Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH3:28])=[C:26]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N:41]4C(C)=CC=C4C)[N:36]=3)[CH2:31][CH2:30]2)[N:25]=[CH:24][N:23]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO>C(O)C.O>[NH2:41][C:37]1[N:36]=[C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:26]3[N:25]=[CH:24][N:23]=[C:22]([NH:21][CH2:20][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:27]=3[CH3:28])[CH2:34][CH2:33]2)[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2cccc(-n3c(C)ccc3C)n2)CC1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Cc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2cccc(N)n2)CC1
Temperature: 90 °C
Yield: 35.6 %

Procedure:
100 mg (0.15 mmol) of tert-butyl 2-benzyloxycarbonylamino-3-{6-[6-(2,5-dimethyl-pyrrol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2.4′]bipyridinyl-1′-yl]-5-methyl-pyrimidin-4-ylamino}-propionate is dissolved in 3 ml of ethanol and 0.3 ml of water. 50 mg (0.75 mmol) of hydroxylamine hydrochloride is added and the reaction medium is heated for 18 hours at 90° C. The solvents are evaporated off under reduced pressure (2 kPa) and the crude residue is purified by chromatography on silica gel eluting with a CH2Cl2/MeOH mixture 90:10. 30 mg of expected product is obtained in the form of a resin.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]2[CH:11]=[C:10]([I:12])[CH:9]=[N:8][C:6]=2[N:7]=1.[CH3:14][CH2:15][O:16]CC>CN(C)C1C=CN=CC=1.C(OC(=O)C)(=O)C>[C:15]([NH:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]2[CH:11]=[C:10]([I:12])[CH:9]=[N:8][C:6]=2[N:7]=1)(=[O:16])[CH3:14]
Reactant: Nc1nc(O)c2cc(I)cnc2n1
Reactant: CCOCC
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(O)c2cc(I)cnc2n1
Temperature: 25 °C
Yield: 87 %

Procedure:
Analogously, a mixture of 0.52 g of 2-amino-4-hydroxy-6-iodopyrido[2,3-d]pyrimidine and 0.03 g of 4-dimethylaminopyridine in 10 ml of acetic anhydride is heated under reflux under nitrogen for 3 hours. After cooling the reaction mixture to room temperature, anhydrous ether is added, and the reaction mixture filtered to give 0.52 g (87%) of 2-acetamido-4-hydroxy-6-iodopyrido[2,3-d]pyrimidine as a tan colored solid: m.p. >280° C.; NMR (DMSO-d6, 80 MHz) delta 2.18 (s, 3H), 8.67 (d, 1H, J=2.5 Hz), 9.02 (d, 1H, J=2.5 Hz); M/S 330 (M+), 315 and 288.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>C(#N)C.CN(C)C1C=CN=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][C:9](=[O:10])[NH:11][C:14]2=[O:15])=[CH:12][CH:13]=1
Reactant: NC(=O)CNCc1ccc(Br)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1
Temperature: 0 °C
Yield: 20.6 %

Procedure:
A mixture of 2-(4-bromobenzylamino)acetamide (1B3) (45.9 mmol, 11.2 g) and carbonyldiimidazole (68.8 mmol, 11.2 g) in acetonitrile (223 ml) was cooled to 0° C. with stirring and 4-dimethylaminopyridine (45.9 mmol, 5.60 g) was added. The mixture was stirred at 0° C. for 24 h and then heated at 80° C. for 18 h. The reaction mixture was diluted with water and the acetonitrile removed under reduced pressure. The mixture was acidified to pH 4 with aqueous HCl and the precipitate collected by filtration and dried in a vacuum oven to give 1-(4-bromobenzyl)imidazolidine-2,4-dione (1B4) 2.55 g (20.2%); 1H NMR (400 MHz, DMSOd6) δ 10.94 (bs, NH) 7.55 (d, 2H) 7.24 (d, 2H) 4.42 (s, 2H) 3.86 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[CH:10][C:11]#[N:12])[CH2:3]1.[C:14](C(P(=O)(OCC)OCC)C)#N>>[CH3:1][C:2]1([CH3:13])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][C:4](=[C:10]([CH3:14])[C:11]#[N:12])[CH2:3]1
Reactant: CC1(C)CC(=CC#N)CC(C)(C)C1
Reactant: CCOP(=O)(OCC)C(C)C#N
Product: CC(C#N)=C1CC(C)(C)CC(C)(C)C1
Yield: 41 %

Procedure:
Prepared according to the procedure for compound 20 (Example 10, a) using diethyl (1-cyanoethyl)phosphonate. Nitrile 21 obtained as a colorless oil with 41% yield. 1H-NMR: (CDCl3, TMS): 0.96 and 1.00 (total 12H, both s, c-Hex-3,5-CH3); 1.34 (2H, s, c-Hex-4-CH2); 1.91 (3H, s, propionitrile-3-CH3); 2.04 and 2.28 ppm (total 4H, both s, c-Hex-2,6-CH2).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.[CH:14](=[O:16])[CH3:15]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH:14]([OH:16])[CH3:15])=[N:10][CH:9]=[N:8]2)=[CH:12][CH:13]=1
Reactant: CC=O
Reactant: Cc1ccc(Cn2cncn2)cc1
Product: Cc1ccc(Cn2ncnc2C(C)O)cc1
Yield: 86 %

Procedure:
1-[1-(4-Methylbenzyl)-1H-1,2,4-triazol-5-yl]ethanol was synthesized in a manner similar to that of the procedure in Example 21B but using 1-(4-methylbenzyl)-1H-1,2,4-triazole and acetaldehyde as the starting materials. The product was isolated as a white solid in 86% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (d, 3H, J=6.9 Hz), 2.22 (s, 3H), 3.27 (s, 1H), 4.88-4.94 (m, 1H), 5.66 (d, 2H, J=5.91 Hz), 7.09 (s, 4H), 7.79 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[CH3:15][C:16]1([CH3:24])[CH2:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[CH2:17]1>C(O)C>[NH2:1][C:2]1[NH:7][CH:6]([CH:19]2[C:20](=[O:22])[CH2:21][C:16]([CH3:24])([CH3:15])[CH2:17][C:18]2=[O:23])[C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1
Reactant: CCCc1nc(C)c2cnc(N)nn12
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CCO
Product: CCCc1nc(C)c2n1N=C(N)NC2C1C(=O)CC(C)(C)CC1=O

Procedure:
2-Amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (1 g.) in aqueous ethanol (20 ml., 1:1) and 5,5-dimethylcyclohexane-1,3-dione (1 g.) in aqueous ethanol (20 ml., 1:1) were mixed. The solid was collected and dried and had m.p. 243°.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([C:23]2[C:24]([S:29][CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[CH:33][CH:32]=3)=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:22])[CH:16]=[C:17]([CH3:19])[CH:18]=1>ClCCl>[CH3:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([C:23]2[C:24]([S:29]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[CH:33][CH:32]=3)=[O:6])=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:22])[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc3ccccc23)c1
Solvent: ClCCl
Product: Cc1cc(C)cc(NC(=O)c2cccnc2S(=O)Cc2ccnc3ccccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
m-Chloroperoxybenzoic acid (65%, 210 mg, 0.72 mmol) was added to a solution of N-(3,5-dimethylphenyl)-2-(quinolin-4-ylmethylthio)pyridine-3-carboxamide (Compound No. 1-3,200 mg, 0.50 mmol) in anhydrous dichloromethane (5.0 mL) under ice-cooling, and then the mixture was stirred at room temperature for 3 hours. The precipitated solid was filtered off with chloroform (30 mL) and 1N sodium hydroxide aqueous solution (30 mL), and washed. The resulting solid was dried at 50° C. under reduced pressure to give 150 mg of the target compound as a white solid (Yield: 70%).
Reaction SMILES: [C:1]([C@H:5]([N:9]([C:11](=[O:20])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[NH2:10])[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([C:23]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])[CH3:22]>>[C:1]([C@H:5]([N:9]([C:11](=[O:20])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[NH:10][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:23]=1[CH2:21][CH3:22])[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC[C@@H](N(N)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Reactant: CCc1c(OC)cccc1C(=O)Cl
Product: CCC[C@@H](N(NC(=O)c1cccc(OC)c1CC)C(=O)c1cc(C)cc(C)c1)C(C)(C)C

Procedure:
Briefly, benzyl carbazate (compound A) was reacted with pivaldehyde to give (E)-N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid benzyl ester (compound B). Compound B was reacted with (S,S)-2-allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (Compound C; see Leighton et al., J. Am. Chem. Soc. 125:9596 (2003) and WO 03/074534) to give (R)—N′-(1-tert-butyl-but-3-enyl)-hydrazinecarboxylic acid benzyl ester (compound D). Compound D was reacted with 3,5-dimethyl benzoyl chloride to give (R)—N′-(1-tert-butyl-but-3-enyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester (compound B). Compound E was hydrogenated to give (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-hydrazide (compound F). Compound F was reacted with 2-ethyl-3-methoxybenzoyl chloride to give Compound 1. The crude material was triturated first with ether (2% ethanol) and then with 1:1 hexanes:ether in a fritted glass Büchner funnel. The product was then washed with deionized water with thorough mixing and allowed to dry in air. Compound 1 was isolated as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([OH:23])=O)[CH:4]=1.C(N(CC)CC)C.C1(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([N:45]=[N+:46]=[N-:47])=[O:23])[CH:4]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(C(=O)O)cc1C2=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1C(=O)c1c(OC)cc(C(=O)N=[N+]=[N-])cc1C2=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
9,10-Dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carboxylic acid (10 g) was suspended in dry DMF (130 ml) and cooled to 0° C. Triethylamine (3.89 g) was then carefully added, followed by a solution of diphenylphosphoryl azide (10.57 g) in dry DMF (20 ml). A yellow precipitate was generated during 12 hours stirring at room temperature. The precipitate was collected by filtration and washed with saturated sodium bicarbonate solution (1×100 ml) and water (5×100 ml). Drying in vacuo over silica gel yielded 9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carbonyl azide as a signal yellow powder. Decomposition point: 139° C.
Reaction SMILES: [NH3:1].[CH3:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:11](=[O:12])[C:9](=[O:10])[C:8]=1OCCCC>CCOCC>[NH2:1][C:8]1[C:9](=[O:10])[C:11](=[O:12])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: N
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Solvent: CCOCC
Product: CCCCOc1c(N)c(=O)c1=O
Reaction time: 3 h
Yield: 92.9 %

Procedure:
Ammonia gas was bubbled into a solution of dibutyl squarate (22.6 g, 100 mmol) in ether (500 mL) contained in a 1 L three-necked, round-bottomed flask equipped with a mechanical stirrer and an acidic scrubber. Precipitation of product ceased after 3 hours, so the reaction was halted and the ether solution was filtered. The solid residue was washed with ether and set aside. The filtrate was allowed to stand at room temperature for a further 3 hours, after which time more solid was observed to have been precipitated. This solid was collected by filtration, washed with ether, and combined with the material set aside previously. Drying in vacuo afforded the product as a white solid (15.7 g, 92.9% yield). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br.BrC[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.Cl>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: BrCc1ccncc1
Agent: Br
Agent: Cl
Product: Clc1ccc2c(c1SCc1ccncc1)CCNCC2

Procedure:
Use a method similar to the Example 387, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-bromomethylpyridine hydrobromide to give, after hydrochloride formation by the General Procedure 2-2, the title compound as a white solid. MS (APCI+) m/z: 305 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9]1)[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CCNC1CCC(C)C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A solution of 2.2 g (0.011 mole) of (rac)-3-(3-methyl-cyclopentylamino)-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-92:8) gave 3.3 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(3-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-58)
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]([S:48](F)(=[O:50])=[O:49])[CH:43]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:44]2[CH:43]=[C:42]([CH3:41])[CH:47]=[CH:46][N:45]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cc1ccnc(S(=O)(=O)F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 69.7 %

Procedure:
To a suspension (3 mL) of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg), 15-crown-5 (330 mg) and 4-methylpyridine-2-sulfonyl fluoride (343 mg) at room temperature, and the mixture was stirred at room temperature for 41 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a pale-yellow oil (yield 333 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[Br:11]N1C(=O)CCC1=O>C(#N)C.OS([O-])=O.[Na+]>[Br:11][C:7]1[CH:6]=[C:5]([F:10])[C:3]([NH2:4])=[C:2]([Cl:1])[C:8]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(F)ccc(F)c1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1c(F)cc(Br)c(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
2-Chloro-3,6-difluoroaniline (18.34 mmol, 3 g) was dissolved in ACN and cooled to 0° C. with an ice bath. A solution of N-bromosuccinimide (18.34 mmol, 3.26 g) dissolved in ACN was added using a dropping funnel maintaining the internal temperature of the reaction mixture below 5° C. After addition the mixture was stirred for 15 min letting the temperature slowly rise to ambient temperature. The reaction mixture was diluted with 10% aq. NaHSO3, stirred for 10 min and evaporated to ⅓ of the original volume. The residue was diluted with water and extracted twice with excess of ethyl acetate. The organics were dried, filtered and evaporated. The product was purified with flash chromatography. 4.087 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 5.97 (s, 2H), 7.42-7.52 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Temperature: 90 °C

Procedure:
To a solution of 4-chloro-6-methoxyquinolin-7-ol (1.0 g, 4.77 mmol) and 4-(3-chloropropyl)morpholine (0.86 g, 5.25 mmol)in DMF (9.5 mL), was added potassium carbonate (2.0 g, 14.3 mmol). The mixture was heated to 90° C. for 15 h. After cooling RT, the mixture was diluted with H2O (30 mL). The mixture was extracted with EtOAc (3×25 mL) and the organic extracts were washed with H2O and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (5% MeOH/CH2Cl2) to yield the title compounds as a light yellow solid. MS (ESI, pos. ion) m/z: 337 (M+1). Mass Calc'd for C17H22ClN2O3: 336.1.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]([CH3:24])[C:13]2=[O:23])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-(6-fluoro-3-methyl-1,2-benzisoxazol-5-yl)-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.00 g, 9.12 mmol) and potassium carbonate (2.52 g, 18.2 mmol) in N,N-dimethylformamide is stirred for 15 minutes, treated with methyl iodide (2.58 g, 18.2 mmol), stirred at room temperature overnight, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid which is recrystallized from a methylene chloride/hexanes solution to give the title product as a white solid (mp 158-159° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].BrCC[F:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH2:29][F:35])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: FCCBr
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 2972, 2934, 1564, 1551, 1498, 1468, 1392, 1377, 1206, 1182, 1123, 1102, 1046, 826, 750 cm−1; OAMS supporting ions at: ESI+ 473.9; MS (EI) m/z 473 (M+); [α]25D=−87 (c 0.77, methylene chloride); Anal. Calcd for C25H26Cl2FN3O: C, 63.30; H, 5.52; N, 8.86. Found: C, 63.10; H, 5.60; N, 8.79.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=O)/[C:7](=[CH:12]/N(C)C)/[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:25]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:24][CH:23]=[C:22]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CCO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:29]=[C:27]([NH:26][C:25]4[C:20]([CH3:19])=[N:21][C:22]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:23][CH:24]=4)[N:28]=[CH:12][C:7]=3[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1nc(NC2CCN(C)CC2)ccc1NC(=N)N
Reactant: CN(C)/C=C1\CC(=O)Nc2cc(Cl)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1nc(NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2
Temperature: 70 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To (4E)-8-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-1-benzazepine-2,5-dione (3.25 g. 12.3 mmol) in EtOH (50 mL) were added N-{2-methyl-6-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}guanidine *xHCl (6.5 g, 14 mmol) and potassium carbonate (13.6 g, 98.3 mmol). The reaction mixture was allowed to stir for 2 days at 70° C. and then allowed to cool to room temperature. The solids were filtered and the filtrate was concentrated to give a thick red oil. Water was added to the residue and the aqueous solution was extracted with EtOAc. The organic solutions were combined, dried, filtered and concentrated to give 9-chloro-2-({2-methyl-6-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (5.3 g, 93%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[OH-].[Na+].Cl>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH:13]=[CH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][O:16][CH3:15])=[CH:26][CH:25]=1
Reactant: COCOc1ccc(C=O)cc1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCOc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.3 %

Procedure:
To a stirred solution containing 1.57 g (8 m moles) of 2'-hydroxy-4',6'-dimethoxyacetophenone and 1.33 g (8 m moles) of 4-(methoxymethoxy)benzaldehyde in 3 ml of ethanol, there were added 30 ml of 15% by volume aqueous sodium hydroxide. After being stirred at room temperature for 2 days, the mixture was poured into 70 ml of ice-water. The pH was adjusted to 7 by adding hydrochloric acid, and the mixture was extracted with two 150 ml portions of dichloromethane. The combined extracts were washed with water, dried over sodium sulfate and then evaporated. The oily residue was crystallized from methanol to yield 780 mg of 2'-hydroxy-4',6'-dimethoxy-4-(methoxymethoxy)chalcone as yellow needles: mp 104.5° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[NH:12][C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[H-].[Na+].[CH3:23]I>COCCOCCOC>[CH3:19][C:17]1[CH:18]=[C:13]2[N:12]([CH3:23])[C:11](=[O:20])[C:10]3[CH:9]=[N:8][C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=4[C:15]=3[N:14]2[N:16]=1
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n(C)c3cc(C)nn3c12
Reaction time: 10 h

Procedure:
2.7 g. of 8-ethyl-2-methyl-4-H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one (0.01 mol.) are added to a suspension of 0.03 g. of sodium hydride in 50 ml. of diethylene glycol dimethyl ether at reflux temperature. The temperature is maintained for one hour and then lowered to 120°. 2.8 g. of methyl iodide are added and heating is continued for 10 hours. The precipitated sodium iodide is filtered off, the solution evaporated to dryness and the residue recrystallized from ethyl-acetate, yield 1.9 g. (68%); m.p. 206°-207°.