Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][N:11]2[C:12](=[O:32])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][C:14]=3[O:27][C:28]([F:31])([F:30])[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1(B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][N:11]2[C:12](=[O:32])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([CH:35]1[CH2:37][CH2:36]1)=[CH:15][C:14]=3[O:27][C:28]([F:29])([F:30])[F:31])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OC(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)cc3C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OC(F)(F)F)cc(C4CC4)cc3C2C1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-trifluormethylsulfonyloxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one (100 mg, 0.19 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101 mg, 0.6 mmol), and potassium carbonate (138 mg, 1.0 mmol) in DME (2 mL) under Ar was added bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (5 mg, 0.006 mmol) and water (0.2 mL). The reaction was heated to reflux for 3 h and then cooled to room temperature. The reaction was quenched with 1M NaOH and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc in vacuo to a brown oil. The oil was purified by flash chromatography (SiO2, 0–50% EtOAc in hexanes) to yield 70 mg of the desired product as a white solid. MS (ESI) 413 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[NH:2]1.Cl.O1CCOCC1>O=[Pt]=O.CC(O)=O>[CH2:1]1[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[C:3](=[O:10])[NH:2]1
Reactant: O=C1NCc2ccncc21
Agent: O=[Pt]=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C1NCC2CCNCC12
Yield: 138.3 %

Procedure:
1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one (19.6 g, 0.146 mol) was placed into a hydrogenation reactor together with 250 mL AcOH and 1 g of PtO2 (Colonial Metals). An H2 pressure of 60 PSI was applied and the mixture hydrogenated until a pressure of 26 PSI was measured. The reaction mixture was filtered and the solvent evaporated. At the end of the evaporation, 4 N HCl in 1,4-dioxane (50 mL, 0.2 mol) was added. The solvent was evaporated to dryness. Ether (800 mL) was added and the mixture was stirred and filtered. The filter, a white solid, was dried to give 28.3 g of the desired product. 1H NMR (300 MHz, d6-DMSO) δ=9.42 (br s, 1H), 8.33 (br s, 1H), 7.88 (s, 1H), 3.44-3.25 (m, overlaps with water peak, observed integral of 6H includes water), 3.11-3.01 (m, 2H), 2.88-2.76 (m, 2H), 2.64 (br t, 1H), 2.55-2.45 (m, 3H) 1.90-1.75 (m, 1H), 1.61-1.42 (m, 1H). LCMS: 1.0 min, M+H=144.1 u/e.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].F[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.O>C1COCC1>[N+:22]([C:21]1[C:16]([O:14][CH:12]2[CH2:13][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ncccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.30 g, 57.64 mmol) was added portionwise into a solution of 1-Boc-3-(hydroxy)azetidine (9.94 g, 57.64 mmol) in anhydrous THF (110 mL) at 0° C. and stirred for 0.5 hour. A solution of 2-fluoro-3-nitro-pyridine (7.80 g, 54.9 mmol) in anhydrous THF (15 mL) was added drop wise and the mixture allowed to warm to ambient temperature overnight. The mixture was cooled in an ice-bath and water (50 mL) added. The product was extracted with EtOAc, washed with water, brine and dried (Na2SO4). The product was purified by flash-column chromatography (petroleum ether (40-60° C.)/DCM) to yield the title compound as a yellow solid (4.37 g, 27%).
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[CH3:5][C:6](O)([CH2:8][CH:9](O)[CH3:10])[CH3:7].O>C1C=CC=CC=1>[CH3:5][C:6]1([CH3:7])[CH2:8][CH:9]([CH3:10])[O:3][B:1]([OH:4])[O:2]1
Reactant: OB(O)O
Reactant: CC(O)CC(C)(C)O
Solvent: c1ccccc1
Solvent: O
Product: CC1CC(C)(C)OB(O)O1

Procedure:
Boric acid (1mole) and 2methyl-2,4-pentanediol (1mole) were placed in a reaction vessel with 1,000 ml of benzene and the mixture refluxed until 2 moles of water were removed. Evaporation of the benzene at reduced pressure gave a liquid which slowly crystallized to give a white solid mp 73-75° C. [literature mp 69°-70° C. C. H. Steinberg and D. L. Hunter, Ind. & Eng. Chem. 49, 174-181 (1957)].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:13]1([C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)O)[OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:14][C:13]3[CH:15]=[CH:17][CH:18]=[CH:19][C:20]=3[O:12]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CCC2(CC1)Oc1ccccc1O2

Procedure:
A mixture of 1-ethoxycarbonyl-4-piperidinone (17 g), pyrocatechol (13 g) and p-toluenesulfonic acid (2.5 g) in 250 ml of dry toluene was refluxed with continous removal of water. After 3 h the reaction mixture was concentrated in vacua, 2% NaOH (200 ml) was added followed by extraction with dichloromethane. After drying over magnesium sulfate and removal of solvent in vacuo, the remaining red oil was applied to a silica gel column (eluent: ethyl acetate/ heptane =1:1) giving 22 g of a slightly yellow oil, 1′-ethoxycarbonyl-spiro[1,3-benzodioxole-2,4′-piperidine].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36](=[O:48])([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[O:37][CH:38](Cl)[CH3:39]>C1COCC1>[C:36](=[O:48])([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[O:37][CH:38]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH3:39]
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)OC3CCCCC3)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (5 g, 10.2 mmol) in THF (36 mL) was added KOH (1.1 g, 20.4 mmol). The reaction was stirred at rt for 0.5 h, followed by the addition of a solution of 1-chloroethyl cyclohexyl carbonate (2.3 g, 11.2 mmol) in THF (9 mL). The mixture was refluxed for 16 h, then cooled to rtand diluted with THF (50 mL). The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the title compound as a white solid (3.49 g, 51.9%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[OH:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([C:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=2)=[CH:3]1
Reactant: Nc1ccc2c(ccn2O)n1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2cn(O)c3ccc(N)nc23)CC1

Procedure:
condensing 1-hydroxy-5-aminopyrrolo[3,2-b ]-pyridine (G) with 1-methyl-4-piperidinone in the presence of a base to provide 1-hydroxy-5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine (H); and
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9]CC)=[O:8])=[C:2]=[S:3].[N-:15]=[N+:16]=[N-:17].[Na+]>O>[C:7]([C:6]1[CH:5]=[C:4]([N:1]2[C:2]([SH:3])=[N:17][N:16]=[N:15]2)[CH:14]=[CH:13][CH:12]=1)([OH:9])=[O:8]
Reactant: CCOC(=O)c1cccc(N=C=S)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(-n2nnnc2S)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a mixture of 69 g of ethyl m-isothiocyanatobenzoate and 26 g of sodium azide was added 500 ml of water and the mixture was refluxed for 2 hours. After removing deposited insoluble matter by filtration, the filtrate was acidified by the addition of concentrated hydrochloric acid (pH about 2), and crystals of 1-(3-ethoxycarbonylphenyl)-5-mercaptotetrazole thus deposited were collected by filtration, mixed with 30 g of sodium hydroxide and 300 ml of water, and the mixture was stirred for 30 minutes at 70° C. The reaction mixture was neutralized by concentrated hydrochloric acid and crystals thus deposited were collected by filtration. The crude crystals were recrystallized from methanol to provide 32 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole. The yield was 42% and the mleting point of the product was 181°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([O:18]C)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][C:23](=[O:27])[CH2:22]3)=[CH:8]2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][C:23](=[O:27])[CH2:22]3)=[CH:8]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc2c(CN3CCNC(=O)C3)cn(Cc3ccc(F)cc3)c2cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CN(Cc2cn(Cc3ccc(F)cc3)c3cnc(C(=O)O)cc23)CCN1
Temperature: 10 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
To a suspension of methyl 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (18.2 g, 46.0 mmol) in methanol (450 mL) and water (200 mL) was added lithium hydroxide (1.40 g 58.3 mmol, 1.3 eq.). The suspension was heated to reflux for 10 h, and the reaction was judge to be 95% complete by HPLC-MS analysis. Methanol (200 mL) and lithium hydroxide (0.7 g, 29.2 mmol) were added and the reflux continued for 18 h total. The volatiles were removed in vacuo to a residue. Water (200 mL) was added and the mixture was cooled to 10° C. and neutrialized with aqueous concentrated hydrochloric acid to pH 7. The white solid precipitated out, and filtered followed by washing with cold water, and dried in vacuoto afford 9.10 g (52%) of 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—1.31 min, m/e=383.20 (M+H+, base). 1H NMR (400 MHz, DMSO-D6) d ppm 2.55 (t, J=5.16 Hz, 2H) 2.92 (s, 2H) 3.11 (s, 2H) 3.75 (s, 2H) 5.57 (s, 2H) 7.16 (t, J=8.81 Hz, 2H) 7.35 (dd, J=8.56, 5.54 Hz, 2H) 7.72 (s, 1H) 7.83 (s, 1H) 8.41 (s, 1H) 8.92 (s, 1H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.CON(C)[C:33]([C:35]1[C:40]2=[N:41][S:42][N:43]=[C:39]2[CH:38]=[CH:37][CH:36]=1)=[O:34]>ClCCl>[N:43]1[S:42][N:41]=[C:40]2[C:35]([C:33]([C:2]3[N:3]=[CH:4][N:5]([C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=3)=[O:34])=[CH:36][CH:37]=[CH:38][C:39]=12
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CON(C)C(=O)c1cccc2nsnc12
Agent: CC[Mg]Br
Solvent: ClCCl
Product: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2nsnc12

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available from Synchem) (6.3 g, 14.4 mmol) in dichloromethane (100 mL) at rt was treated with ethyl magnesium bromide (4.8 mL, 14.4 mmol, 3M in THF) and allowed to react for 1 h. A solution of benzo[1,2,5]thiadiazole-4-carboxylic acid methoxy-methyl-amide (Intermediate L2) (2.0 g, 9.0 mmol) in dichloromethane (50 mL) was added via syringe at rt and stirred for 40 m. The residue was isolated in a typical aqueous workup and purified by chromatography on silica gel with 30% EtOAc:hexane to give benzo[1,2,5]thiadiazol-4-yl-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate L3), 1 g (25%).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]1[CH2:17][C:18]([OH:20])=O.[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH2:27])[S:25][CH:26]=1>>[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH:27][C:18](=[O:20])[CH2:17][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([O:12][C:13]([F:16])([F:15])[F:14])[CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:26]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21
Product: O=C(Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid (79 mg, 0.275 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (35 mg, 0.137 mmol) according to protocol A. Retention time (min)=6.037, method [7], MS (ESI) 514.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.15 (s, 1H), 8.11 (d, J=9.9 Hz, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.41 (s, 1H), 7.26 (m, 1H), 7.10 (s, 1H), 6.81 (d, J=9.9 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:12].[C:13](Cl)(Cl)=[O:14]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:6]([O:8][C:13](=[O:14])[NH:12][C:4]=12)=[O:7]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 10.0 g (60.0 mmol) of 3-methoxyanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.33 g (98%) of the 3-methoxyisatoic anhydride as an off white solid. MS (Cl mode) m/z 176 (M-18, 100%), 194 (M+H, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]1[CH2:8][NH:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(OC2CNC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 3-(2,4-dichlorophenoxy)azetidine-1-carboxylate (1.2 g, 3.78 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (TFA) (7 mL) and the reaction mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure and filtered, washing with chloroform followed by diethyl ether to obtain 3-(2,4-dichlorophenoxy) azetidine (0.800 g, 100%) as a TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:31][C:32]([OH:34])=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:31][C:32]([OH:34])=[O:33])=[CH:4][CH:3]=1
Reactant: O=C(O)CBr
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Product: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[CH:21]1([NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC1CCc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Yield: 56.1 %

Procedure:
Four grams 6-Chloropurine riboside, 2.32 g 1-aminoindane and 2.11 g of triethylamine are refluxed in 100 ml of absolute ethanol under nitrogen for 20 hours. Volatiles are evaporated to dryness. Residue is dissolved in 20 ml 2-propanol and diluted with 200 ml H2O. Clear aqueous solution is decanted and residual oily material is washed with cold water. Coevaporation with ethanol several times gives solid material. Crystallization from CHCl3 /2-propanol (10:1) and hexane affords 3.0 g (56.2%) N(6)-(1-indanyl)adenosine having a melting point of 120°-122° C. (foam).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:1])=[O:15])[CH:11]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1
Reactant: O=C(O)c1cc(Cl)nc(OCc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)nc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
With cooling with ice, oxalyl chloride (5.8 mL) and DMF (3 drops) were added to a CHCl3 (40 mL) solution of 2-chloro-6-benzyloxypyridine-4-carboxylic acid, and stirred at that temperature for 1 hour. DMF (3 drops) was added to it, and stirred overnight at room temperature, then oxalyl chloride (2.9 mL) and DMF (3 drops) were added to it, and stirred at room temperature for 3 hours. The solvent was evaporated away, CHCl3-MeOH was added to the residue, and stirred at room temperature for 30 minutes. Sodium bicarbonate water was added to the reaction solution, extracted with chloroform, and the organic layer was washed with water, saturated sodium bicarbonate water and saturated saline water, and dried with anhydrous sodium sulfate. This was filtered, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([N+:15]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)C>[Pd].O1CCOCC1>[CH3:1][C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]([NH2:15])=[C:10]([NH2:12])[CH:11]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)c1cc(N)c(N)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of 5.3 g of methyl 2-methyl-4,5-dinitrobenzoate, 1.06 g of 10% palladium on carbon (50% water wet), 53 mL of ethanol, and 53 mL of 1,4-dioxane was vigorously stirred at room temperature overnight under a hydrogen atmosphere. The insoluble material was filtered and washed with methanol. The filtrate was concentrated, and then dried under reduced pressure to obtain 3.98 g of methyl 4,5-diamino-2-methyl benzoate.
Reaction SMILES: [C:1]1([N:7]2[C:11](O)=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O.C(O)(=O)C.C(O)(=O)C>[C:1]1([N:7]2[CH:11]=[C:10]([Cl:17])[C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: FC(F)(F)c1nn(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.3 %

Procedure:
A mixture of 2.28 g (10 mmol) of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole and 1.6 g (12 mmol) of N-chlorosuccinimide in 8 ml of 20% TFA/acetic acid and 32 mL of acetic acid was stirred at room temperature for 16 hours and diluted with ice/water with cooling. The white precipitate was filtered and purified by column chromatography (silica gel; 20-33% ethyl acetate/hexane) to afford 550 mg (21%) of 1-phenyl-3-trifluoromethyl-4-chloropyrazole as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[CH3:12][C:13]1=[C:14]([CH3:20])[C:15]([O:17][C:18]1=O)=[O:16]>C(O)(=O)C>[F:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[N:1]1[C:15](=[O:16])[C:14]([CH3:20])=[C:13]([CH3:12])[C:18]1=[O:17]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Nc1cc(C(=O)O)ccc1F
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)N(c2cc(C(=O)O)ccc2F)C1=O
Reaction time: 12 h
Yield: 89.1 %

Procedure:
A mixture of 46.5 g of 3-amino-4-fluorobenzoic acid and 37.8 g of dimethylmaleic anhydride in 200 ml of glacial acetic acid is stirred for 12 hours at an oil bath temperature of 130°-40°. After cooling, the mixture is poured onto ice-water, and the resulting precipitate is filtered with suction, washed with water and dried. Recrystallisation from ethanol/water yields 70.3 g of N-(2-fluoro-5-carboxyphenyl)-2,3-dimethylmaleic acid imide which melts at 238°-240°.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][O:6][CH2:7][CH2:8]Br.[C:10]1([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN1C(=O)CCC1>[C:10]1([C:16]2([C:17]([O:19][CH3:20])=[O:18])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCOCCBr
Reactant: COC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1(c2ccccc2)CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To NaH (60% dispersion in mineral oil (14.2 g, 355 mmol)) was added NMP (142 mL), and the mixture was cooled to 0° C. A solution of 1-bromo-2-(2-bromoethoxy)ethane (17.8 mL, 142 mmol) and methyl phenylacetate (20.00 mL, 142 mmol) in NMP was added dropwise, and the resulting reaction mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water, acidified to pH=2 with concentrated HCl, extracted with 200 mL of diethyl ether, washed 2 times with 100 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound after flash chromatography (15.40 g) as a white solid. MS m/e=221 (M+H)+.