the precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline hydrochloride (84 mg, 34%).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][CH2:5][C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH3:3]>O1CCOCC1.ClCCl>[CH2:2]([O:4][CH2:5][C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([NH2:1])=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH3:3]
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCC(=O)Cl
Reactant: N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOCc1nc2cnc3cccnc3c2n1CCCC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ammonia in dioxane (33 mL of 0.5 M) was added to a solution of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoyl chloride (4.64 mmol, prepared as described in Parts A and B of Example 38) in dichloromethane (20 mL), and the reaction was stirred overnight at ambient temperature. An analysis by HPLC indicated the reaction was incomplete; ammonia gas was bubbled through the solution for 10 minutes. The reaction was then stirred for one hour and concentrated under reduced pressure. The residue was triturated with water and isolated by filtration to provide 1.02 g of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanamide. The filtrate was extracted with dichloromethane (3×20 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an additional 0.39 g of product. The combined solids were mixed with material from another run.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH2:35][CH2:36][S:37][CH3:38])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:48])C=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([O:34][CH2:35][CH2:36][S:37]([CH3:38])=[O:48])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCSC)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
180 mg 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-[2-(methylsulfanyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (0.326 mmol, 1.0 eq.) were dissolved in 1.7 mL chloroform and cooled to 0° C. 80.3 mg 3-chlorobenzenecarboperoxoic acid and the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with DCM and a solution of sodium thiosulfate (10% in water) was added and stirred for 5 minutes. The layers were separated and the aqueous layer was washed with DCM twice. The combined organic layers were washed with saturated sodium hydrogencarbonate solution, was dried over a silicon filter and concentrated in vacuo. The crude product was purified by flash chromatography to provide 136 mg of the analytically pure target compound as a racemate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.[S:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][C:7]=1[C:24]1([OH:27])[CH2:25][CH2:26][S:22][CH2:23]1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Reactant: O=C1CCSC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Nc1ccc(C2(O)CCSC2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-fluorophenyl)-2,2,5 ,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran (16 mL) at -78° C. under N2 is treated with sec-butyllithium (1.3 M in cyclohexane, 3.30 mL) dropwise over 2 mins, and the resulting mixture is stirred at -78° C. for 2 hrs. The mixture is then treated with a solution of tetrahydrothiophen-3-one (423 mg) in dry tetrahydrofuran (4.1 mL) dropwise over 2 mins and is stirred at -78° C, allowing the cooling bath to expire over 4 hrs. The mixture is then quenched with saturated aqueous ammonium chloride (25 mL), diluted with water (25 mL), the layers are separated, and the combined organic phase is washed with saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (16 mL) and treated with anhydrous potassium carbonate (1.09 g), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 3-fluoro-4-[3-(hydroxy)tetrahydrothiophen-3-yl]benzenamine intermediate (Rf =0.37 by TLC, ethlyl acetate/hexane (50/50)). A solution of this intermediate in tetrahydrofuran (16 mL) and water (8 mL) is then treated with sodium bicarbonate (662 mg) and benzyl chloroformate (0.56 mL), and the resulting mixture is stirred at ambient temperature for 4 hrs, diluted with water (8 mL), the layers are separated, and the organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf =0.19 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound, mp 134-135° C.