Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH2:7][C:8](=O)[C:9]([CH3:12])([CH3:11])[CH3:10].CC(C)=[O:16]>>[Br-:6].[CH3:10][C:9]1([CH3:12])[CH2:8][CH2:7][S+:1]([CH2:2][C:3](=[O:16])[CH2:4][CH3:5])[CH2:11]1
Reactant: C1CCSC1
Reactant: CC(C)=O
Reactant: CC(C)(C)C(=O)CBr
Product: CCC(=O)C[S+]1CCC(C)(C)C1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a four-necked flask, were charged 70.17 parts of tetrahydrothiophene and 750 parts of acetone, to which 150 parts of 1-bromopinacolone was added dropwise, followed by stirring at room temperature for 24 hours. The precipitated crystal was collected by filtration, and washed with 100 parts of tert-butylmethyl ether, and dried to obtain 161.3 parts of 3,3-dimethyl-2-oxobutyl thiacyclopentanium bromide.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>CC(O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[CH2:2][OH:1]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: OCC1Cc2ccccc2N1
Solvent: CC(C)O
Product: COc1cc2ncnc(N3c4ccccc4CC3CO)c2cc1OC
Yield: 57 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 57% yield from 2-hydroxymethyl-indoline (1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 145.5°-147° C.; LC-MS: 338 (MH+); anal. RP18-HPLC RT: 4.03 min.).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:10][C@H:9]([OH:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O>>[C:31]([O:11][C@H:9]1[CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccccc1
Reactant: O[C@H]1C[C@@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O[C@H]1C[C@H](c2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of cis-3-phenylcyclobutanol (Eckehard, V. D.; et al. Chem. Ber., 1993, 126, 2759., 4.6 g, 30.2 mmol), triphenylphosphine (3.3 g, 59.1 mmol) and benzoic acid (7.6 mg, 62.3 mmol) was added diethyl azodicarboxylate (DEAD) (10.9 g, 62.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 40 min, then the mixture was concentrated. The residue was dissolved in diethyl ether (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (10:1) to afford 6.52 g (86%) of the title compound as a pale yellow oil: 1H-NMR (CDCl3) δ 7.71-7.20 (10H, m), 5.49-5.41 (1H, m), 3.82-3.72 (1H, m), 2.78-2.64 (4H, m).
Reaction SMILES: C(=[O:3])C.[CH3:4][CH:5]1[CH2:10][CH:9]([O:11][CH2:12][C:13](Cl)=[O:14])[CH:8]([CH:16]([CH3:18])[CH3:17])[CH2:7][CH2:6]1.CO>N1C=CC=CC=1.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.C1COCC1>[CH3:4][CH:5]1[CH2:10][CH:9]([O:11][CH2:12][C:13]([OH:3])=[O:14])[CH:8]([CH:16]([CH3:18])[CH3:17])[CH2:7][CH2:6]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Reactant: CC=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Vinyl L-menthoxyacetate is prepared from acetaldehyde, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), (PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and vinyl L-menthoxyacetate (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl L-menthoxyacetyl-L-lactate and methyl L-menthoxyacetyl-D-lactate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCl (aq) for 2 hours at 100° C. to give pure L- and D-lactic acid, methanol, and L-menthoxyacetic acid. The L-menthoxyacetic acid is recycled to L-menthoxyacetyl chloride by treatment with thionyl chloride.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[C:36]([CH3:43])[CH:35]=1)#[N:33]>ClCCl>[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:8][CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:39])=[C:36]([CH3:43])[CH:35]=1)#[N:33]
Reactant: Cc1cc(C#N)ccc1C(=O)O
Reactant: NC1CCCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(C#N)ccc1C(=O)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
Add cycloheptylamine (0.83 mL, 6.5 mmol), HOBT (838 mg, 6.2 mmol), EDC (1.2 g, 6.2 mmol) and diisopropylethylamine (3.2 mL, 18.6 mmol) to a solution of 4-cyano-2-methyl-benzoic acid (1 g, 6.2 mmol) in dichloromethane (20 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 16 h at room temperature. Wash the mixture with water (20 mL), separate and concentrate the organic layer in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:2 gradient) to obtain the desired intermediate (830 mg, 52%). MS (ES+) m/z: 257.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([S:20](=[O:23])(=[O:22])[NH2:21])[CH:17]=2)[O:12][CH2:11]1)=[O:8].[OH-].[Na+].[CH3:31][NH:32][C:33](=[O:38])C(Cl)(Cl)Cl.C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([S:20]([NH:21][C:33]([NH:32][CH3:31])=[O:38])(=[O:22])=[O:23])[CH:17]=2)[O:12][CH2:11]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NC1COc2cc(OC)c(S(N)(=O)=O)cc2C1
Reactant: CNC(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCC(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 0 °C

Procedure:
1.71 g (4 mmol) of 3-(5-chloro-2-methoxybenzamido)-6-sulfamoyl-7-methoxychroman were heated at 80° C. for 30 minutes in 10 ml of dry DMSO after addition of 0.4 g (10 mmol) of freshly powdered sodium hydroxide and 1.05 g (6 mmol) of N-methyltrichloroacetamide. The cooled reaction mixture was introduced into ice-water, clarified with active charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized twice from ethanol. The product had a melting point of 256°-257° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[NH:14][C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[N:14]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1COc2cc(S(=O)(=O)c3ccccc3)ccc2N1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCN1C(=O)COc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 3 h
Yield: 50 %

Procedure:
A suspension of 7-benzenesulfonyl-4H-benzo[1,4]oxazin-3-one (0.09 g., 0.3 mmol), (2-chloro-ethyl)-dimethyl-amine hydrochloride (0.056 g., 0.39 mmol) and potassium carbonate (0.095 g., 0.69 mmol) in 0.7 mL ethyl acetate was refluxed for 1 hour. To the reaction mixture was added 0.75 mL water, and reflux was continued for 3 hours. 30 mL Ethyl acetate was added, and the reaction mixture was washed three times with 15 mL water, dried over magnesium sulfate and concentrated in vacuo. The residue was purifed by flash chromatography (0 to 5% methanol in dichloromethane) to afford 0.055 g (0.15 mmol, 50%) of 7-benzenesulfonyl-4-(2-dimethylamino-ethyl)-4H-benzo[1,4]oxazin-3-one. MS: 361 (M+H)+, mp: 232.9-235.3° C. (HCl salt).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][C:9](=O)[C:8]=2[CH:13]=1)([O-:3])=[O:2].Cl.[NH:15]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])N>N1C=CC=CC=1>[OH2:2].[OH2:20].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]3[C:25]4[C:17](=[C:18]([C:19]([OH:21])=[O:20])[CH:22]=[CH:23][CH:24]=4)[NH:15][C:9]=3[C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc21
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O
Product: O=C(O)c1cccc2c1[nH]c1c3cc([N+](=O)[O-])ccc3oc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 172.6 %

Procedure:
5-Nitro-3(2H)-benzofuranone (0.500 g, 2.79 mmol)[Tobias, P. et al. J. Amer. Chem. Soc., 1969, 91 (18), 5171-5173] and 2-hydrazinobenzoic acid hydrochloride (0.526 g, 2.79 mmol) were combined in pyridine (10 mL) and stirred overnight at ambient temperature. The mixture was vacuum filtered and dried in vacuo to afford 0.800 g (86%) of title compound as a yellow solid: mp 210° C. (dec) which was used without purification.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:30])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:39])[CH:4]=1)#[N:2].[H-].[Na+].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:30])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:39])[CH:4]=1)#[N:2]
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(CN2CC[C@H](N(Cc3ccccc3)S(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
N-Cbz-7-aminonaphthalene-2-sulfonic acid-[1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.56 g, 1.01 mmol) is dissolved in 10 mL of DMF and cooled to 0° C. Sodium hydride (42 mg of a 60% dispersion in mineral oil, 1.06 mmol) is added and the solution is stirred for 20 minutes. To the mixture is added benzyl bromide (0.18 g, 1.06 mmol). The reaction mixture is stirred at 0° C. for 20 minutes and then at room temperature for 1.5 hours. The solution is poured into a separatory funnel and diluted with 100 mL of EtOAc. The organic layer is washed with water, 1 N HCl and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude residue is purified by column chromatography eluting with a gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to give the title compound (0.34 g, 0.53 mmol) as a solid.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(Cl)Cl>C1COCC1>[C:16]([NH:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:1]
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
FMOC-(O-t-Butyl)tyr-val (1.0 gm, 1.8 mMole) and N-hydroxysuccinimide (210 mg, 1.8 mMole) were dissolved in 40 ml THF under nitrogen at 0° C. Dicyclohexylcarbodiimide (DCC) was added as a methylene chloride solution (0.5 M, 3.6 ml, I.8 mMole) and the reaction mixture was incubated for 2 hours with stirring, then stored overnight at 4° C. TLC showed incomplete reaction, so additional DCC was added (0.45 mMole), and the reaction mixture incubated at room temperature for one day. Dicyclohexylurea (DCU) formed was filtered and the filtrate concentrated to a solid, which was triturated with 4% sodium bicarbonate. The solid was filtered, washed with water dried, then crystallized from chloroform/petroleum ether. A white solid was obtained on filtration and air drying. Yield: 761 mg (65%); Rf: 0.75 [chloroform/methanol 9:1 (silica)]. Elemental analysis for C37H41N3O8.0.5 H2O calculated: C, 66.85; H, 6.37; observed C, 67.04; H, 6.85.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1])[CH3:18]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1Cl
Reaction time: 10 h
Yield: 64.1 %

Procedure:
A mixture of 2-chloro-4-nitrophenol (63.6 g, 0.367 mol), ethyl bromoacetate (67.0 g, 0.4 mol), potassium carbonate (60.7 g, 0.44 mol) and 2-butanone (400 mL) was refluxed under stirring for 10 h, then filtered and the solvent was evaporated. The residue was fractionated yielding 61.1 g (64%) of 2-chloro-4-nitrophenoxyacetic acid ethyl ester, b.p. 150° C./40 Pa.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH:22]2[CH2:36][C:25]3=[C:26]4[C:31](=[N:32][CH:33]=[C:24]3[O:23]2)[CH:30]=[CH:29][C:28]([O:34][CH3:35])=[N:27]4)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:35][O:34][C:28]1[CH:29]=[CH:30][C:31]2[C:26]([N:27]=1)=[C:25]1[CH2:36][CH:22]([CH2:21][C@H:18]3[CH2:19][CH2:20][C@H:15]([NH2:14])[CH2:16][CH2:17]3)[O:23][C:24]1=[CH:33][N:32]=2
Reactant: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)O3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](N)CC1)O3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (821 μL, 10.56 mmol, 15.0 eq) is added at 0° C. to a stirred solution of [trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (300 mg, 0.70 mmol, 1.0 eq) in dichloromethane (12 mL). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and water (10 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexylamine as an orange viscous oil (190 mg, 82% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([CH3:9])[CH:4]=[C:3]1[C:10]([O:12][CH3:13])=[O:11].[Mn]([O-])(=O)(=O)=[O:15].[K+].S([O-])([O-])=O.[Na+].[Na+].[Mn]([O-])(=O)(=O)=O>CC(C)=O.O.O.CC(C)=O>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:5]=1[CH3:9])([OH:15])=[O:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COC(=O)c1cc(C)c(C=O)n1C
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C)c(C(=O)O)n1C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
To a solution of methyl 1,4-dimethyl-5-formylpyrrole-2-carboxylate (0.3 g, 0.0016 m) in acetone (10 ml) at room temperature was added over 15 minutes a solution of potassium permanganate (0.52 g, 0.0033 m) in 1:1 water-acetone (10 ml), and the resulting mixture allowed to stir for 1.5 hours. The reaction mixture was then diluted with water (100 ml), treated with enough sodium sulfite to reduce the excess permanganate, filtered, and the filtrate acidified with dilute hydrochloric acid. The resulting precipitate was filtered, washed well with water and dried to give 0.20 g (64%) of methyl 5-carboxy-1,4-dimethylpyrrole-2-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9][C:10](N)=[C:5]2[C:4]([CH3:18])=[N:3]1.N([O-])=[O:20].[Na+]>S(=O)(=O)(O)O.O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9][C:10](=[O:20])[C:5]2=[C:4]([CH3:18])[NH:3]1
Reactant: Cc1nn(C)c2nc(-c3ccncc3)nc(N)c12
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1[nH]n(C)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
A solution of 1,3-dimethyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-amine (1.99 g, 8.3 mmol) in 50% aqueous sulfuric acid (50 ml) at 0° C. was stirred for 20 minutes and sodium nitrite (5.7 g, 83.0 mmol) in water (25 ml) was added dropwise over 1 hour. The reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. The mixture was poured into ice-water (500 ml) and a white solid was collected by filtration and washed with water, ethanol and finally ether. The solid residue was stirred in 15% KHCO3 (150 ml) for 20 minutes and the product was collected by filtration and washed with water, then ethanol and finally ether. The product was recrystallized from DMF to afford 1.5 g (76%) of 1,3-dimethyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one as a white solid, m.p. >301° C. when dried for 18 hours at 115° C. in high vacuum.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH2:8]([NH:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a solution of 2-phenylethylamine (3.0 g, 24.8 mmol) in DMF (30 ml) was added ethyl bromoacetate (3.0 ml, 27.3 mmol) at 5° C. Then triethylamine (4.15 ml, 29.8 mmol) was added thereto at the same temperature. After stirring the resulting mixture at room temperature for 18 hours, the reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:MeOH, 20:1) to give ethyl phenethylaminoacetate (1.87 g, 37%) as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[S:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2OCCC1(CO)CO
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2OCCC1(CO)COC(=S)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]oxepin-5-one (510 mg, 2.3 mmol) in 29 ml tetrahydrofuran were added, at room temperature, triethylamine (0.35 ml, 2.5 mmol) and 3-(trifluoromethyl)phenyl isothiocyanate (872 μl, 5.74 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 483 mg (50%).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:21][CH2:20][C:14]3[N:15]=[C:16]([NH2:19])[N:17]=[CH:18][C:13]=3[CH2:12]2)[CH:6]=1)C.[OH-].[Na+]>O1CCOCC1>[NH2:19][C:16]1[N:17]=[CH:18][C:13]2[CH2:12][N:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:22])=[O:3])[CH2:21][CH2:20][C:14]=2[N:15]=1
Reactant: CCOC(=O)c1cccc(N2CCc3nc(N)ncc3C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of ethyl-3-(2-amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-benzoate (958 mg, 3.21 mmol) in 1,4-dioxane (35 mL) was treated with 1.0 N NaOH(aq.) (8.24 mL, 8.24 mmol) and the reaction mixture was refluxed for 21 hours. Upon cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water and the pH was adjusted to ˜4 with 1.0 N HCl(aq.). The cloudy mixture was treated with ethyl acetate and the aqueous/organic mixture was stirred at room temperature for approx. 1 hour. The precipitate was filtered off, washed with water, ethyl acetate, and dried in vacuo at 50° C. to give the title compound as a yellow, amorphous solid (710.8 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[CH:4][C:5]([OH:17])=[C:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[CH:4][C:5]2[O:17][C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:8][C:6]=2[CH:7]=1
Reactant: O=C(Nc1cc(Cl)c(C(F)(F)F)cc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc2oc(-c3ccncc3)nc2cc1Cl
Reaction time: 1.5 h
Yield: 21.2 %

Procedure:
To a mixture of 0.55 g of N-[5-chloro-2-hydroxy-4-(trifluoromethyl)phenyl]isonicotinamide, 6 ml of tetrahydrofuran and 0.50 g of triphenylphosphine, 0.83 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the resultant crystals were washed with methanol to give 0.11 g of 5-chloro-2-(pyridin-4-yl)-6-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 78”).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[C:28]([OH:30])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:32]1[C:36](=O)CC[C:33]1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.CNC>O1CCOCC1.C(N(CC)CC)C>[CH3:33][N:32]([CH3:36])[C:28]([CH:9]1[CH2:10][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:30]
Reactant: O=C1CCC(=O)N1O
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C(=O)O)C2)cc(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C(=O)N(C)C)C2)cc(OC)c1OC
Reaction time: 5 h
Yield: 65.8 %

Procedure:
To a mixture of 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylic acid (3.0 g), N-hydroxysuccinimide (1.2 g) and dioxane (30 ml) is added, at room temperature, dicyclohexyl carbodiimide (2.6 g). The mixture is stirred for 5 hours. To a mixture of dimethylamine hydrochloride (8.0 g), triethylamine (10.0g) and dioxane (30 ml) is added dropwise at 0° C the solution of active ester prepared above. The reaction mixture is concentrated, and the concentrate is dissolved in dichloromethane. The solution is washed with a 5% aqueous solution of citric acid and a saturated aqueous solution of sodium hydrogencarbonate, which is then dried and further concentrated. The crude product is subjected to a silica gel column chromatography (ethyl acetate-methanol=9:1) to afford N,N-dimethyl 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2carboxamide (2.1 g) as colorless crystals, m.p. 146-147° C.