Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([Si:19]([O:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Dissolve 3,5 dichlorophenol (1 kg, 6.13 mol) in 3 L dimethylformamide (DMF) and cool to 0° C. Add imidazole (918.74 g, 6.75 mol), followed by tertbutyldimethylsilyl chloride (1017.13 g, 6.75 mol). Warm the mixture to room temperature and stir for 15 minutes. Pour into water (6 L) and extract with ether (4 L). Wash the organic layer with water 2 times, 10% aqueous lithium chloride solution then brine before drying over sodium sulfate. Filter and concentrate under vacuum to obtain tert-butyl-(3,5-dichloro-phenoxy)-dimethyl-silane (1700 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25]([O:27]CC)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].C1COCC1>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)[CH:11]=[C:10]([C:25]([OH:27])=[O:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C(=O)NCc2cnc(C)nc2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)-biphenyl-3-carboxylate (275 mg, 0.706 mmol), lithium hydroxide (85 mg, 3.5 mmol), THF (10 mL), and water (1 mL) was stirred at room temperature for 5 h. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH=4-5. The precipitate was collected by filtration and dried to afford the title compound as a white solid. The filtrate was extracted with EtOAc (100 mL). The organic layer was washed with water and concentrated to afford some additional product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].BrC1C=CC(N=[C:22]=[O:23])=CC=1N=C=O>>[CH3:22][O:23][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13]
Reactant: O=C=Nc1ccc(Br)c(N=C=O)c1
Reactant: O=C=Nc1ccc(Cl)c(N=C=O)c1
Product: COc1ccc(N=C=O)cc1N=C=O

Procedure:
4-chloro-1,3-phenylene diisocyanate; 4-bromo-1,3-phenylene diisocyanate;
Reaction SMILES: [CH2:1]1[C:10]2C(=CC=CC=2)CCN1.[C:11]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([O:24][CH3:25])[CH:21]=2)[CH2:16][N:15]1[CH3:28])([OH:13])=[O:12]>>[C:11]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([O:24][CH3:25])[CH:21]=2)[CH2:16][N:15]1[CH3:28])([O:13][CH2:1][CH3:10])=[O:12]
Reactant: COc1cc2c(cc1OC)CN(C)C(C(=O)O)C2
Reactant: c1ccc2c(c1)CCNC2
Product: CCOC(=O)C1Cc2cc(OC)c(OC)cc2CN1C

Procedure:
The resulting tetrahydroisoquinoline derivative of formula 30 is then esterified with a suitable lower alkanol by standard means to produce a tetrahydroisoquinoline ester of formula 31 (step 2). For example, 3-carboxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (30) is treated with HCl in EtOH to produce 3-carboethoxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (31).
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.C(N(CC)CC)C.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>C1COCC1>[C:18]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: Cc1cc(=O)c(O)co1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(=O)c(OC(=O)c2cccnc2)co1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
Allomaltol (1.266 g, 10 mmol) was dissolved in 40 mL of anhydrous THF. The mixture was cooled to 0° C. Triethylamine (1.8 mL, 13 mmol) was added. Nicotinoyl chloride hydrochloride (1.988 g, 11 mmol) was added portionwise. Cold bath was removed and the mixture was stirred at room temperature overnight. The reaction was neutralized with ammonia hydroxide then extracted with EtOAc. The organic phase was washed with brine 2 times then dried over Na2SO4 and concentrated. The crude product was purified with flash chromatography using DCM/MeOH to give the desired product as an off-white solid (1.35 g, 58%). MP (148° C.). 1H NMR (CDCl3) δ (ppm): 2.27 (d, 3H, J=0.9 Hz), 6.26 (d, 1H, J=0.9 Hz), 7.42 (dd, 1H, J=4.8, 8.1 Hz), 7.95 (s, 1H), 8.37 (td, 1H, J=1.8, 7.8 Hz), 8.79 (br s, 1H), 9.28 (br s, 1H). 13C NMR (CDCl3) δ (ppm): 19.8, 115.3, 123.8, 124.7, 138.2, 140.8, 148.1, 151.3, 154.1, 162.4, 166.4, 172.4.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:15]=[C:16]2[N:26]([C:27]([C:29]3[NH:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([O:38][CH3:39])=[CH:33][CH:32]=4)=[O:28])[CH2:25][CH:24]([CH2:40][Cl:41])[C:17]2=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)C1C=CC=CC=1>O.[Pd]>[Cl:41][CH2:40][CH:24]1[C:17]2=[C:18]3[C:23](=[C:14]([OH:13])[CH:15]=[C:16]2[N:26]([C:27]([C:29]2[NH:30][C:31]4[C:36]([CH:37]=2)=[CH:35][C:34]([O:38][CH3:39])=[CH:33][CH:32]=4)=[O:28])[CH2:25]1)[N:22]=[CH:21][CH:20]=[CH:19]3
Reactant: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(OCc3ccccc3)c3ncccc43)cc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(O)c3ncccc43)cc2c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
THF (6 mL) then HCO2NH4 (0.14 g, 2.21 mmol) in H2O (0.7 mL) were added to cooled (0° C.) mixture of 17d (0.11 g, 0.22 mmol) and 10% Pd/C (0.05 g) under N2. The mixture was stirred at 0° C. for 5 h, and was then filtered through Celite. The Celite was washed with CH2Cl2/H2O. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4) and CH2Cl2 evaporated. Precipitation from CH2Cl2/MeOH gave 18d (0.077 g, 89%) as a grey solid: mp 224–227° C.; 1H NMR [(CD3)2SO]δ 11.66 (s, 1 H), 10.02 (bs, 1 H), 8.77 (dd, J=4.1, 1.3, 1 H), 8.41 (dd, J=8.4, 1.4, 1 H), 8.07 (s, 1 H), 7.57 (dd, J=8.4, 4.1, 1 H), 7.40 (d, J=9.0, 1 H), 7.16 (d, J=2.4, 1 H), 7.12 (d, J=1.6, 1 H), 6.92 (dd, J=8.9, 2.3, 1 H), 4.82 (dd, J=10.8, 9.4, 1 H), 4.57 (dd, J=11.0, 2.3, 1 H), 4.30 (m, 1 H), 4.04 (dd, J=11.1, 3.3, 1 H), 3.91 (dd; J=11.1, 7.2, 1 H), 3.78 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17](O)=[O:18]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]([NH:1][CH:17]=[O:18])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=CO
Product: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 98 %

Procedure:
A solution of 34.7 parts of 2-amino-5-chlorobenzophenone in 100 volume parts of formic acid is refluxed for 1.5 hour, and the excess formic acid is distilled off under reduced pressure. The residue is dissolved in 30 volume parts of ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate and water in this order, and dried over sodium sulfate, followed by distilling off the solvent. Treatment of the residue with n-hexane gives 5-chloro-2-formamidobenzophenone as pale yellow crystals. Recrystallization of the crystals from ethanol gives pale yellow granules melting at 92.5° to 93° C. Yield: 98%
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.Cl.[N:17]1([C:24]([C:26]2[CH:27]=[C:28]3[NH:37][C:36](=[O:38])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]3[CH:39]=2)=[O:25])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)(=O)C>[CH:10]1([C:13]([N:20]2[CH2:21][CH2:22][CH2:23][N:17]([C:24]([C:26]3[CH:27]=[C:28]4[NH:37][C:36](=[O:38])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]4[CH:39]=3)=[O:25])[CH2:18][CH2:19]2)=[O:14])[CH2:12][CH2:11]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(c1cc2[nH]c(=O)c3ccccc3n2c1)N1CCCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(c1cc2[nH]c(=O)c3ccccc3n2c1)N1CCCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Diisopropylethylamine (0.11 mL, 0.63 mmol) and cyclopropane carbonyl chloride (30 μL, 0.33 mmol) were sequentially added to a solution of 2-(homopiperazine-1-carbonyl)pyrrolo[1,2-a]quinazolin-5(4H)-one hydrochloride (Compound 5-1, 70.0 mg, 0.20 mmol) in anhydrous N,N-dimethylformamide (0.50 mL), and the reaction solution was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (20 mL), and washed sequentially with 0.1M sodium hydroxide aqueous solution (20 mL) and brine (20 mL). The aqueous layer was extracted twice with chloroform (20 mL), and combined with the ethyl acetate layer, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate), to obtain the title compound (25.8 mg, yield: 34%) as a colorless powder.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)(=O)OCC)C.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.CC(C)([O-])C.[K+]>O1CCCC1>[Br:16][C:12]1[CH:11]=[C:10]([CH:9]=[C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOP(=O)(Cc1cccc(Br)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To diethyl[(3-bromophenyl)methyl]phosphonate (100 g, 326 mmol) in a 2 L 3-neck flask with mechanical stirrer was added tetrahydrofuran (THF) (700 mL) followed by 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (71.4 g, 358 mmol) and potassium tert-butoxide (38.4 g, 342 mmol), portion-wise with ice-bath cooling to keep the temperature between 20° C. and 25° C. The mixture became more orange and was then stirred at room temperature under nitrogen. Some material was present as a suspension and it was slightly more viscous. Another 3.8 gm (0.1 eq) of potassium tert-butoxide was added. After 1.25 h the mixture had practically gelled and an extra 150 mL of THF were added.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=1.ClC1C=CC(C(O)=O)=C(OC)C=1.S(Cl)(Cl)=O>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([Cl:14])=[CH:16][C:17]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: CCCCc1cc2ccccc2o1
Agent: COc1cc(Cl)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(Cl)cc1OC

Procedure:
Acylation of 13.1 g. (0.075 mol.) of 2-n-butylbenzofuran with 15.4 g. (0.075 mol.) of 4-chloro-2-methoxybenzoic acid chloride, prepared from 4-chloro-2-methoxybenzoic acid and thionyl chloride as previously described, according to the procedure of Example 10 gave 2-n-butyl-3-(4'-chloro-2'-methoxybenzoyl)benzofuran. Demethylation as previously described gave 2-n-butyl-3-(4'-chloro-2'-hydroxybenzoyl)benzofuran.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1)=[CH2:3].[H][H]>[Pd]>[CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10])[CH3:3]
Reactant: [H][H]
Reactant: C=C(C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Product: CC(C)c1cccc(N)c1
Yield: 78.1 %

Procedure:
Treatment of 3-nitroacetophenone (10 g) with methyltriphenyl phosphonium bromide (28 g) and n-butyllithium in hexane (78.4 mmol), as described in Example 1a, gave 3-(1-methylethenyl)nitrobenzene (9.5 g), δ (60 MHz, CDCl3) 2.1 (3H, s, CH3), 5.2 and 5.5 (2H, 2s, CH2), 7.2 to 8.2 (4H, m, ArH). Treatment of the above 3-(1-methylethenyl)nitrobenzene (9.5 g) with hydrogen and palladium on carbon (10%, 1.9 g) as described in Example 1a, gave 3-(1-methylethyl)aniline (6.15 g), δ (60 MHz, CDCl3) 1.1 (6H, d, (CH3)2), 2.6 (1H, m, CH) 3.4 (2H, bs, NH2) and 6.1 to 7.0 (4H, m, ArH).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[NH:15][N:14]=[N:13]1.[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(-n2nn[nH]c2=O)cccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: Cc1c(-n2nnn(C)c2=O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(2-methyl-3-trifluoromethylphenyl)-1,4-dihydrotetrazole-5-one, potassium carbonate 11.20 g, dimethyl sulfate 3.71 g and N,N-dimethylformamide 150 mL was stirred at 25° C. for one hour. To the reaction mixtures was added aqueous saturated sodium bicarbonate solution and the mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The resulting mixtures were concentrated under reduced pressure to give 1-(2-methyl-3-trifluoromethylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 5.13 g.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
5-(2-Fluoro-6-methoxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one was prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with commercially available 4-(trifluoromethoxy)benzaldehyde. Subsequent purification by FC (heptane/AcOEt=1/1) afforded the compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 398.00 g/mol.
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1>C(N)CC>[OH:1][CH:2]([CH2:21][NH:12][CH2:11][CH2:8][CH3:7])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1
Reactant: Cc1cccn2cc(-c3ccc(OCC4CO4)cc3)nc12
Solvent: CCCN
Product: CCCNCC(O)COc1ccc(-c2cn3cccc(C)c3n2)cc1
Temperature: 25 °C

Procedure:
The product of Step C (5.0 g) and propylamine (20 mL) was heated at 40° C. for 18 hours. The reaction was cooled to ambient temperature evaporated and the residue purified via silica gel chromatography (dichloromethane/methanol) to give the title compound which was converted to a HCl salt upon treatment with HCl/methanol.
Reaction SMILES: [Br:1][CH2:2]/[C:3](=[CH:7]/[C:8]([OH:10])=[O:9])/[C:4]([OH:6])=[O:5].C([O-])(=O)/C=C/C([O-])=O.BrCC1C(OC(=O)C=1)=O>>[Br:1][CH2:2]/[C:3](=[CH:7]\[C:8]([OH:10])=[O:9])/[C:4]([OH:6])=[O:5]
Reactant: O=C(O)/C=C(/CBr)C(=O)O
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C1C=C(CBr)C(=O)O1
Product: O=C(O)/C=C(\CBr)C(=O)O

Procedure:
Steps are taken to avoid isomerization of 2-(bromomethyl)-maleic acid (3) to the corresponding fumarate analog by hydrolyzing the anhydride (2) in a dilute aqueous solution and neutralizing the diacid (3) immediately after complete hydrolysis. Any bromomethyl fumaric acid derivative formed is removed in purifying compound (4) as described in more detail below.
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:6]2.[O:21]=[S:22]1(=[O:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1COCC1.O>[O:21]=[S:22]1(=[O:28])[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6]3)[CH2:24][CH2:23]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=[N+]([O-])c1cc(CI)cc2cc(-c3ccccc3)[nH]c12
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CN2CCS(=O)(=O)CC2)cc2cc(-c3ccccc3)[nH]c12
Reaction time: 2 h
Yield: 72.1 %

Procedure:
5-Iodomethyl-2-phenyl-7-nitro-1H-indole (850 mg, 2.5 mmol) prepared in Step A was dissolved in THF (10 mL). 1,1-Dioxo-thiomorpholine (405 mg, 2.25 mmol) was added thereto, and the mixture was stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous magnesium sulfate, and filtered. The residue was recrystallized from DCM and hexane to give the title compound (625 mg, Yield 65%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:8]([O:12][C:13]([O:15]N=C(C1C=CC=CC=1)C#N)=O)([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[C:8]([O:12][C:13]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:15])=[O:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCNCCN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution of diethylenetriamine (0.42 g; 4.1 mmol) in tetrahydrofuran (THF; 5 ml) is stirred at 0° C. under nitrogen for 20 minutes. A solution of 2-(tert-butoxycarbonyloximino)-2-phenylacetonitrile (Boc-ON; 2.04 g; 8.2 mmol) in THF (5 ml) is then added dropwise and the reaction mixture is stirred at 0° C. for 1 hour. The solvent is eliminated at reduced pressure and the resulting residue is purified by silica gel column chromatography with methanol-ammonium hydroxide 100:3. 1.2 g (yield 96%) of an oil having the following characteristics is thus obtained:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C@H:12]([NH:14][C:15]1[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=[C:31](Cl)[N:32]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH3:13].[CH3:34][N:35](C)[CH:36]=O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C@H:12]([NH:14][C:15]1[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=[C:31]([N:35]([CH3:36])[CH3:34])[N:32]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH3:13]
Reactant: CN(C)C=O
Reactant: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: C[C@H](CSc1nc2ccccc2s1)Nc1nc(N(C)C)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 12 %

Procedure:
The title compound was prepared according to general method B by reaction of N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine (1.02 g, 2.0 mmol) (Example 5)in dimethylformamide (10 ml) to provide the desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-(dimethylamino )adenosine (0.12 g, 12%) as a foam (following column chromatography), 1H NMR (DMSO-d6) δ 1.38 (3H, d, --CHCH3), 2.92 (6H, s, --N(CH3)2), 3.40-3.72 (4H, m, H-5'a and H-5'b and --CH2 --), 3.88 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.65 (1H, q, H-2'), 4.72-4.85 (1H, m, --CH--), 4.89 (1H, t, 5'-OH), 5.14, 5.36 (2H, 2d, 2'- and 3'-OH), 5.75 (1H, d, H- 1'), 7.35, 7.46 (2H, 2 t, Ar-H), 7.50 (1H, d, N--H), 7.84, 7.99 (2H, 2d, Ar-H), 7.94 (1H, s, H-8). HPLC retention time 16.8 min [gradient elution, 20-80% acetonitrile/water (containing 0. 1% TFA)].
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[OH:14].[O-]CC.[Na+]>C(O)C>[C:3]([CH2:2][S:1][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[OH:14])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: OC(CCCCCl)c1ccco1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCCCCC(O)c1ccco1

Procedure:
To a stirred, refluxing mixture of 76 g of ethyl mercaptoacetate, 79.5 g of 5-chloro-1-(2-furyl)-1-pentanol and 10 ml of 1.5M sodium ethoxide in ethanol is added an additional 300 ml of 1.5m sodium ethoxide during 15 minutes. The resulting mixture is stirred at reflux for 3 hours, cooled, and concentrated to remove most of the ethanol. The residue is partitioned with ether and water. The ether phase is washed with brine and dried over potassium carbonate. The solution is concentrated, diluted with xylene, and again concentrated to give an oil, pmr spectrum (CDCl3): δ 3.24 (singlet, --S--CH2CO2C2H5) and 4.70 (triplet, CH2CHOH).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[N+:19]([O-:21])=[O:20].[F:22][C:23]([F:39])([F:38])[O:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[C:3]([N+:19]([O-:21])=[O:20])=[C:2]([N:33]3[CH2:34][CH2:35][CH:30]([O:29][C:28]4[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:38])[F:39])=[CH:37][CH:36]=4)[CH2:31][CH2:32]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)c2[N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
A mixture of compound (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (400 mg, 1.22 mmol), 4-(4-trifluoromethoxy-phenoxy)-piperidine (399 mg, 1.34 mmol) and potassium carbonate (336 mg, 2.44 mmol) in DMF (8 ml) was heated in an oil bath at 60° C. for 2 hours. The crude mixture was cooled to 0° C. and quenched with water. The solid was filtered off, rinsed with water and dried in vacuum oven to give product B119 as a yellow solid (604 mg, 90%). 1HNMR (CDCl3, 400 MHz) d 2.01-2.08 (m, 4H), 3.06 (s, 3H), 3.64-3.66 (m, 2H), 3.73-3.75 (m, 2H), 4.62-4.66 (m, 1H), 6.93 (d, 2H), 7.17 (d, 2H), 7.93 (dd, 4H), 8.21 (s, 1H), 10.2 (s, 1H). Exact mass calculated for C23H22F3N5O6S 553.1, found 554.3 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(F)c2c(=O)n1-c1ccccc1Cl
Yield: 64.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2e (200 mg, 0.619 mmol), adenine (92 mg, 0.681 mmol), K2CO3 (94 mg, 0.680 mmol), and DMF (4 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 168 mg of an off-white solid (64%), mp 159-172° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 8.10 (s, 1H); 8.08 (s, 1H); 7.73-7.89 (m, 3H); 7.57-7.71 (m, 2H); 7.37-7.48 (m, 2H); 7.34 (d, J=11 Hz, 1H); 7.30 (d, J=8.3 Hz, 1H); 5.14 (d, J=17 Hz, 1H); 4.94 (d, J=17 Hz, 1H). 13C NMR (DMSOd6) ppm: 160.8 (d, J=264 Hz), 157.5 (d, J=4.2 Hz), 155.8, 152.4, 152.4, 150.0, 148.7, 142.1, 136.4 (d, J=11 Hz), 133.0, 132.2, 132.1, 131.2, 130.9, 129.4, 123.8 (d, J=3.6 Hz), 118.4, 114.5 (d, J=20 Hz), 110.2 (d, J=6.0 Hz), 44.9. MS (ES): m/z 422.0 (M+). Anal. calcd. for C20H13ClFN7O: C, 56.95; H, 3.11; Cl, 8.40; N, 23.24. Found: C, 54.62; H, 3.32; Cl, 9.40; N, 21.29.