Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12].C(O)(=O)C>C(OC(=O)C)(=O)C>[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(O)c1cccc2ccccc12

Procedure:
128 g (1 mole) of naphthalene are dissolved in 102 g (1 mole) of acetic anhydride in an apparatus with a stirrer and a means for the supply of sulphuric acid, a dephlegmator, cooler and vacuum-receiver. Then 98 g (1 mole) of a 100% sulphuric acid are added to the solution of naphthalene in acetic anhydride for 60 minutes at a temperature of 60° C. The removal of the forming acetic acid is effected under vacuum under a residual pressure of 1 to 10 mm Hg. After discontinuation of distillation of acetic acid, i.e. on completion of the reaction of naphthalene sulphonation, there are obtained 208 g (1 mole) of naphthalene-α-sulphonic acid and 118 g (2 moles) of glacial acetic acid. The resulting naphthalene-α-sulphonic acid is poured to 224 g (4 moles) of a preliminary prepared melt of potassium hydroxide having a temperature of 180° C. under vigorous stirring. Then the melt temperature is raised to 285° C. for 5 minutes and the melt is maintained at this temperature for 5 minutes to complete the fusion process. On expiration of 10 minutes, the melt is cooled to a temperature of 80° C., diluted with 200 g of water and the resulting aqueous solution containing potassium α-naphtholate and potassium sulphite is supplied into a mixer provided with a cooling jacket, whereinto a solution of 98 g (1 mole) of sulphuric acid in 400 g of water has been preliminarily charged. Then the resulting mixture is cooled to a temperature of 10° C. and the precipitated α-naphthol is separated from the aqueous solution of the mixture of potassium sulphite, potassium sulphate and non-precipitated α-naphthol and β-naphthol by filtration. The yield of α-naphthol with a purity of 99.5% is 115 g (0.8 mole) as calculated for the employed naphthalene which corresponds to 80% of the theoretical value. The filtrate is treated with an equal volume of carbon tetrachloride and, after separation of the aqueous layer and distilling-off carbon tetrachloride, there are obtained 25 g (0.17 mole) of α-naphthol with a purity of 95%. The total yield of α-naphthol is 97% of the theoretical as calculated for the employed naphthalene.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH2:6]([O:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[S:1]([O:16][CH2:15][CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: OCCOCc1ccccc1
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)OCCOCc1ccccc1

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 2-(benzyloxy)ethanol except the oil obtained was then further purified by high pressure chromatography as described in earlier examples using methylene chloride as eluting agent. Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give title compound in 54% yield as light-yellow, viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[O:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([C:26]4[O:25][CH:29]=[CH:28][N:27]=4)=[CH:36][CH:35]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2ncco2)cc1
Product: CCC(C(=O)Nc1ccc(-c2ncco2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.29 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 73 mg (0.43 mmol, 1.5 eq.) of 4-(1,3-oxazol-2-yl)aniline were reacted according to General Method 7. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 1-10% mixtures). Yield: 89 mg (63% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4c(F)c(F)c(F)c(F)c4F)nc23)CC1
Yield: 85.7 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.053 mMol) 2,3,4,5,6-pentafluorobenzoyl chloride, 0.016 gm (84%) of the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)O)[C:5]([F:8])=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:10]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[O:26][C:20](=[O:21])[NH:19]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2ccc(F)cc2)O1
Temperature: 25 °C
Yield: 15 %

Procedure:
To a 25 mL round bottom flask was added tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(4-fluorophenyl)-2-hydroxyethylcarbamate (1450 mg, 3.38 mmol) in dichloromethane (12 mL). To this solution was added trifluoroacetic acid (2.60 mL, 33.8 mmol) and the reaction was allowed to stir over night at room temperature. The reaction solvent was evaporated in vacuo and the crude oil was diluted with diethylether and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and the solvent was then evaporated in vacuo and the crude residue was diluted with dry tetrahydrofuran. The solution was cooled to 0° C. and carbonyldiimidazole (282 mg, 1.74 mmol) was added and the reaction was allowed to stir overnight. The reaction solvent was then evaporated in vacuo and the crude residue was diluted with 2N ammonia in methanol and stirred for 15 min. The solvent was then evaporated in vacuo and the crude solid was purified by silica gel chromatography 15% EtOAc/85% Hexanes to 50% EtOAc/50% Hexanes affording the desired product and its regioisomer as an inseparable mixture. The inseparable mixture was further purified by reverse phase chromatography using a sunfire col 30×100 45%-55% MeOH/H2O 0.1% TFA over a 20 minute run time affording (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(4-fluorophenyl)oxazolidin-2-one (180 mg, 0.507 mmol, 10.99% yield). 1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 8.10 (d, J=8.0), 7.42-7.38 (m, 2H), 7.19-7.15 (m, 2H), 5.81 (brs, 1H), 5.36 (d, J=4.0, 1H), 5.01 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.17 min. Mass=356.96 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[S:18]([C:21]1[CH:22]=[C:23]([C:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=3)[N:28]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>ClCCl>[CH3:37][C:36]1([CH3:38])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=2)[N:28]=[C:27]1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Nc3ccccc3)c1)=N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a stirred solution of aniline (50 mg, 0.52 mmol) and N,N-diisopropylethylamine (122 mg, 0.86 mmol) in dichloromethane (4 mL) was added methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (170 mg, 0.43 mmol) in dichloromethane (2 mL). The mixture was stirred for 18 h at room temperature and purified on preparative Thin layer chromatography to afford 170 mg of methyl 3,3-dimethyl-2-(3-(N-phenylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O>C(O)(=O)C>[C:14]([O:17][CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: C[Si](C)(CCl)Cc1cccc(F)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC[Si](C)(C)Cc1cccc(F)c1
Yield: 40.2 %

Procedure:
Chloromethyldimethyl-3-fluorobenzylsilane (0.85 g, 3.93 mmol) and potassium acetate (0.83 g, 8.45 mmol) are refluxed in acetic acid (10 ml) for 48 hours. The mixture is then cooled, poured into water (50 ml) and extracted with diethyl ether (50 ml). The organic layer is washed with water, brine, dried over MgSO4 and the solvent is removed in vacuo. Chromatography (silica gel, hexane/ether-80/20 affords the title compound as an oil (0.38 g, 40% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[C:66]([CH:71]=[CH:72][CH:73]=1)[C:67]([O:69][CH3:70])=[O:68]>>[CH3:70][O:69][C:67](=[O:68])[C:66]1[CH:71]=[CH:72][CH:73]=[C:64]([NH:63][C:30]([C@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])[CH:65]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)[C@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.53 mmol), was reacted with diisopropylethylamine (0.28 g, 2.1 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with methyl 3-aminobenzoate (Aldrich) (0.12 g, 0.8 mmol) to give rac-3-{[(2′S,3′R,4′S,5′S)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester as a off white solid (Yield, 0.07 g, 22%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]=[C:10]1[CH2:15][C:14](=O)[CH2:13][CH2:12][NH:11]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:9])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCNC(=O)C1
Reactant: Nc1cccc(F)c1
Product: O=C1C=C(Nc2cccc(F)c2)CCN1
Yield: 67.1 %

Procedure:
A mixture of 3-fluoroaniline (2 g) and 2,4-dioxopiperidine (2.04 g) was heated at 120° under nitrogen for 1 h. The resultant solid was cooled and purified by FCC eluting with System A (100:8:1) to give the title compound (2.49 g), m.p. 188°-190°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13]C)=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(CC(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Methyl 3-ethoxyphenylacetate (7.5 g, 38.6 mmol) was dissolved in ethanol (15 mL) and 1N NaOH (40 mL) was added. The mixture was stirred at room temperature for 30 minutes then acidified by addition of 1N hydrochloric acid (45 mL). A white precipitate formed which was filtered, washed with 1N HCl, water and dried to afford 3-ethoxyphenylacetic acid (6.4 g, 92%). 1H NMR (CDCl3) δ 7.20 (1H, dd), 6.8 (3H, m), 4.0 (2H, q), 3.6 (2H, s), 1.4 (3H, t).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:14][CH3:15])(=[O:13])[C:10]([CH3:12])=[CH2:11]>CO>[CH2:1]([NH:8][CH2:11][CH:10]([CH3:12])[C:9]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(=O)OC
Reactant: NCc1ccccc1
Solvent: CO
Product: COC(=O)C(C)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
To a solution of benzylamine (10.7 g, 100 mmol) in methanol (100 mL) was added methyl methacrylate (10 g, 100 mmol). The reaction solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give methyl 3-(benzylamino)-2-methylpropanoate as a light yellow oil (12 g, 57%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17](Cl)[N:16]=2)[CH:14]=1>CN(C=O)C>[Br:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=2)[CH:14]=1
Reactant: Clc1nccc(-n2cnc(Br)c2)n1
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cn(-c2ccnc(N3CCOCC3)n2)cn1

Procedure:
To a cooled (0° C.) solution of morpholine (0.256 g, 2.94 mmol) in anhydrouse DMF (5 ml) was added NaH (0.117 g, 2.94 mmol, 60% disp' in mineral oil). The mixture was stirred at this temperature for 30 minutes before the addition of 4-(4-Bromo-imidazol-1-yl)-2-chloro-pyrimidine (0.64 g, 2.45 mmol). The reaction vessel was sealed and heated under the infuenceof microwave radiation for 7 minutes (120° C., High absorption setting). Upon cooling the mixture was diluted with water (7 ml) and the resultant yellow precipitate removed by filtration and purified by flash chromatography (SiO2) (4:1—Hexanes:EtOAc) to give the title compound as a white solid in analytically (0.76 g, 38.6%) pure form. m/z (LC-MSW, ESP):310.3 [M+H]+, R/T=3.26 mins.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[O:27][CH3:28])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:39].C(O)C.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.C(O)C>[ClH:39].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:47])[NH2:26])=[CH:21][C:20]=3[O:27][CH3:28])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1OC)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Yield: 67 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 67% of theory, C28H31N7O4 (529.6) Rf value: 0.16 (silica gel; dichloromethane/ethanol=4:1) EKA mass spectrum: (M+H)+ =530
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.O.[NH2:12][NH2:13]>C(O)C.O>[Br:1][C:2]1[CH:9]=[C:8]2[C:5]([C:6]([NH2:7])=[N:12][NH:13]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: N#Cc1ccc(Br)cc1F
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2cc(Br)ccc12
Reaction time: 22 h

Procedure:
A solution of 10 g of 4-bromo-2-fluorobenzonitrile in 300 mL of ethanol is admixed with 7.29 mL of hydrazine hydrate. The reaction mixture is stirred for 22 hours at reflux and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 200 mL of distilled water. The suspended solid is isolated by filtration, washed with water and treated with suction. After drying under vacuum, 10 g of 6-bromo-3-amino-1H-indazole are obtained, whose characteristics are as follows:
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]1=2)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.Cl>O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]2=3)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:20]1[C:21]1[S:22][CH:23]=[CH:24][N:25]=1
Reactant: Nc1nccs1
Reactant: O=CC(CO)OC(C=O)n1cnc2c(=O)[nH]cnc21
Agent: Cl
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2nccs2)C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (inosinedialdehyde), (2.6 g) was dissolved in water (30 ml). To the solution was added 2-aminothiazole (1.0 g). The solution was adjusted at pH 5.0 with dilute hydrochloric acid and stirred at ambient temperature overnight. The precipitate was collected by filtration, washed with acetone and air-dried to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-thiazolyl)morpholin-2-yl]hypoxanthine (2.2 g).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17]N(C=O)C.[H-].[Na+].CI>O>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH3:17])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc2c(C(C)=O)cn(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 3-acetyl-1H-indole-6-carboxylate (0.92 g) and DMF (18 ml) was added sodium hydride (0.18 g) under ice-cooling, followed by stirring at room temperature for 0.5 hour. Next, methyl iodide (0.29 ml) was added thereto under ice-cooling, followed by stirring at room temperature for 5 hours. Then, water was added thereto under ice-cooling, followed by stirring at room temperature. The solid precipitated was collected by filtration, washed with water, and purified by silica gel column chromatography (hexane/THF=2:1→chloroform /THF=9:1) to obtain methyl 3-acetyl-1-methyl-1H-indole-6-carboxylate (0.98 g).
Reaction SMILES: BrC1C=CC=CC=1CN1[C:13]2[C:8](=[N:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)C=C1.C[O-].[Na+].C[N:24]([CH3:27])[CH:25]=O>CO.[Cu]Br>[CH3:15][O:14][C:10]1[CH:11]=[C:12]2[CH:13]=[CH:8][NH:9][C:27]2=[N:24][CH:25]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(ccn2Cc2ccccc2Br)n1
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2[nH]ccc2c1

Procedure:
Under an argon atmosphere and in an anhydrous medium, 1 g (5.07 mmol) of the compound obtained in Step C is dissolved in a mixture of 25 ml of N,N-dimethylformamide and 22 ml of methanol; 6.86 g (126.75 mmol) of sodium methanolate and 1.43 g (10.30 mmol) of copper (I) bromide are added at room temperature. The mixture is heated at reflux for 3 hours. After removal of the solvents by evaporation, the residue is taken up in water and ethyl acetate and then filtered over Celite. The organic phase is washed with water, dried over magnesium sulphate and evaporated to yield a solid, which is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 7:3). The title compound is obtained in the form of a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8][C:7]=1[OH:17])=[O:5])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([Br:25])[C:7]=1[OH:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)cc(O)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1c(O)c(Br)c(O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of ethyl-2,4-dihydroxy-1-naphthoate [Bruggink and McKillop Tetrahedron 31, 2607, 1975] (0.1 g, 0.43 mmol) in acetonitrile (2 mL) was added NBS (84 mg, 0.47 mmol). The mixture was stirred at RT for 30 min. The acetonitrile was removed in vacuo and CCl4 was added. The solution was filtered and concentrated. The crude product was purified by chromatography (eluting with DCM) to give the product (0.13 g, 93% yield) as a white solid. 1H NMR (CDCl3) δ 13.61 (s, 1H), 8.79 (d, 1H), 8.24 (d, 1H), 7.58 (t, 1H), 7.41 (t, 1H), 6.61 (s, 1H), 4.60 (q, 2H), 1.55 (t. 3H). MS APCI negative mode m/z 310.84.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=1[CH:24]([CH3:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:23][O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:14]([CH2:13][OH:12])=[C:15]([CH:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1
Reactant: COC(=O)c1cc(OC)c(OC)cc1C(C)Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(CO)c(C(C)Cc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
Diisobutyl aluminum hydride (22.9 mL, 1.0 M in THF) was added to a solution of 4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-benzoic acid methyl ester (2.886 g, 9.2 mmol) in 100 mL THF at −78° C. over 10 min. The mixture was allowed to stir for 1 h and warmed to room temperature. After 1.5 hours the mixture was quenched by the slow addition of 50 mL saturated Rochelle's salt. After rapidly stirring for 30 minutes the mixture was filtered through a pad of celite and concentrated in vacuo. H2O was added and the slurry was extracted with ethyl acetate, washed with H2O and washed with brine. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. Purification via flash chromatography (3:1 hexane/ethyl acetate) afforded [4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-methanol as a clear oil (1.269 g, 48%).
Reaction SMILES: C1(=O)O[CH:4]=[CH:3]O1.[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([C:13]([NH2:15])=[O:14])=[CH:9][CH:8]=1>O>[CH3:16][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:3]=[CH:4][N:15]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: O=c1occo1
Solvent: O
Product: Cc1ccc(-c2ncco2)cc1
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
Polyphosphoric acid (20 g), vinylene carbonate (5.73 mL, 90.0 mmol) and p-toluamide (12.2 g, 90.0 mmol) were combined and heated at 170° C. for 2 h. The reaction mixture was allowed to cool to ˜80° C., water (˜100 mL) was carefully added, and stirred for ˜10 min. This mixture was extracted three times with ethyl acetate, combined organic extracts were dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 97:3 hexanes/acetone) gave 6.41 g (45%) of the title compound. MS 160 (M+H)+.