Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:10]1[CH:12]([CH3:13])[CH2:11]1>>[OH:10][CH:12]([CH3:13])[CH2:11][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[CH3:1]
Reactant: CC1CO1
Reactant: Cc1cccc(N)c1C
Product: Cc1cccc(NCC(C)O)c1C
Yield: 71.8 %

Procedure:
2,3-Dimethylaniline is reacted with 1,2-epoxypropane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-2,3-dimethylaniline; b.p.: 153°-155° C./1 mm Hg, yield: 71.8%.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH2:6]1[O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[CH:9][C:8]=2[O:7]1>O>[CH2:6]1[O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH2:16][CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[CH:9][C:8]=2[O:7]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: O=CC(=O)O
Solvent: O
Product: O=C(CC(O)C(=O)O)c1ccc2c(c1)OCO2
Reaction time: 3 h

Procedure:
29.6 g (0.2 M) of glyoxylic acid, 50% in water, are heated under reduced pressure until about 80% of the water present has been eliminated; then, after cooling, 65.5 g (0.4 M) of 3', 4'-methylenedioxyacetophenone are introduced into the reaction medium. Heating is performed for 3 hours at 95° C. under reduced pressure, the residual water present being simultaneously distilled off. After the medium has been cooled, there are introduced 200 cm3 of chloroform and 400 cm3 of water containing 12 g of sodium carbonate.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[CH3:22])=[C:16]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH:15]=1>C(O)C>[CH3:22][C:21]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:16]2[CH:15]=[C:14]([C:13](=[O:35])[NH:12][CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=3)[CH:19]=[CH:18][C:17]=2[N:20]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Acetic acid (2 ml) and ethanol (5 ml) are added to an N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzamide (0.490 g) and the solution is stirred for eight hours at 70° C. The residue obtained by reduced pressure condensation is purified using silica gel column chromatography (eluate: ethyl acetate/methanol=9/1), and crystallization is performed in ethyl acetate. The crystals are separated through filtration, dried and thus, 2-methyl-1-(3,4-methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.270 g) is obtained. 1H-NMR (CDCl3, δ): 2.59 (3H, s), 4.78 (2H, d, J=4.8 Hz), 5.28 (2H, s), 5.93 (2H, s), 6.51 (1H, d, J=1.6 Hz), 6.55 (1H, dd, J=1.4 and 7.9 Hz), 6.72 (2H, d, J=8.0 Hz), 7.22 (1H, dd, J=6.7 and 5.0 Hz), 7.34 (1H, d, J=7.7 Hz), 7.62 (1H, br t), 7.67-7.75 (3H, m), 7.96 (1H, d, J=1.1 Hz), 8.58 (1H, d, J=4.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][O:2][C:3]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-methoxycyclopropyl)-phenylethynyl]-benzoate (Compound 67, 110.0 mg, 0.34 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 85.0 mg (86%) of the title compound as an orange solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[Cl:19])[N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=[C:13]2[NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:18]1[CH:17]=[C:16]2[C:12]([C:13]([NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])=[N:14][N:15]2[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])=[CH:11][C:10]=1[C:3]1[CH:4]=[CH:5][O:1][CH:2]=1
Reactant: OB(O)c1ccoc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccoc3)cc12
Yield: 82.4 %

Procedure:
377 mg of 3-furylboronic acid are added to 1 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in Example 58, in 90 cm3 of dioxane, followed by addition of 570 mg of sodium carbonate in 18 cm3 of water and finally 173 mg of tetrakis(triphenylphosphine)palladium, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate and 50 cm3 of water. The organic phase is separated out after settling of the phases has taken place, washed with 50 cm3 of water and 50 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (85/15 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 800 mg of N-[6-chloro-5-(3-furyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2cccc(Cl)c2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(3-chlorophenyl)-boronic acid (CAN 63503-60-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 408.0719 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O.C(O)(=O)C>C(O)C.O>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=Cc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1cccs1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium hydroxide (2.0 g) was added to a suspension of estrone (1.352 g, 5.0 mmol) and thiophene-2-carboxaldehyde (561 mg, 5.0 mmol) in ethanol (40 mL). The resulting dark brown solution was stirred for 4 hours at room temperature, then acetic acid (5 mL) and water (5 ml) were added, the product started to precipitate after a few minutes and was filtered off, washed with water (20 mL), ethanol (10 mL) and diethyl ether (10 mL) and dried under high vacuum. Yield: 1.614 g (89%) yellow solid. 1H-NMR (CDCl3, 400 MHz) δ: 0.98 (s, 3H, —CH3), 1.44-1.78 (m, 5H), 2.02-2.14 (m, 2H), 2.26-2.46 (m, 3H), 2.84-3.02 (m, 3H), 4.98 (s, 1H, —OH), 6.62 (d, J=2.7 Hz, 1H), 6.67 (dd, J=8.6, 2.7 Hz, 1H), 7.14 (dd, J=5.1, 3.5 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.35 (d, J=3.5 Hz, 1H), 7.53 (d, J=5.1 Hz, 1H), 7.67 (s, 1H). LRMS (FAB+): 365.2 (100, [M+H]+).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17].[S:18]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]1>C(O)C.CCCCCCC.C(OCC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2/[C:15](=[CH:23]/[C:20]1[CH:21]=[CH:22][S:18][CH:19]=1)/[C:16]#[N:17]
Reactant: O=Cc1ccsc1
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3ccsc3)c2c1
Temperature: 50 °C

Procedure:
To a solution of sodium methanolate (204 mg, 3.8 mmol, 1.4 eq.) in anhydrous ethanol (30 mL) were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (500 mg, 2.7 mmol, 1.0 eq.) and, after 30 minutes stirring, thiophen-3-carbaldehyde (235 μL, 2.7 mmol, 1.0 eq.). The reaction apparatus was protected from light and the mixture heated at 50° C. for 18 hours. The reaction was allowed to cool to room temperature and then, the solvent was removed under reduced pressure and the crude taken up in ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and then, evaporated. The residue was purified by silica gel flash-column chromatography (eluent: CH2Cl2) to afford, after trituration with heptane and diethyl ether, the compound (50) as a beige solid (310 mg, 41%). IR νmax (cm−1): 2212 (νCN), 3340 (νN—H); 1H NMR (DMSO, 300 MHz) δ (ppm): 3.82 (3H, s, 5′-methoxy), 6.88 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.4 Hz, H6′), 7.38 (1H, d, J7′-6′=8.9 Hz, H7′), 7.42 (1H, d, J4′-6′=2.4 Hz, H4′), 7.69 (1H, d, J4″-5″=5.1 Hz, H4″), 7.70 (1H, m, H3), 7.72 (1H, m, H2′), 7.79 (1H, dd, J5″-4″=5.1 Hz, J5″-2″=1.3 Hz, H5″), 8.10 (1H, m, H2″), 11.54 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 55.5 (5′-methoxy), 101.7 (C4′), 103.8 (C2), 109.9 (C3′), 112.1 (C6′), 113.0 (C7′), 118.1 (C1), 124.0 (C3a′), 126.5 (C4″ and C5″), 127.3 (C2′), 128.0 (C2″), 130.6 (C3), 132.2 (C7a′), 136.6 (C3″), 154.3 (C5′); ESI-MS: m/z 281.1 ([M+H]+), 303.1 ([M+Na]+); HRESI-MS: m/z 303.0568 (calcd for C16H12N2ONaS+, 303.0568).
Reaction SMILES: [I:1]I.[CH3:3][C:4]1([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][C:7](=[CH2:10])[CH2:6][CH2:5]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[I:1][CH2:10][C:7]12[CH2:6][CH2:5][C:4]([CH3:3])([CH2:9][CH2:8]1)[C:11](=[O:13])[O:12]2
Reactant: II
Reactant: C=C1CCC(C)(C(=O)O)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC12CCC(CI)(CC1)OC2=O
Yield: 46.6 %

Procedure:
7.5 g of iodine was added to a solution of 1.3 g of 1-methyl-4-methylene-1-cyclohexanecarboxylic acid in 50 ml of acetonitrile. The solution was reacted for 3 hours at room temperature. After reaction, 100 ml of an aqueous solution of sodium thiosulfate was added to the reaction solution. The solution was extracted five times with 30 ml of ethyl acetate. The organic layer obtained was washed three times with aqueous sodium thiosulfate solution and two times with an aqueous sodium chloride solution, and was dried over magnesium sulfate. The solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 10 g of silica gel. From the fraction eluted with hexane and ethyl acetate=1:1, the solvent was removed in vacuo, yielding 1.1 g of 1-iodomethyl-4-methyl-2-oxabicyclo[2.2.2]octan-3-one as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH2:7][C:5]1[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=[C:2]([N:1]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1
Reactant: CNC(=S)n1nc(N)nc1N
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: CNC(=S)n1nc(N=Cc2ccccc2)nc1N
Temperature: 60 °C
Yield: 47 %

Procedure:
The compound (3.00 g) obtained in Example 31, ethanol (100 ml), benzaldehyde (1.99 g) and DL-camphor-10-sulfonic acid (110 mg) were stirred with heating in an oil bath at 60° C. for 5 hours. After the reaction, the mixture was cooled to room temperature and the resulting crystals were collected by filtration, which were washed with ethanol and dried to give 2.13 g of pale-yellow crystals (yield 47%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.[C:20]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:20])[C:7](=[O:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
(7R)-2-Chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one 1n (3.50 g, 12.50 mmol) was dissolved in 80 mL of acetone followed by the addition of methyl p-toluenesulfonate (3.40 g, 18.70 mmol) and potassium carbonate (3.45 g, 25 mmol). The resulting mixture was heated to reflux for 2 hours with stirring and then cooled down to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (3.40 g, yield: 93.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.[OH-:13].[K+].Cl>>[Cl:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Cn1ccc2c(Cl)nc(Cl)nc21
Agent: Cl
Agent: [K+]
Product: Cn1ccc2c(=O)[nH]c(Cl)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (2.39 g, 11.8 mmol) was treated with a 2M aqueous potassium hydroxide solution (70 mL, 140 mmol). The reaction was warmed to 100° C., where it was stirred overnight. The reaction was allowed to cool down to room temperature gradually, where it stirred for an additional 2 nights. The reaction was brought to pH ˜7-8 with a 3N aqueous hydrochloric acid solution. The resulting light yellow mixture was cooled in an ice/water bath and filtered, rinsing twice with a small amount of water. The filtrate was brought to pH ˜2-3 with additional 3N aqueous hydrochloric acid solution. The resulting opaque light yellow mixture was filtered through the original filter cake. The solids were dried in vacuo to afford 2-chloro-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as an off-white solid (2.18 g, 100%). NMR (300 MHz, DMSO-d6) δ ppm 3.67 (s, 3H) 6.46 (d, J=3.39 Hz, 1H) 7.11 (d, J=3.39 Hz, 1H) 12.83 (br. s., 1H). LC-MS calcd. for C7H7ClN3O [(M+H)+] 184, obsd, 183.9.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:6]=1)[CH3:4]>C(O)(=O)C>[Br:1][C:9]1[C:5]([CH2:3][CH3:4])=[N:6][N:7]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:8]=1[CH2:10][CH3:11]
Reactant: CCc1cc(CC)n(-c2c(C)cc(C)cc2C)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCc1nn(-c2c(C)cc(C)cc2C)c(CC)c1Br
Reaction time: 1 h

Procedure:
A solution of 6.4 g (0.04 mol) of bromine in 20 mL of glacial acetic acid was added dropwise to a stirred solution of 9.00 g (37 mmol) of 3,5-diethyl-1-(2,4,6-trimethylphenyl)pyrazole in 100 mL of glacial acetic acid. After 1 hour at room temperature, the acetic acid was evaporated under reduced pressure and the residues were dissolved in ethyl acetate. This solution was washed with saturated sodium bicarbonate to remove residual acetic acid, dried with brine and magnesium sulfate, and was concentrated on the rotovap. The product was a tan solid (10.26 g, purification. 1H-NMR (CDCl3):0.92 (3H, t, J=7), 1.15 (3H, t, J=7), 1.86 (6H, s), 2.24 (3H, s), 2.32 (2H, q, J=7), 2.60 (2H, q, J=7), 6.82 (2H, s).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][N:11]=[C:10]3[NH:19][CH:20]=[CH:21][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:19][CH:20]=[CH:21][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of ethyl 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]-pyridine-5-carboxylate (7 mg) in ethanol was added 1M NaOH solution and the mixture was stirred at 90° C. for 18 hours The mixture was cooled to 4° C. and acidified with 1M HCl and extracted with a 4:1 solution of chloroform and methanol. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to give 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (6.3 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1cc(-c2ccc(C(F)(F)F)nn2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (176 mg, 0.749 mmol), K2CO3 (310 mg, 2.25 mmol) and PdCl2(dppf) (61 mg, 0.075 mmol) were stirred in DMSO (4 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80° C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to 50:50) afforded the title compound (115 mg, 60%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03 (s, 3H).
Reaction SMILES: [CH:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11](F)=[C:10]([F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[ClH:22]>CN(C)C(=O)C.O1CCOCC1>[ClH:22].[CH:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[C:10]([F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(F)c(F)c1)C1CCC1
Reactant: C1CNCCN1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(N2CCNCC2)c(F)c1)C1CCC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To 2.8 mmol 4-cyclobutanesulfonyl-1,2-difluoro-benzene in 20 ml N,N-dimethylacetamide was added 8.3 mmol piperazine, and the mixture was heated at 80° C. for 45 min. The mixture was then concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: ethyl acetate/methanol gradient). The product-containing fractions were combined and concentrated in vacuo. The residue was resuspended in 100 ml dioxane, and 6.0 mmol HCl (as a 4 M solution in dioxane) was added. After stirring for 10 min, the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(O[CH:15](N(C)C)[N:16]([CH3:18])[CH3:17])(C)(C)C>O1CCCC1>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1cccnc1
Solvent: C1CCOC1
Product: CN(C)C=CC(=O)c1cccnc1
Reaction time: 24 h

Procedure:
To a mixture of 0.10 mole of 3-acetylpyridine in 100 ml of tetrahydrofuran was added 0.10 mole of tert.-butoxy-bis-(dimethylamino)methane. The mixture was stirred for 24 hours and the solvent removed, giving 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([N:8]([N:11]([C:25](=[O:27])[CH3:26])[C:12]1[S:13][C:14]2[C:15](=[CH:17][C:18]3[N:19]=[C:20]([NH2:24])[S:21][C:22]=3[CH:23]=2)[N:16]=1)[CH2:9][CH3:10])[CH3:7].O.N1C=CC=CC=1>CN(C)C=O>[CH2:6]([N:8]([N:11]([C:25](=[O:27])[CH3:26])[C:12]1[S:13][C:14]2[C:15](=[CH:17][C:18]3[N:19]=[C:20]([NH:24][C:3](=[O:4])[CH2:2][Cl:1])[S:21][C:22]=3[CH:23]=2)[N:16]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)N(C(C)=O)c1nc2cc3nc(N)sc3cc2s1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)N(C(C)=O)c1nc2cc3nc(NC(=O)CCl)sc3cc2s1

Procedure:
500 mgm of chloroacetyl chloride were added to a stirred solution of 950 gm of 2-(diethylamino-acetylamino)6-amino-benzo[1,2-d:5,4-d']bisthiazole in 5 ml of dimethylformamide at 0° to 5° C. The mixture was heated for 30 minutes on a waterbath, then cooled, admixed with 50 ml of water and made alkaline with pyridine. The resulting precipitate was collected, washed and recrystallized from dimethylformamide.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[BH4-].[Na+]>CO.O>[OH:16][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:9][CH:10]=1)[CH3:15]
Reactant: CC(=O)c1ccc(C2=CCCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(C2=CCCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of 49 g of this ketone in 100 ml of methanol is stirred dropwise into a solution, cooled to 0° C, of 11 g of sodium borohydride in 500 ml of methanol and 100 ml of water. The reaction solution is stirred for another hour and a half at 5° to 10° C and then allowed to stand at room temperature for 16 hours. Finally, 600 ml of water are added and the batch is extracted with methylene chloride, dried over sodium sulfate and evaporated. In this manner, 1-hydroxy-1-[para-(1-cycloheptenyl)-phenyl]-ethane is obtained as an oily, colorless residue.