Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(NS(=O)(=O)c2ccccc2)c1
Reaction time: 16 h
Yield: 86 %

Procedure:
To 6.17 g (44.7 mmol) of 3-nitroaniline and 8.41 mL (48.2 mmol) of N,N-diisopropylethylamine in 150 mL of anhydrous diethyl ether was added 5.14 mL (40.2 mmol) of benzenesulfonyl chloride. The mixture was heated to reflux under nitrogen with stirring for 16 h, cooled and the resulting two-phase mixture scratched to crystallize the insoluble oil. After decanting the ether layer, the derived solid was dissolved in 300 mL of dichloromethane and the solution washed with 2N HCl (3×200 mL), saturated NaHCO3 (200 mL), brine (200 mL), dried (Na2SO4) and concentrated to give 9.62 g (86%) of the title compound as a light tan solid. 1H-NMR (300 MHz, CDCl3) δ 7.96 (m, 2H), 7.86 (m, 2H), 7.41-7.63 (m, 5H), and 7.30 (br s, 1H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C12H10N2O4S: 301.0 (M+Na). Found: 301.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([OH:35])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:38]([O:45][C:46](=[O:49])[CH2:47]Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][CH2:47][C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:49])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 1.5 g of Bromo-acetic acid benzyl ester in 38 ml of DMF, 2 g of cesium carbonate was added. The reaction mixture was stirred for 4 h at RT, diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.8 g.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:20]([OH:22])=[S:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:22][C:20]([C:11]1[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)=[S:21]
Reactant: Cc1ccc2c(c1)cc(C(O)=S)n2S(=O)(=O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=S)c1cc2cc(C)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 1-benzenesulfonyl-5-methylthioindole-2-carboxylic acid (3.5 g), sulfuric acid (10 ml) and methanol (10 ml) was heated, under reflux for 12 hours. The reaction mixture was poured into ice-water and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane) to obtain 3.4 g of the desired product as a white crystal.
Reaction SMILES: [Na].[OH:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.Cl.CN(C)CCCN=C=NCC.[CH3:33][C@H:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>N1C=CC=CC=1.O.CN(C=O)C>[OH:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([N:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:42][C@@H:34]3[CH3:33])=[O:20])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1
Reactant: C[C@H]1Cc2ccccc2N1
Reactant: O=C(O)Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a three-necked flask under argon, 0.35 g of the sodium salt of (−)-[4-(2-hydroxymethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid (example 31b, step 2b) is placed in 5 ml of pyridine and 5 ml of DMF whitish heterogeneous solution. N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added at ambient temperature, 0.18 g of (S)-2-methylindoline (CAS 22160-09-4) is added, and the mixture is stirred at ambient temperature for 72 hours. 25 ml of water are added, extraction is carried out with 3 times approximately 25 ml of dichloromethane, washing is carried out with 25 ml of water, washing is carried out with twice approximately 15 ml of 1M hydrochloric acid solution, washing is carried out with 25 ml of water, washing is carried out with 25 ml of saturated NaCl solution, drying is carried out over MgSO4, filtration is carried out through a VF filter, and the resulting product is concentrated under vacuum. The compound obtained is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and ethanol (95/5, v/v). The fractions containing the expected compound are combined and evaporated. The compound obtained is triturated from dichloromethane and diisopropyl ether, filtered, and dried at ambient temperature (20° C.). (+)-6-(2-Hydroxymethylmorpholin-4-yl)-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one is isolated (0.11 g).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:16][C:5]1[N:1]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=2[O:14][CH3:15])[CH:2]=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(C=O)ccc1-n1ccnc1
Solvent: ClC(Cl)Cl
Product: COc1cc(C=O)ccc1-n1cncc1Cl
Yield: 23.9 %

Procedure:
To a chloroform (3 mL) solution of the 4-(1H-imidazol-1-yl)-3-methoxybenzaldehyde (50 mg) obtained in Example 111, N-chlorosuccinimide (35 mg) was added, and the reaction solution was heated to reflux for 1.5 hours. The reaction mixture was allowed to be cooled and then purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system), and 4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde (13 mg) and 4-(5-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde (14 mg) were obtained.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:8].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[C:16]=2[O:20][CH3:21])[C:11]1=[O:24].C([BH3-])#N.[Li+].O1CCOCC1.Cl>CO>[ClH:8].[CH:1]1([NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[C:16]=3[O:20][CH3:21])[C:11]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Li+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2c(c1OC)CCC(NC1CCCCC1)C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a mixture of 200 volume parts of dry methanol and 200 volume parts of cyclohexanone is dissolved 10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride and under nitrogen sparging and cooling at 0° C, there is added 9 parts of a molecular compound consisting of 1 mole lithium cyanoborohydride and 2 moles dioxane (LiBH3CN.2C4H8O2). At a constant temperature of 5° C, the reaction mixture is stirred for 2 hours. After the addition of dilute hydrochloric acid, the methanol is distilled off. The remaining mixture is washed with benzene and evaporated to dryness under reduced pressure. The residue is dissolved in ethanol, treated with activated carbon and recrystallized from a mixture of ethanol and ethyl ether. The procedure yields 9.65 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride as colorless crystals melting at 180°-190° C (decomposition).
Reaction SMILES: C(OC1C=CC(C([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=O)=CC=1)CCCCCC.[OH-].[Na+].CO.CC(O)=O>C1COCC1>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[C:24](=[O:43])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[CH:27][CH:26]=2)=[CH:20][CH:21]=1
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reaction time: 1 h
Yield: 56 %

Procedure:
Prepared using General Procedure 9: To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-5 (6.38 g, 8.83 mmol) in THF (50 mL) was added 1N NaOH (16 mL). The reaction was stirred for 1 h. MeOH (10 mL) was added causing the turbid reaction mixture to clarify. The reaction was stirred for 3 h then neutralized with AcOH. The crude mixture was concentrated then diluted with DCM (60 mL) and washed with brine (30 mL). The organic layer was concentrated and purified by chromatography (EA/hexanes) to afford 2.5 g (56%) of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7. LCMS-ESI (m/z) calculated for C29H32N2O6: 504; found 503 [M−H]−, tR=2.09 min. (Method 3). 1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.41-9.29 (m, 1H), 7.69-7.59 (d, J=8.1 Hz, 2H), 7.42-7.20 (m, 4H), 7.19-6.96 (m, 2H), 6.91-6.84 (m, 2H), 6.76-6.68 (m, 2H), 4.58-4.35 (m, 2H), 3.90-3.76 (m, 2H), 3.71 (s, 3H), 3.57 (s, 2H), 1.49-1.21 (m, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br.BrC[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: BrCCc1ccccn1
Agent: Br
Product: Cl
Product: Clc1ccc2c(c1SCCc1ccccn1)CCNCC2

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-(2-bromoethyl)-pyridine hydrobromide to give, after deprotection using a method similar to the General Procedure 1-4, the title compound. MS (ES+) m/z 319 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[Ca+2:34].[OH-]>O1CCCC1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ca:34]
Reactant: [Ca+2]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: [Ca]
Reaction time: 72 h

Procedure:
A physical mixture of Raltegravir free hydroxy (25.8 mg) and calcium hydroxide (˜4.6 mg) was suspended in 70/30 tetrahydrofuran/water. The mixture was shaken well and the resulting suspension was temperature cycled between room temperature and 50° C. using a Heidolph shaker and incubator with a power source programmed to switch on and off every 4 hours. After approximately 72 hours, excess solvent was decanted off using a syringe and the solid residue was dried at ambient temperature under vacuum for approximately 24 hours. The product was characterised by XRPD.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11](=O)[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=O)[CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[CH2:22]1[N:27]2CN3CN(C2)C[N:23]1C3.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:39]C(O)=O>>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[N:23]=[CH:22][NH:27][C:12]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:8]=[CH:7][N:6]=1)([CH3:39])([CH3:3])[CH3:2]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(=O)O
Reactant: CC(C)Nc1nccc(C(=O)C(=O)c2ccc(F)cc2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)Nc1nccc(-c2nc[nH]c2-c2ccc(F)cc2)n1
Temperature: 65 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A mixture of 1-(2-iso-propylamino-pyrimidin-4-yl)-2-(4-fluoro-phenyl)-ethane-1,2-dione (12.5 g, 43.5 mmol), hexamethylenetetramine (12.2 g, 87.1 mmol), NH4OAc (17 g, 220 mmol), and Na2SO4 (12 g) in AcOH (150 mL) was heated at 65° C. After 4 h, the mixture was cooled to rt. The mixture was filtered, washing with AcOH. The filtrate was concentrated, and the residue was dissolved in CH2Cl2. The organic solution was washed with 1 N NaOH, dried (Na2SO4), and concentrated. The crude product was purified by column chromatography (MeOH/hexanes) to afford the title compound as a light yellow solid (6.8 g, 52%). TLC (10% MeOH/CH2Cl2): Rf=0.21. 1H NMR: 8.13 (br s, 1H), 7.84 (br s, 1H), 7.61 (br s, 2H), 7.14 (t, J=7.8 Hz, 2H), 6.87 (br s, 1H), 5.31 (br s, 1H), 4.14 (br s, 1H), 1.26 (d, J=9.8 Hz, 6H). HRMS (ESI): [M+H]+ calcd. for C16H17FN5, 298.1463; found, 298.1461.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:17][CH:16]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cn1
Reactant: COC(=O)Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)nc1
Reaction time: 15 h
Yield: 86.6 %

Procedure:
To a mixture of [6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methanol (1.00 g), methyl 2-(2-hydroxyphenyl)acetate (0.50 g), tributylphosphine (1.21 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.51 g) at room temperature and the mixture was stirred for 15 hrs. The precipitated crystals were filtered off. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give crystals (1.20 g, 87%) of methyl 2-[2-[[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][CH:16]=[C:11]2[C:10]([C:17]2[O:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(O)(=O)C>C(O)CC>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][CH:16]=[C:11]2[C:10]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2nn(Cc3ccccc3)c3ncncc23)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCCO
Solvent: CC(=O)O
Product: OCc1ccc(-c2nn(Cc3ccccc3)c3ncncc23)o1
Reaction time: 0.25 h

Procedure:
0.6 g (1.97 mmol) of 1-benzyl-3-(5-formyl-2-furyl)pyrazolo[3,4-d]pyrimidine (Rf=0.65, SiO2, ethyl acetate) is treated with 60 mg of NaBH4 with good stirring in 20 ml of 1-propanol at room temperature. After 15 min, 50 ml of water and 2.5 ml of glacial acetic acid are added. After partially concentrating in a rotary evaporator, the mixture is extracted with ethyl acetate, and the extract is dried and concentrated in a rotary evaporator after addition of toluene. After chromatography on SiO2, 74.8 mg (12.4% of theory) of product are obtained (m.p. 165° C., Rf=0.43, SiO2, ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:28]([O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
4-Hydroxy cinnamic acid (10 g, 61 mmol) was combined with 1-hexadecanol (14.0 g, 58 mmol), p-toluenesulfonic acid (1.2 g, 6.3 mmol) and 100 ml toluene and heated to 140° C. for 24 h with continual removal of water using a Dean-Stark distillation apparatus. The mixture was cooled to room temperature and 50 ml ethyl acetate added. The solution was washed with water, 5% sodium hydrogen carbonate, brine and then dried over magnesium sulfate. The product was recrystallized from ethyl acetate to give 4.8 g 3-(4-hydroxy-phenyl)-acrylic acid hexadecyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH3:20])[C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)cc1Br
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Br)cn(-c2cccc(C(F)(F)F)c2)c1=O
Yield: 98.3 %

Procedure:
To a solution of 5-bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 97) (150.0 mg) and potassium carbonate (181.6 mg) in N,N-dimethy formamide (4.0 ml) was added at room temperature, methyl iodide (0.042 ml) and the resulting mixture was stirred at 70° C. for two and a half hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (20.0 ml), and the resulting mixture was extracted with ethyl acetate (20 ml×2) and the organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-bromo-3-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (153.6 mg).
Reaction SMILES: ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:13]1[C:18]([NH2:19])=[C:17](Cl)[C:16]([Cl:21])=[C:15](Cl)[C:14]=1[Cl:23].C1(O)C=CC=CC=1.IC1C=CC=CC=1O.[H][H]>[Ta]>[Cl:21][C:16]1[CH:17]=[C:18]([CH:13]=[C:14]([Cl:23])[CH:15]=1)[NH2:19]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: [H][H]
Agent: [Ta]
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Agent: Oc1ccccc1I
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 95 %

Procedure:
131 parts of a tetrachloroaniline/pentachloroaniline mixture, 200 parts of phenol and 10 parts of 2-iodophenol are reacted in the presence of 12.5 parts of ruthenium-on-charcoal catalyst (5%) in a tantalum autoclave with hydrogen under a pressure of from 29 to 50 bars at a maximum temperature of 165° C., during the course of 8 hours, whilst stirring. 87.5 parts of 3,5-dichloroaniline are obtained after working up the reaction mixture. Yield: 95% of theory.
Reaction SMILES: [H-].[BH3:2].[Na:3].[CH2:4]1[CH2:8][O:7][CH2:6][CH2:5]1.[C:9]1(=[O:14])[O:13][CH2:12][CH:11]=[CH:10]1>CN(C=O)C.C(O)C>[O:7]1[CH:8]=[CH:4][CH:5]=[CH:6]1.[C:12]1(=[O:7])[O:13][C:9](=[O:14])[CH:10]=[CH:11]1.[BH3:2].[Na:3]
Reactant: O=C1C=CCO1
Reactant: C1CCOC1
Agent: B
Agent: [H-]
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1C=CC(=O)O1
Product: c1ccoc1

Procedure:
In general, as a method for obtaining a lactone from an acid anhydride, a method of reducing the acid anhydride using hydride reducing agents is widely known. For example, J. Org. Chem., 35, 3574 (1970) describes a method of synthesizing a lactone compound by applying sodium boron hydride as a reducing agent to various types of cyclic acid anhydride in a THF or DMF solvent. Synthesis, 42 (1974) describes a method of synthesizing γ-crotonolactone, which comprises reducing a cyclic acid anhydride obtained by the Diels-Alder reaction between furan and maleic anhydride with sodium boron hydride in an ethanol solvent, so as to obtain the corresponding lactone. As a method of isolating lactone, the above-described document, J. Org. Chem., 35, 3574 (1970) describes a method which comprises neutralizing the reaction solution obtained by reduction with a hydrochloric acid solution, and then extracting with ether followed by condensation.
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][C:7]#[N:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.[CH3:15][C:16](O)([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH3:17].S(=O)(=O)(O)[OH:26]>C(O)(=O)C>[C:4]1(=[O:9])[N:5]([CH2:6][C:7]([NH:8][C:16]([CH3:17])([CH3:15])[CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[O:26])[C:1](=[O:14])[C:2]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:3]12
Reactant: CCCC(C)CC(C)(C)O
Reactant: O=S(=O)(O)O
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Product: CCCC(C)CC(C)(C)NC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
2-Phthalimidoacetonitrile (3.85 g) was dissolved in glacial acetic acid at 70° and 2,4-dimethylheptan-2-ol (3 g) was added; followed dropwise by conc. sulphuric acid (2.8 ml) the temperature being maintained between 65° and 70°. The final mixture was stirred for 15 minutes and then added slowly to ice cold water (150 ml). The resulting solid was collected, washed with water and dried in vacuo. It was dissolved in hot benzene, a little insoluble material filtered off and light petroleum (b.p. 40°-60° ) added to give 2-phthalimido-N-(1,1,3-trimethylhexyl)acetamide as a colourless solid, m.p. 131.6°.