Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH:6]([OH:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>CCOCC>[C:13]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:6]([OH:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])(=[O:15])[CH3:14]
Reactant: CC(C)=CCC(O)C(C)CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCCC(C)C(O)CC=C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
A mixture of 3,7-dimethyl-4-hydroxy-6-octen-1-ol (5.06 g, 29 mmole), acetic anhydride (3.06 g, 30 mmole), pyridine (4.75 g, 60 mmole) and ether (100 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (200 ml) and washed with saturated cupric sulfate solution (2×100 ml). The organic phase is dried (Na2SO4) and evaporated in vacuo to give 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene as a colorless oil (2.27 g, 45%).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]#[N:12].[C:13]([N:21]=[C:22]=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[C:11]([C:3]1[C:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]=2[S:10][C:2]=1[NH:1][C:22]([NH:21][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23])#[N:12]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1c(N)sc2c1CCOC2
Solvent: C1COCCO1
Product: N#Cc1c(NC(=O)NC(=O)c2ccccc2)sc2c1CCOC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carbonitrile (Example 159b) (400 mg, 2.22 mmol) in 1,4-dioxane (30 mL) was added benzoyl isocyanate (327 mg, 2.22 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with 1,4-dioxane, and dried in the air to give the title compound (577 mg, 80%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.62 (t, J=5.2 Hz, 2H), 3.87 (t, J=5.2 Hz, 2H), 4.62 (s, 2H), 7.56-7.53 (m, 2H), 7.67-7.65 (m, 1H), 8.04-8.01 (m, 2H), 11.60 (brs, 1H), 12.13 (brs, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:34][C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:8][CH2:9]2)=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1CN1CCC(O)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3[N+](=O)[O-])CC2)cc1
Yield: 92.6 %

Procedure:
0.5 g (0.00212 mol) of 1-(2-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.561 ml (0.00424 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.696 g (93%) of 1-(2-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals; m.p. 86°-87°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:27])[C:4]=1[OH:28])[CH3:2].[CH2:29]([C@@H:31]1[O:33][CH2:32]1)Cl>[OH-].[Na+].C(O)(C)C.CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:27])[C:4]=1[O:28][CH2:29][C@@H:31]1[CH2:32][O:33]1)[CH3:2]
Reactant: ClC[C@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Reaction time: 8 h
Yield: 66.8 %

Procedure:
A mixture of 2-ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenol (355 mg, 931 μmol) and (R)-epichlorohydrine (861 mg, 9.31 mmol) in 3 M aq. NaOH (4 mL) and isopropanol (15 mL) is stirred at rt for 18 h before a second portion of (R)-epichlorohydrine (430 mg, 4.65 mmol) is added. Stirring is continued at rt for 8 h. The mixture is diluted with EA (100 mL) and washed twice with 1 N aq. NaOH solution (2×15 mL) followed by brine (25 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[(2S)-3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(1-ethyl-propyl)-6-methoxy-pyridine (272 mg) as a white powder; LC-MS: tR=1.25 min, [M+H]+=438.09.
Reaction SMILES: Br[CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[NH3:20]>>[NH2:20][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: N
Reactant: O=c1cc(-c2ccncn2)nc2n1CCOCC2Br
Product: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A suspension of 18.7 g (57.89 mmol) of (+/−)-9-bromo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one in 520 mL of ammonia (7N solution in MeOH) in sealed tubes was stirred at 100° C. for 4 hours. The cooled solution was evaporated to remove solvent. After an acido-basic work-up and extraction with dichloromethane, the mixture was washed with saturated solution of sodium chloride. The organic phase was dried over sodium sulfate and concentrated. The residue was organised in diethyl ether to afford 6.70 g (44%) of product as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([O:39]C)=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([OH:39])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)OC)c3ccccc3n2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
Alternatively, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (200 mg, 0.359 mmol) was treated with LiOH (2 eq.) in a solution of THF:H2O (3:1, 8 mL). The reaction mixturre was stirred at ambient temperature for 5 hours. The pH value was adjusted to between pH 3 and pH 4 with 1N HCl solution. Evaporation of the solvents, extraction with ethyl acetate, washing with H2O and brine, followed by evaporation and flash column chromatography with 100% ethyl acetate, 1–5% MeOH in ethyl acetate gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-carboxyquinoline (106 mg). To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-carboxyquinoline (500 mg (two batches combined), 0.922 mmol) in THF (10 mL) was added 1-methyl 5-t-butyl ester glutamic acid (300 mg, 1.5 eq), EDCI (216 mg, 1.2eq.), HOBt (140 mg, 1.1 eq.), and the resulting mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-(methoxycarbonyl)-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (387 mg); NMR (CDCl3) 1.28 (t, 3), 1.40 (s, 9), 1.47 (s, 9), 1.83 (m, 1), 2.16 (m, 2), 2.35–2.50 (m, 5), 3.5–3.76 (m, 8), 3.8 (s, 3), 4.18 (q, 2), 4.85 (m, 1), 5.35 (m, 1), 7.15 (d, 1), 7.65 (m, 1), 7.80 (m, 1), 8.20 (d, 1), 8.30 (d, 1), 8.35 (s, 1), 8.70 (d, 1) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2nc(CO)cs2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(c2nc(C=O)cs2)CC1

Procedure:
The reaction described in Preparation 44 was repeated, but using 2.4 g of 2-(4-methyl-1-piperazinyl)thiazol-4-yl-methanol, 5.4 g of sulfur trioxide pyridine complex, 3.4 g of triethylamine, and 30 ml of dimethyl sulfoxide, giving the title compound as a pale brown oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18](=[O:19])/[C:17](=[CH:20]/[C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[C:38]([F:41])([F:40])[F:39])[N:25]=[CH:24]4)/[S:16][C:15]2=[O:42])[CH:10]([OH:43])[CH2:9]1)=O)(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:26]2[C:27]3[C:23](=[CH:22][C:21](/[CH:20]=[C:17]4/[C:18](=[O:19])[N:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][C:10]5=[O:43])[C:15](=[O:42])[S:16]/4)=[CH:29][CH:28]=3)[CH:24]=[N:25]2)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNCCC1N1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5Z)-4-{5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.13 mmol) in DCM (2 mL) was added Dess-Martin periodinane powder (0.16 mmol). The mixture was stirred at rt for 18 h, then purified by silica gel chromatography (0-30% EtOAc/hexanes). The product was obtained as pale yellow solid, which was treated with TFA/DCM following General Procedure M to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:25](OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNc2ccccc2)COC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1[C@@H](CN(Cc2ccccc2)c2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester (495 mg; example 2.a) at r.t. in 1,2-dichloroethane (10 ml) under an argon atmosphere were added benzaldehyde dimethyl acetal (0.37 ml), trifluoroacetic acid (0.13 ml) and sodium triacetoxyborohydride (571 mg). The mixture was stirred at room temperature overnight. The mixture was directly adsorbed on silica gel and purified by chromatography (SiO2; gradient:heptane->heptane/EtOAc 7:3) to give (S)-4-[(benzyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (492 mg, 77%) as a colourless viscous oil. MS (ISP): 397.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:11][CH2:12][N:13]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:14][CH2:15]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCN(S(C)(=O)=O)CC4)ccc3Cl)ncc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 50 mg (0.11 mmol) N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide, 65 μL triethylamine and 15 μL methanesulphonic acid chloride in 1 mL dichloromethane is stirred for three hours at ambient temperature. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and the organic phase is evaporated down. The residue remaining is purified by RP-HPLC. Yield: 23 mg yellow solid (MH+=542; RT=3.07; Method A)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[Cl:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][N:32]=[C:31]4[Cl:37])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Product: COCCC(C(=O)Nc1ccc2[nH]nc(Cl)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
170 mg (451 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 92.4 mg (purity 90%, 496 μmol, 1.1 eq.) of 5-amino-3-chloro-1H-indazole were reacted according to General Method 1. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 113 mg (48% of theory)
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:31][CH:32]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.09 g, 0.3 mmol), 4-iodo phenyl acetic acid methyl ester (U.S. Pat. No. 6,252,090, 0.092 g, 0.33 mmol), triethyl amine (3 mL), copper(I)iodide (0.029 g, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.064 g, 0.09 mmol) followed by flash column chromatography over silica gel (230–400 mesh), the title compound was obtained as a yellow oil (0.085 g, 65%).
Reaction SMILES: Cl.O1CCCC1.C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:23]1[C:24](=[O:35])[C:25]2[C:30]([C:31](=[O:34])[C:32]=1[CH3:33])=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C>C(OCC)(=O)C>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:23]1[C:24](=[O:35])[C:25]2[C:30]([C:31](=[O:34])[C:32]=1[CH3:33])=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OCCCCCC(C1=C(C)C(=O)c2ccccc2C1=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(C(CCCCCO)c2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 83.7 %

Procedure:
6N Hydrochloric acid (20 ml) was added to a tetrahydrofuran solution (20 ml) containing 1-acetoxy-6-(3-methyl-1,4-naphthoquinon-2-yl)-6-phenylhexane (2.8 g, 7.2 mmole), followed by stirring for 5 hours with heating at 70° C. After cooling, ethyl acetate was added to the reaction solution, and the organic layer was separated out, washed with water, dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether-ethyl acetate (1:1), followed by recrystallization of the object compound from isopropyl ether to give 1-hydroxy-6-(3-methyl-1,4-naphthoquinon-2-yl)-6-phenylhexane (2.1 g). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 75, 79 and 81 were prepared.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][O:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][O:25]/[N:24]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NOCCO
Product: C/C(=N\OCCO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 21 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)ethanol in 21% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CD2Cl2) δ ppm 9.40 (s, 1H), 8.91 (m, 1H), 8.18 (d, 2H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.45 (dd, 1H), 6.13 (s, 2H), 4.46 (t, 2H), 3.97 (t, 2H), 2.39 (s, 3H). LCMS (method A): [MH]+=364, tR=4.28 min.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])[CH3:4].OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:9]1[CH:8]=[C:7]([CH3:11])[C:6]([OH:12])=[C:5]([CH2:3][CH3:4])[CH:10]=1
Reactant: CCc1cccc(C)c1O
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(C)c1O
Reaction time: 2 h

Procedure:
A solution of 12.7 mL (247 mmol) bromine in 10 mL chloroform was added dropwise at RT to a solution of 33.6 g (247 mmol) 2-ethyl-6-methyl-phenol in 350 mL chloroform and the mixture was stirred for 2 h. The reaction mixture was combined with an aqueous NaHSO3 solution and stirred for 20 min. The phases were separated and the organic phase was washed with saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation i.vac. Column chromatography (silica gel, Cyc/EtOAc 9:1) yielded the product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4](=[N:8][S:9][N:10]=2)[N:5]=[CH:6][N:7]=1.N.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Cl>>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][NH:1][C:2]1[C:3]2[C:4](=[N:8][S:9][N:10]=2)[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2nsnc12
Reactant: Fc1cccc(Cl)c1CCl
Agent: N
Product: Fc1cccc(Cl)c1CNc1ncnc2nsnc12
Temperature: 110 °C
Yield: 25 %

Procedure:
An autoclave was charged with 1.54 g. (0.01 mole) of 7-amino[1,2,5]thiadiazolo[3,4-d]pyrimidine prepared by the process set forth in Example 1, 5.1 g. (0.3 mole) ammonia and 4.48 g. (0.025 mole) 2-chloro-6-fluorobenzyl chloride. The vessel was sealed and the contents heated at 110° C. for 15 hours. After cooling and evaporation of the excess ammonia, the resulting solid was collected by filtration, washed successively with water and hexane to afford a 25% yield of product.
Reaction SMILES: C(OC(CCCCC([O:17][C:18]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:20][C:19]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O)=O)C1C=CC=CC=1.C1COCC1>[OH-].[OH-].[Pd+2].CCO>[OH:17][C:18]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:20][C:19]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(CCCCC(=O)Oc1c(-c2ccccc2)oc2ccccc2c1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1c(O)c(-c2ccccc2)oc2ccccc12
Yield: 126.5 %

Procedure:
A mixture of 3-(benzyloxycarbonylbutylcarbonyloxy)flavone (312 mg, 0.7 mmol) and Pd(OH)2 (49.4 mg) in 9:1 THF:EtOH+0.05% acetic acid (15 mL) was treated with H2 for 5 h. The crude product was filtered (Celite), the filtrate was concentrated and the residue was purified by flash chromatography (10-25% EtOAc in toluene+1% acetic acid) to give the hemiadipate as a light yellow solid (0.211 g, 89%). A small portion was crystallized from EtOAc/petroleum spirits, mp=118-121° C.; 1H NMR (399.7 MHz, CDCl3) δ 1.66-1.83 (m, 4H, CH2CH2CO2); 2.38 (t, J=6.8 Hz, 2H, CH2CO2); 2.63 (t, J=6.8 Hz, 2H, CH2CO2); 7.42 (dd, 1H, J5,6=8.0 Hz, J6,7=8.0 Hz, H6); 7.47-7.53 (m, 3H, H3′,4′, 5′); 7.54 (d, 1H, J7,8=8.4 Hz, H8); 7.70 (ddd, 1H, J5,7=1.6 Hz, J6,7=8.0 Hz, J7,8=8.4 Hz, H7); 7.81-7.86 (m, 2H, H2′, 6′); 8.24 (dd, 1H, J5,6=8.0 Hz, J5,7=1.6 Hz, H5). 13C NMR (100.5 MHz, CDCl3) δ 25.01, 25.20 (2C, CO2CH2CH2); 34.57 (2C, CO2CH2); 119.20, 124.66, 126.33, 127.21, 129.41, 129.76, 131.04, 132.40, 134.70, 135.10, 156.74, 157.60 (14C, Ar); 171.52, 173.38, 179.36 (3C, C═O). Anal. Found: C, 68.89; H, 4.91; C21H18O6 requires C, 68.85; H, 4.95%. HRMS (ESI+) m/z 389.1000, C21H18NaO6 [M+Na]+ requires 389.1001].
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[N:21]=2)[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(C2CCCN2C(=O)c2ccccc2)ccn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 83.8 %

Procedure:
4-(1-Benzoyl-2-pyrrolidinyl)-2-pyridinecarbonitrile (0.42 g, 1.5 mmol) and methyl thiosalicylate (1.03 g, 6.1 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 14 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (4:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 82%) as amorphous crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[CH3:12][C:13]1[C:14](Cl)=[N:15][C:16]([Cl:20])=[N:17][C:18]=1[CH3:19]>>[CH3:12][C:13]1[C:14]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]2[CH3:1])=[N:15][C:16]([Cl:20])=[N:17][C:18]=1[CH3:19]
Reactant: CC1NCCc2ccccc21
Reactant: Cc1nc(Cl)nc(Cl)c1C
Product: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Yield: 60.4 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1-methyl-1,2,3,4-tetrahydroisoquinoline(3.9 g, 26.4 mmol) and 5,6-dimethyl-2,4-dichloropyrimidine(4.3 g, 24 mmol) prepared in the above Step 1 were used as starting materials, 4.17 g of the titled compound was prepared. (Yield: 60.4%)