Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1>CN(C)C=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)=[N:31][CH:32]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)cn1
Reactant: Fc1ccc(CCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cn4)cc3)no2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To 4-(5-(6-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (20.0 mg, 0.07 mmol) described in Manufacturing Example 177-1-1 were added tetrahydrofuran (3 mL) and a 5 N sodium hydroxide aqueous solution (14.9 μL, 0.07 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of the solid obtained above and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of the 2-chloromethyl-5-fluoro-pyridine (12.0 mg, 0.08 mmol) described in Manufacturing Example 41-1-2, which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (3.0 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][S:12][CH2:13][CH2:14][CH:15]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:15]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13][S:12][CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CSCCC=O
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CSCCC(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
4-Chlorobenzamide, 3-methylthio-1-propanal, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[C:4]1([NH2:1])[CH:5]=[CH:6][CH:7]=[C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=12
Reactant: [H][H]
Reactant: O=C1CCCCc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cccc2c1CCCCC2
Reaction time: 16 h

Procedure:
A solution of 1-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one (CAS #251554-42-4, 2.5 g, 12 mmol), palladium (413 mg, 10% on carbon, 0.4 mmol) in acetic acid (25 ml) under the hydrogen atmosphere (60 PSI) was heated at 60° C. and stirred at for 16 hours. The mixture was filtered through a layer of diatomaceous earth, washed with methanol and concentrated under reduced pressure to provide the title compound. 1H NMR (CDCl3) δ 1.50-1.69 (m, 4H), 1.75-1.86 (m, 2H), 2.71-2.86 (m, 4H), 5.46 (s, 2H), 7.03-7.12 (m, 3H). MS (M+H)+ m/z 162.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.[C:12]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[CH:7]=1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (2.600 g; 17.10 mmol), and K2CO3 (2.598 g; 18.80 mmol) in anh. acetone (40 ml) was stirred at rt, under nitrogen, for 1 h. Iodomethane (13.340 g; 94.00 mmol) was then added, and the resulting mixture was heated at reflux, under nitrogen, for 2 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the filtrate was concentrated to dryness under reduced pressure. Et2O and water were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine as a yellow oil. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 167.11 g/mol.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=NN[CH:13]=2)[O:3]1.I[CH2:16][CH:17]1[CH2:22]C[O:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].[CH3:29][N:30](C=O)C>>[CH3:29][N:30]1[C:22]2[C:17](=[CH:16][CH:13]=[C:9]([B:4]3[O:3][C:2]([CH3:14])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]3)[CH:10]=2)[CH2:18][C:19]1=[O:20]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ICC1CCOCC1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1C(=O)Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 3.8 %

Procedure:
2 g (10.3 mmol) 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2.9 mL (20.6 mmol) 4-(iodomethyl)-tetrahydro-2H-pyran are dissolved in 200 mL DMF and 4.274 g (30.9 mmol) K2CO3 are added. The mixture is shaken at 80° C. for 5 h. After cooling to r.t. the mixture is filtered, the filtrate is concentrated in vacuo to approximately 60 mL. The product is separated using HPLC-MS (Gilson, mass flow 120 mL/min, 10 μm, 200 g Sunfire RP18, ACN/water/TFA). The product fractions are combined and freeze-dried to yield 115 mg product (3.8%) R7.6.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[C:26]([O:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2(CO)CCC(=O)CC2)cc1OC
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C2(COC(C)=O)CCC(=O)CC2)cc1OC
Reaction time: 20 h
Yield: 57 %

Procedure:
The 4-hydroxymethyl-4-(3,4-dimethoxyphenyl)cyclohexanone is dissolved in 20 ml. of pyridine and 10 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water and brine, and evaporated to dryness to give 6.43 g. (57% yield) of 4-acetoxymethyl-4-(3,4-dimethoxyphenyl)cyclohexanone, as an amorphous gum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].Cl[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9].Cl>[OH-].[Na+]>[CH2:11]([O:10][C:8]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCC(=O)O
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOC(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
20 g (224.46 mmol) of β-alanine were dissolved in 225 ml of 1N sodium hydroxide solution. 44 ml of octyl chloroformate were then added dropwise, while keeping the pH of the reaction medium above 9 by simultaneous addition of one molar equivalent of 1N sodium hydroxide. After stirring for 6 hours at room temperature, the mixture was acidified with about 1.1 molar equivalents of 3N hydrochloric acid solution. The heterogeneous mixture was extracted with 300 ml of ethyl acetate. The organic phase was washed with 3 times 80 ml of water, dried and then evaporated to dryness. The solid residue was taken up in heptane and then filtered and dried. 51 g of a white product were obtained (yield of 93%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([CH3:13])(=[O:12])=[O:11].[Li+].[BH4-].Cl>C1COCC1>[CH3:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][OH:2])(=[O:11])=[O:12]
Reactant: COC(=O)c1ccccc1S(C)(=O)=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1CO
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-methanesulfonylbenzoic acid methyl ester (1.5 g, 7 mmol) in THF (20 mL) is added LiBH4 (616 mg, 30 mmol) and the mixture is stirred at ambient temperature for 14 h. Additional LiBH4 (310 mg, 15 mmol) is added and the mixture is heated at 65° C. for 45 min. Then under ice cooling, 1N HCl solution is added to quench the excess of LiBH4 before EtOAc is added. The organic layer is washed with brine (2×) and water (1×), dried with MgSO4, and concentrated to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([N:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:56](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([N:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:56])[CH2:20][CH2:19]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OC3CCNCC3)c2)n1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-n3nc(C(C)(C)C)cc3NC(=O)N[C@H]3CC[C@@H](Oc4ccc5nnc(N6CCCCC6)n5c4)c4ccccc43)ccc2Cl)CC1
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a stirred solution of Example 68 (605 mg, 0.82 mmol) in DCM (8 mL) was added formaldehyde solution (37 wt % in H2O, 610 μL, 8.19 mmol), followed by acetic acid (47 μL, 0.82 mmol), and then sodium triacetoxyborohydride (347 mg, 1.64 mmol) and the reaction stirred at RT under a N2 atmosphere. After 3 h, the reaction was partitioned between H2O and DCM, and passed through a phase separator cartridge. The organics were concentrated in vacuo and subjected to FCC, eluting with 0-7.5% 2M NH3 in MeOH/DCM, and the product purified further by HPLC (XBridge C18 column, 45-85% MeCN in H2O, 0.1% NH4OH, 20 min gradient, 18 mL/min) to afford the title compound (331 mg, 54%). LCMS (Method 5): Rt 3.61 min, m/z 752, 754 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.58-1.65 (2H, m), 1.65-1.77 (6H, m), 1.80-1.97 (4H, m), 2.11 (3H, s), 2.12-2.23 (4H, m), 3.14 (4H, t, J=5.1 Hz), 4.45-4.55 (1H, m), 4.76-4.83 (1H, m), 5.55 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.04 (1H, broad d, J=8.4 Hz), 7.08 (1H, dd, J=2.3, 8.6 Hz), 7.15 (1H, dd, J=2.2, 9.7 Hz), 7.22-7.36 (4H, m), 7.36-7.41 (1H, m), 7.52-7.56 (1H, m), 7.59-7.65 (2H, m), 8.13 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH:11](Br)[CH3:12])=[CH:7][C:6]=12.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH:11]([N:15]([CH3:14])[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH3:12])=[CH:7][C:6]=12
Reactant: CNc1ccc(C)cn1
Reactant: CC(Br)c1ccn2ncc(Br)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(N(C)C(C)c2ccn3ncc(Br)c3c2)nc1
Temperature: 90 °C
Yield: 46.1 %

Procedure:
A suspension of 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18, 400 mg, 1.32 mmol), N,5-dimethylpyridin-2-amine (230 mg, 1.98 mmol) and K2CO3 (546 mg, 3.96 mmol) in acetonitrile was heated to 90° C. in a sealed tube for overnight. The reaction mixture was cooled to room temperature and water (10 mL) was added. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4 and solvents were removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (petroleum ether/EtOAc, 0-4% EtOAc) to afford 210 mg (46%) of N-(1-(3-bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-N,5-dimethylpyridin-2-amine (I-19) as a yellow solid. ESI-LC/MS (m/z): [M+H]+ 345.2, [(M+2)+H]+ 347, RT 3.31 min.
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:10])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C>[CH2:29]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:3]([CH2:1][CH3:2])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[C:4]1=[O:10])[CH:28]=[CH2:27]
Reactant: CCC1(c2cccc(OCc3ccccc3)c2)CCCCNC1=O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCCCC(CC)(c2cccc(OCc3ccccc3)c2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-ethyl-3-(3-benzyloxy-phenyl)-azepan-2-one, as described above in Step A, (1.65 g, 5.1 mmol) in DMF (25 mL) at 0° C. was added NaH (0.265 g, 6.63 mmol) and the mixture was stirred for 20 min at 0° C. and 20 min at 25° C. Allyl bromide (0.66 mL, 7.65 mmol) was added. After 5 hr, additional NaH (0.13 g, 3 mmol) and allyl bromide (0.33 mL, 3.5 mmol) were added and stirring was continued for 16 hr. The reaction was quenched with H2O and the solvents removed in vacuo . The residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was separated, washed with brine and dried (MgSO4). Filtration and concentration gave the title compound after chromatography on silica gel with hexane and ethyl acetate 9:1.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:25])[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[C:8]2[CH3:26])=[CH:4][CH:3]=1>C1COCC1.CO.BrCCBr>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)C=CC(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Solvent: CO
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)CCC(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Yield: 32.7 %

Procedure:
To the ester (520 mg, 1.17 mmol) of Step 3 dissolved in a THF/MeOH mixture (4.0 mL/20.0 mL) was added an excess of Mg and a few drops of 1,2-dibromoethane. The reduction was initated by heating at reflux. After standing for a few hours at room temperature, the reaction mixture was quenched by the addition of a 25% aqueous NH4OAc solution, extracted with EtOAc, dried over MgSO4 and evaporated in vacuo. The desired reduced product was purified by flash chromatography (25% EtOAc in hexane) to provide 170 mg of an oil.
Reaction SMILES: CO.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][NH2:24])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.[CH3:25][C:26]([CH3:28])=O>>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][N:24]=[C:26]([CH3:28])[CH3:25])[N:16]([CH2:17][C:18]([OH:20])([CH3:19])[CH3:21])[C:12]=2[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)=O
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3cccnc3c21
Solvent: CO
Product: CC(C)=NOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)O
Reaction time: 0.25 h

Procedure:
Methanol (21 mL) and acetone (2.6 mL) were added to 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol (1.31 g, 4.3 mmol). The reaction was stirred for 15 minutes then concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 0.7% methanol in chloroform) followed by recrystallization from acetonitrile/water to yield 0.56 g of acetone O-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]-1,5-naphthyridin-2-yl]methyl}oxime as a white solid, mp 198-200° C.
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]1[N:5]=[CH:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[N:10]([CH3:19])[CH2:9][C:8]=12.N12CCCN=C1CCCCC2.O>CN(C)C=O>[C:3]([C:4]1[N:5]=[CH:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[N:10]([CH3:19])[CH2:9][C:8]=12)#[CH:2]
Reactant: CN1Cc2c(/C=C\Cl)ncn2-c2ccccc2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
2.20 g (8 mmol) of 3-[(Z)-2-chlorovinyl]-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 145° for 6 hours together with 1.43 ml (9.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 30 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into water and extracted five times with methylene chloride. The organic extracts were washed five times with water, dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there was obtained 3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of melting point 191°-193°.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C#CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred mixture of 9.81 g. (0.10 moles) of 5-hexyn-1-ol, 33.5 g. (0.12 moles) of triphenylmethyl chloride, and 200 ml. of dry pyridine is refluxed for 60 minutes. The cooled mixture is poured into water and extracted with ether. The extract is washed successively with water, ice-cold N-hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The extract is dried with magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on Florisil to give an oil, λ max. 3290 (acetylenic hydrogen), 1600, 1072, and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: COC1C=C(C2[C@H]3[C@H](CC=CC3)C(=O)NN=2)C=CC=1OC.C(Cl)C1C=CC=CC=1.[CH2:30]([N:37]1[N:46]=[C:45]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=2)[C@H:44]2[C@H:39]([CH2:40][CH2:41][CH2:42][CH2:43]2)[C:38]1=[O:57])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]1[N:46]=[C:45]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=2)[C@H:44]2[C@H:39]([CH2:40][CH:41]=[CH:42][CH2:43]2)[C:38]1=[O:57])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Solvent: ClCc1ccccc1
Product: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and benzylchloride as described for compound 78. Purified by chromatography [ethyl acetate: petroleum ether (60°-80° C.)/1:3]. Crystallized from diethyl ether. M.p. 133°-135° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH:15]1[NH:19][CH2:18][CH2:17][S:16]1>ClCCCl.C(N(CC)CC)C>[Cl:1][CH2:2][C:3]([N:19]1[CH2:18][CH2:17][S:16][CH:15]1[CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][C:3](=[O:4])[CH2:2][Cl:1])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Oc1ccccc1CCC1NCCS1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(CCl)Oc1ccccc1CCC1SCCN1C(=O)CCl
Temperature: -10 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
α-Chloroacetylchloride (13.4 g, 9.5 ml) is added, with exclusion of humidity, under stirring, in 30 minutes, to a solution of the above thiazolidine (12 g) in 1,2-dichloroethane (120 ml) and triethylamine (18 ml), cooled at -10° C. Stirring is continued for 1 hour at 0° C. and the mixture is partitioned with water. The organic phase is separated, washed with water, dried on CaCl2 and the solvents are evaporated to dryness in vacuum. Crystallization from Et2O gives 3-α-chloroacetyl-2-[2'-(o-α-chloroacetoxy-phenyl)ethyl]thiazolidine (12 g), m.p. 88°-89° C. (hexane/AcOEt 7:3, Rf =0.5). A solution of this compound (6 g) in acetone (30 ml) is treated with potassium thioacetate (4.1 g) under stirring for 30 minutes. The mixture is filtered from the inorganic materials, the acetone is evaporated under vacuum and the residue is partitioned between water and EtOAc. From the organic phase after the usual work-up it is obtained 3-acetylthioacetyl-2-[2'-(o-acetylthioacetoxyphenyl)ethyl]thiazolidine as a colourless oil (hexane/AcOEt 7:3, Rf =0.4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[CH:18]=O.Cl>CO>[CH3:24][O:23][C:21]1[CH:20]=[C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:16]=[C:15]([O:14][CH3:13])[CH:22]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Solvent: CO
Product: COc1cc(C=C2CCc3cc(O)ccc3C2=O)cc(OC)c1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3,5-dimethoxybenzaldehyde 1.23 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 1.276 g.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][CH:21]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CN=C1.O>C(#N)C>[Cl:3][C:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][CH:21]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Cl)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Temperature: 0 °C
Yield: 70.6 %

Procedure:
Thionyl chloride (0.57 g) was added dropwise to a solution of ethyl (RS)-2-hydroxy-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (0.2 g) and imidazole (0.32 g) in dry acetonitrile (7 cm3), whilst the reaction temperature was maintained at 0° C. The mixture was allowed to warm to the ambient temperature and stirred for a period of sixteen hours, after which time it was poured into water, and extracted into dichloromethane. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate, passed through a short plug of silica, and concentrated by evaporation of the solvent under reduced pressure to give ethyl (RS)-2-chloro-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate as a yellow oil (0.15 g).