Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25](OCC)=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1.[NH:34]1[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]1>>[CH3:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([N:34]2[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]2)=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1C
Reactant: O[C@@H]1CCNC1
Product: Cc1cnc(Nc2cccc(N3CCN(C)CC3)c2)nc1Nc1ccccc1C(=O)N1CC[C@@H](O)C1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
Ethyl 2-[(5-methyl-2-{[3-(4-methyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)amino]benzoate (120 mg, 0.27 mmol) and (R)-(+)-3-pyrrolidinol (0.65 mL, used as solvent) were combined in a vessel, which was sealed and heated with stirring at 125° C. for 18 h. The reaction was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified using normal phase HPLC eluting with a gradient of dichloromethane/methanol/ammonium hydroxide (90:10:0-90:10:1) affording the title compound as an off-white solid; yield 63 mg. (48%). (MS: M(C27H33N7O2)=487.60, (M+H)+=488.2.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][CH3:17])[O:11][C:10]1=[O:18])[CH2:7][CH3:8])[CH:2]=[CH2:3].C[OH:20]>CC(C)=O.O>[CH2:1]([O:4][NH:5][C:6]([CH:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][CH3:17])[O:11][C:10]1=[O:18])([OH:20])[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCONC(CC)=C1C(=O)C=C(CC)OC1=O
Reactant: CO
Solvent: CC(C)=O
Solvent: O
Product: C=CCONC(O)(CC)C1C(=O)C=C(CC)OC1=O

Procedure:
1.0 g of 3-(1-allyloxyaminopropylidene)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione (ND26.5 :1.5389) was dissolved in 50ml of acetone containing 5% of water. After it was poured shallowly into the vessel having an area of (30×35)cm2, it was allowed to stand for a day in the sunlight. 630mg of the crude product was obtained by the distillation of methanol after the precipitated crystal on the container was recovered by washing with methanol. The crude product was recrystallized three times from the mixture of ethanol and water and 300mg of 3-(1-allyloxyamino-1-hydroxypropyl)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione having a melting point of 62.5° to 64°C as a white crystal was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].[CH3:18][N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1.O.[OH-].[Na+]>CS(O)(=O)=O>[CH3:18][N:19]1[CH2:23][CH2:22][CH:21]([O:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:20]1
Reactant: CN1CCC(O)C1
Reactant: OC(c1ccccc1)c1nc2ccccc2[nH]1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(OC(c2ccccc2)c2nc3ccccc3[nH]2)C1
Temperature: 25 °C

Procedure:
A mixture of (1H-benzimidazol-2-yl)phenylmethanol (611 mg) and 1-methyl-3-pyrrolidinol (263 mg) in methanesulfonic acid (1.3 mL) is heated for 4 hours in a sealed tube at a temperature close to 140° C. The mixture is cooled back to room temperature, poured into water which is then made alkaline with concentrated sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate, concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to give 2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole melting at 53° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:7].[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:33]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][CH2:9][N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:6](=[O:7])[C:5]1[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1cc(C(=O)N(CCC2CCCN2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(=O)N(CCC2CCCN2Cc2ccccc2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Trimethoxy-N-(2-methyl-3-phenyl-allyl)-N-(2-pyrrolidin-2-yl-ethyl)-benzamide 0.11 g (2.5 mmol) and freshly distilled benzaldehyde 0.026 g (2.5 mmol) was taken in 10 ml of dry methanol. Acetic acid 0.022 ml (3.7 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 30 min and sodium cyanoborohydride 0.023 g (3.7 mmol) was added at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 14 hr. The reaction mixture was concentrated, and the residue was diluted with water and extracted with chloroform (3×20 ml). Organic layer was washed with 10% NaHCO3 solution, water and brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography over silica gel to yield the pure desired compound. This was converted to its hydrochloride salt using dry HCl in ether to obtain 90 mg of product. Yield: 63%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=2[CH2:27][S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:15][C:14]=1[CH3:35]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=2[CH2:27][S:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:9])=[CH:15][C:14]=1[CH3:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c(CSc2ccccc2)c(-c2ccc(F)c(C)c2)c1
Product: Cc1cc(C)c(CS(=O)c2ccccc2)c(-c2ccc(F)c(C)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
m-Chloroperbenzoic acid (tech. grade, approximately 75% peroxide; 1.19 g, approximately 5 mmoles) was added in small portions to a stirred solution of (4'-fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl-methyl)phenyl sulfide (1.68 g, 5 mmoles) at -78° C. The reaction mixture was then stirred at -78° C. for 30 minutes and allowed to warm to room temperature. The solution of the product was separated by filtration from the 3-chlorobenzoic acid which was washed with methylene chloride. The combined methylene chloride solutions of the product were diluted with methylene chloride to 100 ml then washed with dilute sodium hydroxide solution (2×50 ml) dried (MgSO4), filtered, and the solvent was evaporated in vacuo to leave 1.7 g of crude product. This was purified by flash chromatography on silica gel using a 40×150 mm column eluting with 3.5% (v:v) acetone in methylene chloride to give 1.55 g of the title compound as a gum. Dry toluene was added and evaporated in vacuo four times to dry the product, which then crystallized, m.p. 75°-85° C.
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C([C:16]1([CH2:26][O:27][C:28]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:31]([C:32](O)=[O:33])=[C:30]([F:40])[CH:29]=2)C2CC3C[CH:21]([CH2:25][CH:17]1C3)[CH2:22]2)#N.C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCC1>>[N:6]1([S:10]([NH:13][C:32](=[O:33])[C:31]2[CH:35]=[C:36]([CH:37]3[CH2:39][CH2:38]3)[C:28]([O:27][CH2:26][CH:16]3[CH2:22][CH2:21][CH2:25][CH2:17]3)=[CH:29][C:30]=2[F:40])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2CCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCCC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.037 g, 37%): 1H NMR (300 MHz, DMSO-d6) δ 11.60 (br s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 4.15-3.89 (m, 6H), 2.42-2.28 (m, 1H), 2.23-2.10 (m, 2H), 2.08-1.96 (m, 1H), 1.87-1.71 (m, 2H), 1.70-1.46 (m, 4H), 1.45-1.28 (m, 2H), 0.95-0.82 (m, 2H), 0.73-0.64 (m, 2H); MS (ES+) m/z 397.2 (M+1)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22].CC(C)([O-])C.[K+].O>CN(C)C(=O)C>[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=2)=[CH:16][C:15]=1[CH3:22]
Reactant: Cc1cc(O)cc(C)c1N
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNc1cc(Oc2cc(C)c(N)c(C)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of N-(5-chloro-2-nitrophenyl)-N-methylamine (4.0 g) in N,N-dimethylacetamide (56 ml) were added 4-amino-3,5-dimethylphenol (2.9 g) and potassium t-butoxide (2.9 g) with stirring under ice-cooling, and the resulting mixture was stirred at 75-80° C. for 1 hour. After stirring, water (74 ml) was added to the reaction mixture, and the resulting mixture was cooled gradually to room temperature. The crystals precipitated were collected by filtration and dried in vacuo to afford the title compound (4.9 g, yield: 80%) as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[N:9]=[C:10]([CH3:16])[S:11][C:12]=2C(O)=O)[CH:7]=1.BrC1SC([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=C(C2C=C(Cl)C=CC=2OC)N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[N:9]=[C:10]([CH3:16])[S:11][C:12]=2[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nc(Br)sc1NC(=O)OC(C)(C)C
Reactant: COc1ccc(Cl)cc1-c1nc(C)sc1C(=O)O
Product: COc1ccc(Cl)cc1-c1nc(C)sc1NC(=O)OC(C)(C)C

Procedure:
Using 4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylic acid, the title compound was prepared following the synthetic procedures described for tert-butyl 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate to give tert-butyl 4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-ylcarbamate. LCMS (ESI) m+H=355.3; 1H NMR (400 MHz, DMSO-d6): δ 7.40 (dd, 1H); 7.32 (d, 1H); 7.11 (d, 1H); 3.77 (s, 3H); 2.55 (s, 3H); 1.42 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.ClCCl.[CH3:34][N:35]([CH3:39])[CH2:36][C:37]#[CH:38]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:38]=[C:37]([CH2:36][N:35]([CH3:39])[CH3:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), 1-dimethylamino-2-propyne (0.070 mL). The reaction is stirred at room temperature for 10 days. The reaction is concentrated under reduced pressure, treated with ethanol (5 mL) and heated to 70° C. for 2 days. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 1% to 4% methanol in dichloromethane. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid which is crystallized from acetonitrile. The crystals are treated with hydrochloric acid (2 mL, 4N in dioxane). The suspension is diluted with methanol and concentrated under reduced pressure. The residue is triturated with small volumes of methanol-toluene, toluene, methanol-ether and ether. The solid is treated with dichloromethane and partitioned against saturated aqueous sodium carbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.06 g of the title compound as a tan solid.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH2:10])[C:4]([N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[N+:14]([O-:16])=[O:15].C(O[NH2:25])C1C=CC=CC=1.C[O-].[Na+].Cl>CS(C)=O>[CH:1]1[C:2]([N+:14]([O-:16])=[O:15])=[C:3]([NH2:25])[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([NH2:10])[C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NOCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
DMSO (15 ml) is added with rapid stirring to a mixture of picramide (0.477 g, 2.09 mmol), O-benzylhydroxylamine (1.64 g, 10.3 mmol) and sodium methoxide (1.91 g, 35.4 mmol). The brown suspension is stirred at ambient temperature for 15 hr. The reaction mixture is poured into cold 0.12N aqueous HCl (200 ml). The resulting precipitate is collected, washed with water and dried to yield 0.444 g (87%) of DATB.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([CH3:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:19][CH:20]1[CH2:21][C:22]([CH3:29])([CH3:30])[N:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:16]
Reactant: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)O
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Yield: 42.8 %

Procedure:
A solution of (2Z,4E)-5-(benzofuran-2-yl)-2-methoxy-2,4-pentadienoic acid (122 mg, 0.5 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (85 mg, 0.5 mmol), 1-hydroxy-7-azabenzotriazole hydrate (65 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol) in DMF (2 ml) was stirred at RT overnight. After the same work-up described in example 3 the residue was triturated with isopropyl ether to produce a solid that was recovered and dried to give pure title compound (85 mg, 0.214 mmol, yield 42.8%) as yellow crystals, m.p.=152°.
Reaction SMILES: [CH:1]1N=CN(C(N2C=NC=C2)=O)[CH:2]=1.[CH:13]1([N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:35])=[C:23]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)[C:24]=3[F:26])[C:19](=[O:36])[C:18]([C:37]([OH:39])=[O:38])=[CH:17]2)[CH2:15][CH2:14]1>CN(C=O)C.C(O)C>[CH:13]1([N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:35])=[C:23]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)[C:24]=3[F:26])[C:19](=[O:36])[C:18]([C:37]([O:39][CH2:1][CH3:2])=[O:38])=[CH:17]2)[CH2:15][CH2:14]1
Reactant: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)cc(C)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
1,1'-Carbonyldiimidiazole (CDI) (3.9 g, 0.024 mol) was added to a suspension of (6.0 g, 0.016 mol) 1-cyclopropyl-7-(2, 6-dimethyl-4-pyridinyl )-6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, described in U.S. Pat. No. 5,075,319, and incorporated herein by reference, in DMF (40 mL) and the mixture was stirred at 100° C. for 2 hr under a N2 atmosphere. The resulting solution was cooled to 25° C., diluted with and 60 mL ethanol and heated at reflux 17 h. Removal of the solvents in vacuo gave a residue that was stirred in 20 mL ethanol; after cooling in ice a solid separated and was collected (5.5 g, 86%); a 4.5 g portion of this material was recrystallized from ethanol to give 4.25 of ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, mp 193°-195° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][C:20]1[CH:31]=[CH:30][C:23]2[O:24][C:25]([C:27](=[O:29])[CH3:28])=[CH:26][C:22]=2[CH:21]=1>CC#N>[C:27]([C:25]1[O:24][C:23]2[CH:30]=[CH:31][C:20]([NH:19][C:2]3[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:21][C:22]=2[CH:26]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Solvent: CC#N
Product: COCCN1C(=O)C(Nc2ccc3oc(C(C)=O)cc3c2)=C(c2ccccc2)C1=O
Temperature: 150 °C
Yield: 17.1 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.26 mmol, 70 mg) and 1-(5-aminobenzo[b]furan-2-yl)ethan-1-one (0.53 mmol, 92 mg) was dissolved in dry CH3CN (2 mL) and the reaction mixture was subjected to microwave heating single node 150° C. for 15 min and purified on SiO2 (EtOAc:heptane, 1:1) to give 18 mg (15%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.53 (bs, 1H), 7.40 (d, 1H), 7.24-7.09 (m, 5H), 7.06 (dd, 1H), 6.92 (d, 1H), 3.98 (t, J=5.6 Hz, 2H), 3.78 (t, J=5.6 Hz, 2H), 3.52 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:24]([CH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1)([O-])=[O:25].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:25][N:24]=[C:27]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:41][CH:42]=3)[CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Reactant: C#Cc1cccnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 8 h

Procedure:
Under stirring at room temperature, to a solution of di-tert-butyl(3-ethinyl pyridin-2-yl)imidodicarbonate described in Preparation Example 3-1-1 (12 g), 2-(4-(2-nitro-ethyl)-benzyloxy)pyridine described in Preparation Example 1-3-4 (19.4 g), 4-dimethyl aminopyridine (230 mg), tetrahydrofuran (200 mL) was added di-tert-butyl dicarbonate (28.8 g) divided into four portions over 8 hours. After the additions were finished, stirring was carried out at room temperature for an additional 22 hours. Silica gel was added to the reaction solution and the solvent was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:1 then 2:1) to obtain the title compound (11.8 g, containing approximately 70% of the target compound).
Reaction SMILES: O[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:30].C(N(C(C)C)CC)(C)C>CCOC(C)=O>[Cl:30][C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[N:3]=1
Reactant: Oc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n3cnnc23)c1
Temperature: 25 °C

Procedure:
5-hydroxy-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine (0.3 g, 0.76 mmol), POCl3 (0.459 g, 3 mmol), and diisopropylethylamine (0.387 g, 3 mmol) in a 50-ml r.b.flask with a stir bar was stirred at 120° C. overnight. The reaction solution was cooled to room temperature and 20 ml of EtOAc and 5 g of SiO2 gel were added into the cooled solution. The solvents were evaporated in vacuo at 40° C. The resulting brown solid was placed on a cake of SiO2 gel (˜20 g) and washed with 250 ml of EtOAc. The brown filtrate was evaporated in vacuo to give 5-chloro-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine; MS m/z (M)+ 410; C17H8Cl2F3N5 requir. 410.2.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:6]1=[O:25].[Cl-].[NH4+]>O1CCCC1.CCOCC>[OH:24][C:22]([CH3:1])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:7]1[C:8](=[O:17])[C:9]2[N:10]([CH2:14][CH2:15][CH3:16])[CH:11]=[N:12][C:13]=2[N:5]([CH3:4])[C:6]1=[O:25]
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
22.4 g (0.3 mol) of methylmagnesium chloride in the form of a 20% strength solution in tetrahydrofuran are added dropwise with vigorous stirring at room temperature to a suspension of 61.3 g (0.2 mol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 2 l of anhydrous ether, the internal temperature rising to approximately 30° C. The mixture is then warmed with stirring and under reflux for 2 hours, treated with saturated aqueous ammonium chloride solution to decompose the alkoxide formed, and the organic phase is separated off and washed twice with 500 ml of water each time. The collected water phases are extracted thoroughly with dichloromethane again. The dichloromethane extract is combined with the ethereal phase, dried over sodium sulfate, filtered and evaporated under reduced pressure, 59.0 g of crude product (91.5% of theory) being obtained, which is purified by recrystallization from diisopropyl ether.