Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][S:13](=[O:16])(=[O:15])[C:12]([CH3:18])([CH3:17])[C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:38](Br)[CH:39]=[CH2:40]>C1COCC1>[CH2:40]([C@H:14]1[S:13](=[O:15])(=[O:16])[C:12]([CH3:18])([CH3:17])[C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:10][C@@:9]1([C:4]1[C:5]([F:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:27])[CH:39]=[CH2:38]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)CS(=O)(=O)C1(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To a solution of (R)-tert-butyl (5-(5-bromo-2-fluoropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (1.02 g, 2.197 mmol) in THF (13 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (1 M in THF, 13.2 mL, 13.2 mmol) dropwise. The solution was stirred at −78° C. for 30 min and allyl bromide (0.570 mL, 6.59 mmol) was added. The reaction mixture was stirred at −78° C. for 70 min, quenched with saturated NH4Cl, warmed to room temperature and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, concentrated. Purification by flash column chromatography on silica gel (40 g, 10% to 40% EtOAc in hexanes) gave tert-butyl ((5R,6R)-6-allyl-5-(5-bromo-2-fluoropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.703 g, 1.39 mmol, 63% yield) as a white solid, LC/MS (ESI+) m/z=504 (M+H); and tert-butyl ((5R,6S)-6-allyl-5-(5-bromo-2-fluoropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.280 g, 0.555 mmol, 25% yield) as white solid, LC/MS (ESI+) m/z=504 (M+H). The two products were recombined and used in the next step.
Reaction SMILES: C([C:4]1[C:5]([F:11])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)=CC.[I-].[K+].O=[O+][O-].O=O.O=O.O=[O+][O-].[I-].II.[C:27](O)(=[O:29])C>O>[F:11][C:5]1[CH:4]=[CH:9][CH:8]=[C:7]([CH:27]=[O:29])[C:6]=1[OH:10]
Reactant: CC=Cc1cccc(O)c1F
Reactant: CC(=O)O
Agent: II
Agent: O=O
Agent: O=[O+][O-]
Solvent: O
Product: O=Cc1cccc(F)c1O
Reaction time: 5.5 h
Yield: 87.4 %

Procedure:
To effect the desired ozonolysis, 87 grams of the propenyl-o-fluorophenol which was prepared above along with 600 grams of glacial acetic acid and 75 grams of water were placed in a 1 liter round bottom flask equipped with a mechanical stirrer, thermometer, gas inlet through a sintered glass sparger and a gas outlet leading to a scrubber containing 400 cc of 2% potassium iodide solution and then to a wet test gas meter. The contents of the flask were cooled to 0° C. under a nitrogen blanket following which an ozone-oxygen gas stream was passed into the stirred reactants at a rate of 8 cubic feet per hour. The stream was generated by passing oxygen through an ozonator so that the stream contained 1.2% ozone. After a period of 5.5 hours, the scrubber containing the potassium iodide solution turned dark due to the ozone oxidation of iodide to iodine thus indicating that the reactants were no longer absorbing ozone. The ozonized solution was transferred to a liquid/liquid extractor containing 1200 cc of water and was extracted for a period of 16 hours with 2.5 liters of benzene. Upon completion of the extraction, the aqueous phase was discarded and the organic phase was washed with a total of 2 liters of benzene. The organic phase was then washed with a total of 2 liters of water which had been saturated with sodium chloride in order to remove the acetic acid and then with 250 cc of a 4% aqueous sodium bicarbonate solution which was also saturated with sodium chloride. The benzene was evaporated on a rotary evaporator to give 70 grams of crude 3-fluorosalicylaldehyde.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[I:1][C:2]1[C:7]([O:8][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1I
Reactant: OCCc1ccsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ncccc1OCCc1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution containing 2-iodo-3-hydroxypyridine 12 (1.85 g, 8.37 mmol), 2-(3-thienyl)ethanol (1.20 mL, 10.9 mmol), and triphenylphosphine (2.85 g, 10.9 mmol) in tetrahydrofuran (46.2 mL, 5.70 mmol) was added diisopropyl azodicarboxylate (2.14 mL, 10.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography EtOAc/Hex (0-100%) eluted at 30% to give 13 (yield 90%). MS: (ESI+) 332.2
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.Cl.[CH:25]1([C:28]([NH2:31])([CH3:30])[CH3:29])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:25]1([C:28]([NH:31][C:21]([C:18]2[C:16]3=[N:17][C:12]([C:4]4[C:5]5[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=5)[N:2]([CH3:1])[N:3]=4)=[CH:13][N:14]=[C:15]3[NH:20][CH:19]=2)=[O:23])([CH3:30])[CH3:29])[CH2:27][CH2:26]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Reactant: CC(C)(N)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C5CC5)c4n3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.8 %

Procedure:
To a stirred mixture of 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and 2-cyclopropylpropan-2-amine hydrochloride (53 mg, 0.39 mmol) in DMF (3 mL), was added EDCI (100 mg, 0.52 mmol) followed by DMAP (63 mg, 0.52 mmol). The mixture was stirred at room temperature for 16 hours, and then poured into water (5 mL) and filtered. The crude solid was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 58% acetonitrile/42% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 88% acetonitrile/12% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(2-cyclopropylpropan-2-yl)-2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (25 mg, 25%) as a white solid. MS: (M+H)+=389; 1H NMR (300 MHz, DMSO): δ 9.10 (s, 1H), 8.39-8.36 (m, 2H), 7.97 (s, 1H), 7.55 (s, 1H), 7.08 (d, 1H, J=8.1 Hz), Hz), 4.16 (s, 3H), 2.52 (s, 3H), 1.59-1.53 (m, 1H), 1.25 (s, 6H), 0.47-0.43 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.CO.[C:32](=O)([O-])[O-:33].[Cs+].[Cs+].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C>[Cu]I.CN1CCCC1=O>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16]([O:33][CH3:32])[N:15]=2)=[N:6]1
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(C)c12
Temperature: 180 °C
Yield: 10.5 %

Procedure:
200 mg (0.399 mmol) of the compound obtained in example 107 were admixed in a microwavable flask with methanol (3 ml), N-methylpyrrolidone (1 ml), 260 mg (0.798 mmol) of cesium carbonate, 8 mg (0.04 mmol) of copper(I) iodide and 19 mg (0.08 mmol) of 3,4,7,8-tetramethyl-1,10-phenanthroline. The flask was purged with argon while being treated with ultrasound for 5 min, and then closed with an appropriate septum. Then it was heated in a microwave at 180° C. for 8 h. After cooling, the reaction mixture was filtered and concentrated, and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 17 mg of the title compound were obtained (10% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)([CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:32][OH:33]>>[OH:33][NH:32][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:10])=[O:11])([CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: CCCCCC#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 67 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide was prepared according to the procedure outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.71 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.48 g of the product was isolated. Yield 67%; off-white solid; mp 65° C.; MS: 445.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=6.8 Hz, 3H), 1.10-1.40 (m, 6H), 1.85-2.00 (m, 2H), 2.79 (d, J=17.9 Hz, 1H), 2.90 (d, J=17.9 Hz, 1H), 3.50 (d, J=13.7 Hz, 1H), 3.74 (d, J=13.7 Hz, 1H), 3.89 (s, 3H), 7.19 (d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.85-7.89 (m, 1H), 8.37-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm-1): 3157 m, 3095 m, 2954 s, 2932 s, 2858 m, 1671 m, 1593 s; Anal. Calc'd for C23H28N2O5S·HCl·0.9H2O: C, 55.56; H, 6.24; N, 5.63. Found: C, 55.84; H, 6.19; N, 5.59.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2].Br[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:15]=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:4][CH2:5][C:6]1[C:7]2[N:8]([C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][N:12]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccnc1N
Reactant: O=CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)OCc1cccn2c(-c3ccccc3)cnc12
Yield: 59.2 %

Procedure:
A mixture of 4.4 g (26 mmole) of 3-(acetoxymethyl)-2-pyridinamine and 6.0 g (30 mmole) of 2-bromo-2-phenylacetaldehyde was heated at 65°. The mixture was dissolved in water, made basic with aqueous potassium carbonate, and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether to yield 4.1 g of 8-(acetoxymethyl)-3-phenylimidazo[1,2-a]pyridine as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C16H14N2O2 : C, 72.17; H, 5.30; N, 10.52. Found: C, 71.90; H, 5.25; N, 10.43.] The title compound (1.5 g) was prepared by the method described in Example 26 using 1.3 g (5 mmole) of 8-(acetoxymethyl)-3-phenylimidazo[1,2-a]pyridine instead of 8-hydroxymethyl-2-phenylimidazo[1,2-a]pyridine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH:13]([C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ncnc2cnccc12
Reactant: Nc1ccccc1
Product: c1ccc(Nc2ncnc3cnccc23)cc1
Temperature: 100 °C
Yield: 23 %

Procedure:
A mixture of 4-methylthiopyrido[3,4-d]pyrimidine (75 mg, 0.42 mmol), and aniline (1 mL) is heated to 100° C. under N2 for 2 h. The reaction mixture is then chromatographed on silica using MPLC and eluting with a gradient system (CHCl3 to 5% MeOH in CHCl3). The fractions are concentrated under reduced pressure, and the resulting solid is recrystallized from Et2O to yield 4-anilinopyrido[3,4-d]pyrimidine (21.2 mg, 23%) as a yellow solid. 1H NMR (DMSO) δ 10.09 (1H, s), 9.18 (1H, s), 8.74 (1H, d, J=5.3 Hz), 8.46 (1H, d, J=5.8 Hz), 7.89 (2H, d, J=8.5 Hz), 7.45 (2H, t, J=7.9 Hz), 7.21 (1H, t, J=7.4 Hz).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])C.O=CCCCNC(C1CCCCC1)=O>>[O:3]=[CH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10]
Reactant: CCOC(CCCNC(=O)C1CCc2ccccc2C1)OCC
Agent: O=CCCCNC(=O)C1CCCCC1
Product: O=CCCCNC(=O)C1CCc2ccccc2C1

Procedure:
1,2,3,4-Tetrahydro-naphthalene-2-carboxylic acid (4-oxo-butyl)-amide (23C) is prepared from 23B as described for 20B.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C=O)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.4 %

Procedure:
A mixture of {1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazol-4-yl}methanol (0.50 g), activated manganese dioxide (1.50 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazole-4-carbaldehyde as colorless crystals (0.42 g, yield 84%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 104-105° C.
Reaction SMILES: [CH2:1]([N:8](C)[C:9](=[O:25])[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:15]=1)=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2([OH:13])[N:8]([CH3:1])[C:9](=[O:25])[CH2:10][CH2:11]2)=[CH:15][C:16]=1[S:21](=[O:24])(=[O:23])[NH2:22]
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)CCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
2 g of 4-(4-chloro-3-sulfamoylphenyl)-4-oxobutanoic acid N-benzyl-N-methylamide are hydrogenated in the presence of 0.5 g of palladium black in 40 ml of methanol in a duck-shaped shaking vessel until the theoretical amount of hydrogen has been taken up, the catalyst is filtered off, the filtrate is concentrated and the residue is worked up analogously to the instructions 1, to give 5-(4-chloro-3-sulfamoylphenyl)-5-hydroxy-1-methyl-2-oxopyrrolidine. Melting point 147°-149° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl.O>[NH2:38][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCCC1
Reaction time: 24 h

Procedure:
To a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (1.90 g, 5.60 mmol) in CHCl3 (43 mL) was added m-chloroperoxybenzoic acid (m-CPBA, 77% w/w, 1.26 g, 5.60 mmol) over 15 min. The reaction was monitored by thin layer chromatography (TLC) and more m-CPBA was added over 1 h until the starting material was consumed. Water (40 mL) and solid K2CO3 were added to the reaction mixture until the pH=10. The mixture was poured into a separatory funnel and extracted with chloroform, resulting in an emulsion. The aqueous layer was extracted with chloroform three times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated to yield a crude white solid (1.51 g). The white solid (1.51 g, 4.24 mmol) was dissolved in dichloromethane (25 mL) at rt and concentrated ammonium hydroxide (16 mL) was added, followed by p-toluenesulfonyl chloride (TsCl, 0.81 g, 4.24 mmol). The mixture was stirred 1 day (d). Water (25 mL) was added and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine (25 mL) and were dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution with 98:1:1 CH2Cl2/MeOH/NH4OH to 94:5:1 CH2Cl2/MeOH/NH4OH) then crystallized from acetonitrile to yield 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol as pale orange crystals that were dried under high vacuum (0.32 g, 16% over two steps), mp 186-188° C. 1H NMR (300 MHz, CDCl3) δ 8.15 (dm, J=8.4 Hz, 1H), 7.81 (dm, J=8.4 Hz, 1H), 7.52 (m, 1H), 7.32 (m, 1H), 5.38 (br s, 2H), 4.90 (br s, 2H), 4.74 (br s, 2H), 3.66 (q, J=7.0 Hz, 2H), 3.00 (s, 1H), 1.71-1.52 (m, 10), 1.25 (t, J=7.0 Hz, 3H). MS (APCI) m/z 355 (M+H+). Anal. calcd for C20H26O2N4: C, 67.77; H, 7.39; N, 15.81. Found: C, 67.52; H, 7.57; N, 15.78
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:26][C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]([CH2:26][C:27]#[N:28])[C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)n1CC#N

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 7) was treated with bromo-acetonitrile and potassium carbonate in N,N-dimethylformamide at room temperature to yield the {4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-6-oxo-6H-pyrimidin-1-yl}-acetonitrile as a yellow solid; m.p. 213-215° C. (decomposition); MS: [M+H]+=372.
Reaction SMILES: ClCCl.[C:4]1([N:10]2[CH2:15][CH2:14][N:13]([C:16]([NH2:18])=[O:17])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][N:20]=[C:21]=[O:22]>O>[CH3:19][NH:20][C:21](=[O:22])[NH:18][C:16]([N:13]1[CH2:12][CH2:11][N:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH2:14]1)=[O:17]
Reactant: CN=C=O
Reactant: NC(=O)N1CCN(c2ccccc2)CC1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)NC(=O)N1CCN(c2ccccc2)CC1
Yield: 51.5 %

Procedure:
Into 70 ml of dichloromethane, were dissolved 4.1 g of 4-phenylpiperazine-1-carboxamide and 1.2 g of methyl isocyanate. To the solution, while being stirred and cooled in ice, was added dropwise 5.2 g of stannic chloride. After 15 hours of reaction at room temperature, water was added to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate and freed from the solvent by distillation. The residue was recrystallized from ethanol to obtain 2.7 g (51% yield) of 1-(4-methylallophanoyl)-4-phenylpiperazine having a melting point of 198°-200° C.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8])=[O:2].[CH2:14](O)[CH3:15].OS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH2:14]([O:8][C:7]([CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[CH:1]=[O:2])=[O:9])[CH3:15]
Reactant: O=Cc1ccccc1OCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COc1ccccc1C=O
Yield: 87.4 %

Procedure:
A mixture of 2-formylphenoxyacetic acid (9.01 g, 0.05 mol), ethanol (4.6 g), concentrated H2SO4 (0.4 ml) and toluene (40 ml) was heated to reflux with azeotropic removal of water for 1 hour. The reaction mixture was poured into 10% KHCO3 (100 ml), the layers were separated and the aqueous layer was extracted with ether (2×75 ml). The organic layers were combined, and concentrated in vacuo to afford 9.1 g (95%) of 2-(ethoxycarbonylmethoxy)benzaldehyde.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([NH2:13])([NH2:12])(=[O:11])=[O:10]>C(O)C>[NH2:12][S:9]([N:13]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: NS(N)(=O)=O
Solvent: CCO
Product: NS(=O)(=O)N=Cc1ccccc1
Temperature: 25 °C

Procedure:
Benzaldehyde (5 g, 4 mmol) and sulfamide (9.06 g, 94 mmol) were dissolved in anhydrous ethanol (100 mL). The reaction mixture was heated to reflux for 2 hours then cooled to room temperature. The resulting solid was filtered and dried to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1COCCC)[C:7]([O-:9])=[O:8])([O-:3])=[O:2].[Li+].[OH-].[CH2:20]1C[O:23][CH2:22][CH2:21]1>CCO.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:23][CH2:22][CH2:21][CH3:20])[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: CCCOCc1ccc(C(=O)[O-])cc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a stirred solution of 3-nitro-4-propoxymethylbenzoate (0.35 g, 1.46 mmol) in a mixture of THF and EtOH (3 ml:1 ml) the solution of LiOH (0.345 g; 15 mmol) in H2O (1 ml) was added and the mixture was stirred for 4 h at room temperature. The solvent was distilled off and the residue was treated with 1M HCl and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.32 g, 97%), as creamy solid. 1H NMR (CDCl3) 8.53 (d, 1H, J=1.65 Hz); 8.21 (dd, 1H, J=8.79, 1.62 Hz); 7.12 (d, 1H, J=8.82 Hz); 4.14 (t, 2H, J=6.39 Hz); 1.94-1.82 (m, 2H); 1.07 (t, 3H, J=7.35 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)=[O:2].C(=O)=O.CC(C)=O.[C:30]1([Mg]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[OH:2][CH:1]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(C)cc(C(O)c3ccccc3)c2OC1C(F)(F)F
Reaction time: 4 h
Yield: 54 %

Procedure:
The ethyl 8-formyl-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605a, Step 1 (0.45 g, 1.43 mmole) was dissolved in anhydrous THF (5 mL) and the solution was cooled to −78° C. (dry ice/acetone). Phenylmagnesium bromide (1.58 mL, 1.58 mmole) was added to the above solution dropwise, which was allowed to stir for 4 hours. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give an orange oil. The oil was purified by flash chromatography (silica gel) with 100% CH2Cl2 to give a light yellow oil (0.3g, 54%): GCMS m/z 392.0 (M+). 1H NMR (CDCl3/400 MHz) 7.62 (s, 1H), 7.32 (m, 6H), 6.95 (s, 1H), 6.10 (s, 1H), 5.68 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 2.28 (s, 3H), 1.32 (m, 3H).