Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2.Cl[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: Fc1ccc(Oc2cc(Br)c3cn[nH]c3c2)c(F)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2c(Br)cc(Oc3ccc(F)cc3F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
Sodium hydride (98 mg of 60% weight in mineral oil, 2.45 mmol) was washed with hexanes and added to 5 mL of dry DMF, and the mixture was placed under nitrogen atmosphere and cooled to 0° C. 4-Bromo-6-(2,4-difluoro-phenoxy)-1H-indazole (0.50 g, 1.54 mmol) dissolved in 5 mL dry DMF was added to the reaction mixture. The reaction mixture was stirred for 30 minutes at room temperature, then cooled to 0° C. again. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.386 g, 2.32 mmol) was added, and the reaction mixture was stirreed for 21 hours at room temperature under nitrogen. The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with brine and water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-25% EtOAc in hexanes) to give 0.181 g of 4-bromo-6-(2,4-difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole, MS(M+H)=455.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16].Cl>C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:15]([OH:16])([CH3:17])[CH3:14])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Fc1ccc(Br)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(O)c1nc(Br)ccc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (25 g, 142 mmol) in diethylether (600 ml) was slowly added n-butyllithium (2.5 M in hexane, 56.8 ml, 142 mmol) at −78° C. under a nitrogen atmosphere. The resulting yellow reaction mixture was stirred at −78° C. for 2 hours and dry acetone (11.47 ml, 156 mmol) was added over 30 minutes. Stirring was continued at −78° C. for 1 hour. HCl (2N, 50 ml) was added and the reaction mixture was warmed to 0° C. The pH of the mixture was adjusted to ˜7 with 2N HCl solution. The reaction mixture was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (29.36 g) was chromatographed over silica gel (cyclohexane:ethyl acetate 9:1): 22.3 g (67.1% yield). TLC (cyclohexane/ethyl acetate 9:1) Rf=0.33; LCMS RtH5=0.89 min (ES+ 234, 236). 1H-NMR (360 MHz, DMSO-d6): 7.72-7.62 (m, 2H), 5.27 (s, 1H, OH), 1.50 (s, 6H, 2×CH3).
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1)[C:8]#[N:9].[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH3:2][O:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1)[C:8](=[NH:9])[O:18][CH2:16][CH3:17]
Reactant: COCc1cc(C#N)cc(COC)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cc(COC)cc(COC)c1
Reaction time: 5.5 h
Yield: 46 %

Procedure:
Hydrogen chloride gas was passed through a solution of 3,5-bis-methoxymethyl-benzonitrile (1 g, 5.2 mmol) in anhydrous ethanol (150 mL) at room temperature. After 5.5 h, hydrogen chloride gas was stopped. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford ethyl 3,5-bis-methoxymethyl-benzimidate hydrochloride (658 mg, 46%). It was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C=O)C>[CH2:17]([N:10]1[C:11](=[O:13])[CH2:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[C:9]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CN(c2cccc(I)c2)C(=O)N1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(c2cccc(I)c2)C(=O)N1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
1-(3-Iodophenyl)imidazolidine-2,4-dione (0.5 g) was taken up in dry DMF (10 ml) and treated with sodium hydride (60% oil dispersion, 73 mg) and stirred for 20 min under nitrogen. Benzyl bromide (0.295 ml) was added and stirring continued for 3 h. 2M HCl (100 ml) was added and the mixture extracted with EtOAc. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate (50 ml), brine (50 ml) and dried (MgSO4). This was recrystallised from MeOH to give the title compound (0.255 g). LCMS RT 3.53 min.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]([CH2:15][C:16]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C=O.[C:30](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[CH3:30][N:19]1[CH2:20][CH2:21][C:16]([CH2:15][N:5]([C@@H:6]2[CH2:8][C@H:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18]1
Reactant: CC(=O)O
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@H]2C[C@@H]2c2ccccc2)CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-((2,2,2-trifluoro-N-((1S,2R)-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (270 mg, 0.702 mmol) in 1,2-dichloroethane (DCE) (3 mL) and methanol (1.500 mL) were added formaldehyde (0.129 mL, 1.405 mmol) and acetic acid (0.060 mL, 1.054 mmol), and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (223 mg, 1.054 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was quenched with 10% N NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 265 mg of product as pale yellow oil. MS: (M+H)+=399.2.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][Cl:13].O>O1CCCC1>[Cl:13][CH2:12][CH2:11][CH2:10][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1
Reactant: Ic1c[nH]cn1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ClCCCn1cnc(I)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
To a stirred solution of 4-iodo-1H-imidazole (291, 2 g, 10.3 mmol) La) Y. He et al., Tet. Lett. 45, 2004, 5529-5532, b) Panosyan, F. B., Still, I. W. J., Can. J. Chem. 79, 2001, 1110-1114.] in dry tetrahydrofuran (40 mL) at 0° C. under nitrogen was added sodium hydride (60% in oil, 0.91 g, 22.7 mmol). The mixture was stirred for 20 min. at 0° C., 1-bromo-3-chloropropane (1.2 mL, 12.4 mmol) was added and stirring was continued for 24 h at room temperature. Water was added and the aqueous solution was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent ethyl acetate-dichloromethane, 4:96) to afford 292 (1.35 g, 5.0 mmol, 49% yield) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.63 (d, J=1.2 Hz, 1H), 7.42 (d, J=1.2 Hz, 1H), 4.08 (t, J=6.8 Hz, 2H), 3.55 (d, J=6.8 Hz, 2H), 2.16 (q, J=6.8 Hz, 2H). MS (m/z): 271.0 (M+H, 100%), 273.0 (M+H, 32%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][C:20]=1[CH3:26]>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:21][C:20]=1[CH3:26]
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Cc1cc(S)ccc1Br
Product: Cc1cc(SCCCCOc2ccc3c(c2)CCC(=O)N3)ccc1Br

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 4-bromo-3-methyl-thiophenol.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25](=[O:40])[CH2:26][C:27]2[NH:28][C:29](=[O:39])[CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:32]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(O)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([NH:24][C:25](=[O:40])[CH2:26][C:27]2[NH:28][C:29](=[O:39])[CH:30]=[C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:32]=2)=[C:17]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(F)ccc2NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.7 %

Procedure:
1.5 ml of 4M hydrochloric acid in dioxane are added to a solution of 223 mg of 4-{5-fluoro-2-[2-(4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetylamino]phenoxymethyl}piperidine-1-carboxylic acid tert-butyl ester in 6 ml of ethanol. After stirring at ambient temperature for 20 h, the reaction medium is concentrated under reduced pressure, taken up with a solution of aqueous ammonia in methanol, and then again concentrated to dryness. After purification by silica column chromatography, eluent: 90/10 CH2Cl2/MeOH, 65 mg of N-[4-fluoro-2-(piperidin-4-ylmethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained, the characteristics of which are the following:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]([F:20])([F:19])[F:18])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:17]([F:18])([F:19])[F:20])[CH:11]=1
Reactant: [H][H]
Reactant: COc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
30 g (106.28 mmol) of 1-benzyloxy-4-methoxy-2-trifluoromethyl-benzene were dissolved in 60 mL ethyl acetate and then combined with 3 g palladium/C 10%. The mixture was shaken at RT and 50 psi hydrogen pressure for 4 h. The reaction mixture was suction filtered through Celite and the filtrate was evaporated down. The residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate).
Reaction SMILES: [NH2:1][P:2]([NH2:15])([NH:4][C:5](=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:3]>CO>[NH2:1][P:2]([NH2:15])([NH:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:3]
Reactant: NP(N)(=O)NC(=O)C=Cc1ccccc1
Solvent: CO
Product: NP(N)(=O)NC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
N-(Diaminophosphinyl)cinnamamide (1 g) was dissolved in methanol (200 ml), and 10% Pd--C (wet) (0.4 g) was added. The mixture was hydrogenated at room temperature under atmospheric pressure for 30 minutes, and the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with diethyl ether and recrystallized from methanol to give the desired compound.
Reaction SMILES: [CH2:1]([S:11]([OH:14])(=[O:13])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[OH-].[Ca+2:16].[OH-].CC(C)=O>O>[CH2:1]([S:11]([O-:14])(=[O:13])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:8])=[O:9].[Ca+2:16]
Reactant: O=S(=O)(O)CCSSCCS(=O)(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)([O-])CCSSCCS(=O)(=O)[O-]
Yield: 85 %

Procedure:
A solution of 2,2′-dithiobis ethane sulfonic acid (2.5 g, containing 9% water, 8.1 mmol) in water (1.0 mL) was titrated with calcium hydroxide (98+% purity, Acros Organics) aqueous solution until the pH of the reaction solution was adjusted to 7.0. Overall, 0.60 g (8.1 mmol) calcium hydroxide was used. Acetone (200 mL) was added to the reaction solution to precipitate the product. The resulting white solid was isolated by filtration and dried under high vacuum to give 2.20 g of product (85% yield). The purity of the product was 97.4% from HPLC analysis.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].[CH2:7]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:45])[C@@H:19]([NH:29][C:30]([C:32]2[CH:37]=[C:36](Cl)[N:35]=[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:33]=2)=[O:31])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13]1)=[O:11])[CH3:8].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:7]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:45])[C@@H:19]([NH:29][C:30]([C:32]2[CH:37]=[C:36]([S:4][CH2:1][CH2:2][CH3:3])[N:35]=[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:33]=2)=[O:31])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCCS
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-propanethiol (11 μl) was added to a suspension of NaH (4 mg) in anhydrous DMF (0.3 ml) at 0° C. After 1 h stirring at 0° C., 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (50 mg) dissolved in DMF (0.1 ml) was added. The mixture was allowed to warm to RT and was stirred at RT until completion. A NaHCO3 solution was added and the resulting mixture was extracted with DCM. The org. phases were dried (Na2SO4) and evaporated off. The crude was directly used in the next step.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.O[C:23]1C=CC2C3(C)CCN(C(OC(C)(C)C)=O)CC3OC=2C=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH3:23])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(O)cc3OC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Product: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(I)cc3OC2C1

Procedure:
Synthesized as described for tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from tert-butyl 7-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate. MS m/z 360 [M-tBu+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21](O)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:53][C:54]1[C:62]([NH2:63])=[CH:61][CH:60]=[CH:59][C:55]=1[C:56]([NH2:58])=[O:57]>CN(C=O)C>[NH2:53][C:54]1[C:55]([C:56](=[O:57])[NH2:58])=[CH:59][CH:60]=[CH:61][C:62]=1[NH:63][C:21]([CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:22]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)C1c2ccccc2CCN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(NC(=O)C2c3ccccc3CCN2C(=O)OCc2ccccc2)c1N
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Step-1: To a solution of 2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (560 mg, 1.8 mmol) in anhydrous DMF (7 ml) was added EDC.HCl (1.035 g, 5.4 mmol), HOAt (367 mg, 2.7 mmol) and triethylamine (0.375 ml, 2.7 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (302 mg, 2 mmol) was added and heated to 55° C. over night. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitate formed was filtered and dried under vacuum to yield benzyl 1-((2-amino-3-carbamoylphenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 445.22 [M+H]+
Reaction SMILES: [C:1]([N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[OH-].[Na+].Cl>O1CCOCC1.O>[C:1]([N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(OCCCN(C(N)=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)N(CCCOc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.1 %

Procedure:
Methyl 4-[3-[N-carbamoyl-N-(4-chlorophenyl)amino]propoxy]benzoate (1.5 g) was dissolved in dioxane (30 ml), and thereto was added a solution of sodium hydroxide (0.33 g) in water (6 ml), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was neutralized with conc. hydrochloric acid (0.7 ml), and the mixrure was concentrated under reduced pressure. The residue was crushed in aqueous methanol, and collected by filtration to give the desired product (1.27 g). mp. 172°-174° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:25](=[O:27])=[O:26]>O1CCCC1>[C:1]1([CH2:7][C:8]2[CH:17]=[C:16]([C:25]([OH:27])=[O:26])[C:15]3[C:10]([C:9]=2[O:18][CH3:19])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(Cc2ccccc2)ccc2ccccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(Cc2ccccc2)cc(C(=O)O)c2ccccc12
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of the compound of Example 94 Part B (5.00 g, 0.015 mole) in dry tetrahydrofuran (50 mL) was cooled to -78° and treated dropwise with n-butyllithium (1.55M in hexane; 10.9 mL. 0.017 mole). The mixture was stirred at -78° for 45 minutes, and a stream of gaseous carbon dioxide was directed onto the surface of the stirred solution. The cooling bath was removed from the reaction vessel and the addition of carbon dioxide was continued for 5 minutes. The mixture was then poured into 1.0N hydrochloric acid, and the crude product isolated by extraction with methylene chloride. This was recrystallized (methylcyclohexane) to provide the title compound (4.0 g 90%) as a pale yellow solid, mp 146°-148°.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([S:14][CH3:15])[N:6]=1)(=[O:3])[CH3:2].[CH2:16]([O:23][C@H:24]1[C@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:27]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:26][C@@H:25]1Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:25]2[O:26][C@H:27]([CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@H:24]2[O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([S:14][CH3:15])[N:6]=1)(=[O:3])[CH3:2]
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CSc1nc(NC(C)=O)nc2nc[nH]c12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1nc(NC(C)=O)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A mixture of 4.46 g. of 2-acetamido-6-methylthiopurine, 4.87 g. of 2,3,5-tri-O-benzyl-α-D-arabinofuranosylchloride, 2 g. of triethylamine and 200 ml. of acetonitrile was stirred with 4-A molecular sieves at room termperature for one week. The mixture was filtered, and the filtrate, which contained the product, was evaporated to a syrup in vacuo. The syrup was dissolved in methanol treated with Dowex-1 (bicarbonate) and the product was purified by chromatography on a Silica gel column, eluted with benzene-ethyl acetate. Evaporation of the solvent gave the syrup 2-acetamido-6-methylthio-9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl) purine. To a solution of 1.13 g. of the compound isolated from the previous step in 20 ml. of ethanol, 0.25 ml. of 10N NaOH plus 0.5 ml. of water were added. The stirred solution was kept at 70° for 30 min. and then evaporated to dryness in vacuo. The product was extracted into ether. After evaporation of the ether, 0.92 g. of 2-amino-6-methylthio-9-( 2,3,5-tri-O-benzyl-β-D-arabinofuranosyl) purine was obtained. The identity was established by its NMR spectrum.
Reaction SMILES: C1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)C=CC=1C(O)=O.[C:17](O)(=O)C1C=CC(C(O)=O)=CC=1.[N+]([O-])(O)=O>C1(C)C(C)=CC=CC=1>[CH3:17][C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][C:7]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Solvent: Cc1ccccc1C
Solvent: O=[N+]([O-])O
Product: Cc1ccccc1C(=O)O

Procedure:
Organic acids, such as naphthalene-2,6-dicarboxylic acid or terephthalic acid, are highly useful in the manufacture of polyester-type and polyamide-type resins, including polyethyleneterephthalate. Such organic acids customarily have been prepared by a liquid phase oxidation of an alkyl-substituted aromatic precursor in the presence of an aqueous acidic reaction medium, and usually in the presence of a metal catalyst. For example, U.S. Pat. No. 2,766,281 discloses the preparation of phthalic acids, including terephthalic acid, by a step-wise oxidation of a corresponding xylene with concentrated nitric acid at atmospheric pressure and in the presence of an inert organic reaction medium that is liquid at the reaction temperatures. In the first step, the xylene starting material is reacted with the nitric acid at a temperature of from about 120 ° C. up to the boiling point of the xylene starting material, while removing water by distillation, to form a toluic acid. In the second step, nitric acid is slowly added to the toluic acid at a temperature in excess of about 140 ° C., while removing water by distillation, to form the product phthalic acid.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:6]([CH3:11])[C:7](=[O:10])[C:8]=1Cl)=[O:5])#[N:2].[CH3:12][OH:13]>>[C:1]([C:3]1[C:4]([N:6]([CH3:11])[C:7](=[O:10])[C:8]=1[O:13][CH3:12])=[O:5])#[N:2]
Reactant: CO
Reactant: CN1C(=O)C(Cl)=C(C#N)C1=O
Product: COC1=C(C#N)C(=O)N(C)C1=O
Yield: 88 %

Procedure:
43 parts of 2-cyano-3-chloro-N-methylmaleimide are introduced into 100 parts by volume of methanol, the mixture is heated at the boil for fifteen minutes and then cooled, and thereafter the precipitate is filtered off under suction, washed with a small amount of methanol and dried. 37 parts (88% of theory) of 2-cyano-3-methoxy-N-methylmaleimide of melting point 123°-125° C. are obtained. IR (KBr): 2220, 1720, 1640 cm-1.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11](Cl)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Product: O=c1c2[nH]c(N3CCOCC3)nc2n(CC2CC2)c(=O)n1CC1CC1

Procedure:
1,3-Di-cyclopropylmethyl-8-morpholino xanthine was prepared from 1,3-di-cyclopropylmethyl-8-chloroxanthine (0.3 g, 0.001 mol) and morpholine (0.2 g, 0.0022 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. >250° C., yield 0.09 g (26%).