Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:25]=[C:26]=[O:27].N[C:29]1[C:34]2[O:35][CH2:36][C:37](=[O:39])[NH:38][C:33]=2[CH:32]=[CH:31][CH:30]=1>CCOC(C)=O.CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:26]([NH:25][C:29]2[C:34]3[O:35][CH2:36][C:37](=[O:39])[NH:38][C:33]=3[CH:32]=[CH:31][CH:30]=2)=[O:27])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: [N-]=C=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(C(F)(F)F)cc2)N1
Temperature: 80 °C
Yield: 24 %

Procedure:
Commercially available 4-trifluoromethylbenzylamine (0.6 ml, 4.2 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.2 g, 4.2 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1f (460 mg, 2.8 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 250 mg of a white solid. Yield=24% 1HNMR (DMSO, 200 MHz) δ 4.31 (2H, d, J=6.2 Hz), 6.46 (1H, dd), 6.70 (2H, t), 6.81 (1H, t), 7.45 (2H, d, J=8 Hz), 7.70 (4H, m), 8.16 (1H, s), 10.72 (1H, bs); [M+1] 366.1 (C17H14F3N3O3 requires 365.3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[C:10](OC(=O)C)=[CH:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(-n2ccc3cc(Cl)ccc32)cc1
Temperature: 25 °C

Procedure:
1-(4-flourophenyl)-3-acetoxy-5-chloroindole (100.0 g, 0.33 mol) was dissolved in 1000 mL EtOH. During the next hour sodium borohydride pellets (18.7 g, 1.5 eq.) were added batchwise at reflux. The reaction mixture was stirred over night at reflux and cooled to room temperature. Concentrated HCl (appr. 50 mL until pH 1) was added and the reaction mixture was stirred at room temperature for 1 hour. 200 mL demineralized water was added, and the resulting suspension was filtrated. The filter cake was washed with further 50 mL water and 10 mL EtOH. The product was dried over night in vacuum at 50° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Br:11])=[C:6]([OH:12])[C:5]=1[CH2:13][C:14]([CH3:16])=[CH2:15].B(F)(F)F.CCOCC.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Br:11])=[C:6]2[O:12][C:14]([CH3:16])([CH3:15])[CH2:13][C:5]=12)=[O:17]
Reactant: C=C(C)Cc1c(C(=O)OC)cc(O)c(Br)c1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(O)c(Br)c2c1CC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a stirred solution of 4-bromo-3,5-dihydroxy-2-(2-methyl-allyl)-benzoic acid methyl ester (197c) (85 g, 0.28 mol) in CH2Cl2 (1500 mL) was added drop wise BF3.Et2O (180 mL, 1.41 mol) at 0° C. The mixture was stirred at room temperature for 2 hr. After TLC (petroleum ether/EtOAc=5/1) showed the reaction was complete, the reaction mixture was poured into water (1 L). The organic phase was separated and washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated to give a yellow solid. The crude solid was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (37 g, 44% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 5.43 (s, 1H), 3.80 (s, 3H), 3.29 (s, 2H), 1.45 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][O:9][CH2:8][C:7]=2[CH:6]=[C:5]([CH:13]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=C(C)O[N:34]=3)=[CH:29][CH:28]=2)[C:14]2[NH:15][C:16](=[O:25])[N:17]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:18]=2)[CH:4]=1.O.[C:40]([OH:43])(=[O:42])[CH3:41]>CO.[Fe]>[C:40]([OH:43])(=[O:42])[CH3:41].[CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][O:9][CH2:8][C:7]=2[CH:6]=[C:5]([CH:13]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH2:37])=[NH:34])=[CH:29][CH:28]=2)[C:14]2[NH:15][C:16](=[O:25])[N:17]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[N:18]=2)[CH:4]=1
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 814 mg of 5-{(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one in 15 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 1 g of iron powder, and the mixture was stirred overnight at 60° C. under a nitrogen atmosphere. After adding 7.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent to the reaction mixture, the mixture was further stirred at 60° C. for 5 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (476 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]1COCC1.[CH3:16][N:17]1[CH:21]([CH3:22])[CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([C:29](=[O:38])/[CH:30]=[CH:31]/[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:18]1=[O:39]>C1COCC1.C1(C)C=CC=CC=1.[Zn+2].[I-].[I-]>[CH3:16][N:17]1[CH:21]([CH3:22])[CH:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:19]([C:29](=[O:38])[CH2:30][C@@H:31]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:11][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:18]1=[O:39]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CC1C(c2ccccc2)N(C(=O)/C=C/c2cccnc2)C(=O)N1C
Reactant: C1CCOC1
Agent: [I-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@@H](CC(=O)N2C(=O)N(C)C(C)C2c2ccccc2)c2cccnc2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 4-methoxyphenylmagnesium bromide in THF (0.33 M, 495 mL, 163.5 mmole) was added dropwise to a stirred suspension of (4 R, 5 S)-3,4-dimethyl-1-[(E)-3-(pyridin-3-yl)prop-2-enoyl]-5-phenylimidazolidin-2-one (17.53 g, 54.5 mmole), CuBr-DMS complex (14.1 g, 65.4 mmole), and ZnI2 (20.9 g, 65.4 mmole) in THF/toluene (270 mL) at −15° C. After 1 hr the reaction was quenched with 9:1 saturated NH4Cl/conc. NH4OH and the mixture was stirred open to the air for 30 min. The mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated. The residue was taken up in methyl tert-butyl ether (MTBE, 200 mL) and stored at −20° C. overnight. The solid was collected, washed with MTBE, and dried in vacuo. This material was recrystallized from 3:1 hexanes/EtOAc to provide the title compound (19.408 g. 80%): 1H NMR (400 MHz, CDCl3) δ 8.72 (br s, 2 H), 7.50 (narrow m, 1H), 7.12-7.35 (m, 4 H), 6.97-7.03 (m, 2 H), 6.94 (d, J=8.6 Hz, 2 H), 6.72 (d, J=8.6 Hz, 2H), 5.11 (d, J=8.4 Hz, 1 H), 3.70-3.90(m, 2 H), 3.70 (s, 3 H). 3.43-3.58 (m, 1 H), 3.03-3.18 (m, 1 H), 2.75-2.95 (m, 2 H), 2.71 (s, 3 H), 0.66 (d, J=6.5 Hz, 3 H); MS (ES) m/e 444 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=1.[C:20](Cl)(Cl)=[O:21].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:14][C:12]1[N:13]=[C:9]([N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:20]2=[O:21])[S:10][C:11]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1sc(Nc2ccccc2N)nc1C
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1sc(-n2c(=O)[nH]c3ccccc32)nc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a suspension of ethyl 2-(2-aminophenylamino)-4-methylthiazole-5-carboxylate (0.24 g, 0.87 mmol) in dichloromethane (12 mL) was added phosgene solution (purum, ˜20% in toluene, 0.48 mL, 0.91 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 16 h followed by the addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (30 mL), washed with water and brine, dried over sodium sulfate, filtered, concentrated to small volume, and triturated with diethyl ether (5 mL) to precipitate the product. The solid was collected by filtration, washed with water (3×5 mL) and hexanes (5 mL), and dried in vacuo to afford ethyl 4-methyl-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)thiazole-5-carboxylate as a white solid (0.21 g, 80% yield): MS (ES+) m/z 304.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[OH:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:43]3[CH:44]=[CH:45][C:40]([OH:39])=[CH:41][CH:42]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(O)cc2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (80 mg, 0.14 mmol) in EtOH (4 mL)/H2O (1 mL) were added 4-hydroxyphenylboronic acid (38 mg, 0.28 mmol), potassium carbonate (77 mg, 0.56 mmol) and Pd(PPh3)4 (3 mg, 0.0028 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: [OH-].[Na+].O.CO.[CH3:6][C:7]([CH3:21])([CH:14](Cl)[CH2:15][C:16](Cl)([Cl:18])[Cl:17])[CH2:8][C:9]([O:11]CC)=[O:10]>CCOCC>[CH3:6][C:7]1([CH3:21])[CH:14]([CH:15]=[C:16]([Cl:18])[Cl:17])[O:11][C:9](=[O:10])[CH2:8]1
Reactant: CCOC(=O)CC(C)(C)C(Cl)CC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Reaction time: 2 h
Yield: 92 %

Procedure:
To a mixed solution of 12.0 parts of sodium hydroxide, 40 parts of water and 60 parts of methanol was added dropwise under reflux 31.0 parts of ethyl 3,3-dimethyl-4,6,6,6-tetrachlorohexanoate and, after the dropwise addition had been completed, the mixture was stirred at that temperature for 2 hours. The reaction mixture was then distilled under reduced pressure to remove the methanol, and the residue was neutralized with hydrochloric acid and extracted with diethyl ether. From this ether layer was obtained 19.2 parts of 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide (yield 92%) which had the following properties.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1=O.[OH:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][NH2:24]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][OH:27])[CH2:20][CH2:19][OH:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCN(CCO)CCO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCN(CCO)CCO)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
5 g of para-fluoronitrobenzene were added to a solution of 60 ml of N-methylpyrrolidinone, 6.29 g of N,N-bis(2-hydroxyethyl)ethylenediamine, and 4.3 g of triethylamine. The reaction medium was heated at 60° C. for 15 hours and, after cooling to room temperature, was poured into a water/ice mixture. A yellow precipitate formed, which was filtered off, reslurried in water, and then dried over P2O5. 7.5 g of 2-[[2-(4-nitrophenylamino)ethyl]-(2-hydroxyethyl)amino]ethanol (19) were obtained.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].Br[CH2:32][C:33]([CH:35]1[CH2:39][N:38]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)[C:37](=[O:50])[CH2:36]1)=[O:34].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[O:34]=[C:33]([CH:35]1[CH2:36][C:37](=[O:50])[N:38]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:47])[F:48])[CH:41]=2)[CH2:39]1)[CH2:32][N:25]1[CH:26]=[C:22]([C:9]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]3[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:30])[N:6]([CH2:27][CH2:28][CH3:29])[C:7]=3[N:8]=2)[CH:23]=[N:24]1
Reactant: O=C(CBr)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC(=O)C4CC(=O)N(c5cccc(C(F)(F)F)c5)C4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 95 °C
Yield: 27.8 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.200 g, 0.462 mmol), 4-(2-Bromo-acetyl)-1-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one (0.240 g, 0.693 mmol), Cs2CO3 (0.30 g, 0.924 mmol) and acetonitrile (2 ml) were heated at 90-100° C. in a sealed tube for 6 hrs. Reaction mixture was cooled to 20-25° C. and filtered off. The organic volatiles were evaporated. The crude product was purified by preparative TLC to obtain pure 8-(1-{2-oxo-2-[5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.090 g, 28%) as a brown mass.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=C(Cl)[N:15]=1.O>CN(C)C=O>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:15]=1
Reactant: O=CNc1ccc(Cl)cc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
N-(4-Chloro-phenyl)-formamide (766 mg, 4.93 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (60% in mineral oil, 240 mg, 5.91 mmol) was added and the mixture was stirred for 30 min. 2,6-Dichloro-9-methyl-9H-purine (1.0 g, 4.93 mmol) was added and the reaction mixture was heated to 80° C. for 2 hours; cooled to room temperature and poured into water. The resulting precipitate was collected by filtration, washed with water and dried to give (2-chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine (1.2 g, 4.08 mmol, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH3:19].O1CCCC1>CC(=O)CC>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6])[CH3:19]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCC(C)=O
Product: CCOc1cc(C(=O)O)ccc1I
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 3-hydroxy-4-iodo-benzoic acid (4 g, 15.15 mmol) in 2-butanone (100 mL) were added potassium carbonate (20 g, finely ground) and ethyl iodide (4.85 mL). The mixture was stirred at reflux overnight. Upon cooling to room temperature, the solids were filtered off, and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water, and the organic layer was washed with 10% sodium carbonate solution, brine, and concentrated. The residue reconstituted in methanol. 1.0 M sodium hydroxide was added giving a cloudy solution. Tetrahydrofuran was added to clarity and the mixture stirred at room temperature for one hour. The volatiles were evaporated and the residue was dissolved in water. It was washed once with diethyl ether and then acidified with 37% hydrochloric acid to precipitate a white solid. The solid was filtered, washed with water and dried in a vacuum oven to give 3-ethoxy-4-iodo-benzoic acid (2.73 g, 62%). LC-MS: 293 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(Cl)Cl.[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH2:23])[CH3:19]>C(N(CC)CC)C>[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH:23][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:13])[C:10]([NH2:12])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:19]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CCN(CC)CCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Reaction time: 18 h
Yield: 60.5 %

Procedure:
2-Methoxy-4-amino-5-chlorobenzoic acid (1.0 g) and 1-methanesulfoyloxy-1,2,3-benzotriazole (1.07 g) are suspended into chloroform (15 ml) and therto is added dropwise triethylamine (0.7 ml) with stirring under ice-cooling to give a clear solution. To the solution is added 2-(diethylamino)ethylamine (0.6 g) at room temperature and the mixture is allowed to stand for 18 hours. The solvent is then distilled off and thereto are added water and 1 N aqueous sodium hydroxide. The resulting crystals are separated by filtration, washed with water and then dried to give N-(2-diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide (0.9 g), melting point: 145°-146° C. The product is identified with an authentic sample by infrared spectrum.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].C[O-].[Na+].[C:27](=O)=[O:28]>CO>[CH3:27][O:28][C:19]([C:4]1[C:3]([S:21]([CH3:23])=[O:22])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[NH:20]
Reactant: O=C=O
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Temperature: 0 °C

Procedure:
To a stirred suspension of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (5.0 g) in anhydrous methanol was added a 25% w/w solution of sodium methoxide (8.95 ml) in methanol, at 20° C. The mixture was stirred for 16-hours, cooled to 0° C. and diluted with ice-cold anhydrous methanol. Carbon dioxide was passed into the solution for 15-minutes until a pH of 8 was attained. The precipitate was filtered off, washed (ethyl acetate) and evaporated to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidic acid methyl ester (3.65 g), 1H NMR (CDCl3) in ppm: 8.34(s,1H), 7.79(s,2H), 5.11(brs,2H), 3.93(s,3H), 2.94(s,3H). By proceeding in a similar manner the following compound was prepared: 5-Amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-trifluoromethylsulfinyl-1H-pyrazole-3-carboximidic acid methyl ester, m.p.179-180° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27](=[CH2:31])[C:28]([OH:30])=[O:29].[CH2:32](O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CCCCCC.C(OCC)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27](=[CH2:31])[C:28]([O:30][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29]
Reactant: OCc1ccccc1
Reactant: C=C(C(=O)O)c1cc(F)ccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(C(=O)OCc1ccccc1)c1cc(F)ccc1F
Reaction time: 17 h

Procedure:
Under a nitrogen atmosphere, dicyclohexyl carbodiimide (206 mg, 1.0 mmol) was added to a methylene chloride solution (10 ml) of 2,5-difluorophenylacrylic acid (184 mg, 1 mmol), benzyl alcohol (104 ml, 1 mmol), and N,N-dimethylaminopyridine (36 mg, 0.3 mmol) at room temperature and the resulting mixture was stirred for 17 hours. After concentration of the reaction mixture under reduced pressure, 10 ml of hexane-diethyl ether (4:1) was added to the residue. The precipitate thus formed was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1), whereby the title compound (242 mg, 88%) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:7](=[O:23])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][N:10]=2.C(N(CC)CC)C.O.Cl>C(Cl)Cl>[C:17]1([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][N:10]=3)[C:15](=[O:16])[C:6]3([CH2:5][CH2:4][CH2:3][CH2:2]3)[C:7]2=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1c(CCCCBr)c(O)c2cccnc2n1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1c2cccnc2N(c2ccccc2)C(=O)C12CCCC2
Temperature: 25 °C

Procedure:
A suspension of 3-(4-bromobutyl)-4-hydroxy-1-Phenyl-1,8-naphthyridin-2(1H)one (5g.) in methylene chloride (350 ml.), in an atmosphere of nitrogen, was stirred at room temperature and to it was added triethylamine (4.1 ml.). The mixture was stirred at room temperature for 16 hrs. Water (300 ml.) was added and the aqueous layer was adjusted to pH 4.5 with hydrochloric acid. The organic layer was separated and the aqueous layer was back-extracted with methylene chloride. The combined organic layers were washed with water, dried (Na2SO4) , filtered and evaporated to yield a solid which was recrystallized from-isopropanol to yield 1'-phenylspiro[cyclopentane-1,3'-(1,8) naphthyridine]2',4'-(1'H)dione, m.p. 178°-179° C.
Reaction SMILES: [C:1]([O:9][CH2:10]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:12].[Na+]>C(#N)C.O>[C:1]([O:9][CH2:10][I:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(OCCl)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(OCI)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
Chloromethyl benzoate (2.87 g, 16.82 mmol) was dissolved in acetonitrile (20 mL) and treated portionwise with sodium iodide (5.04 g, 33.6 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (3.15 g);