Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[N:13]=1.C(Cl)(=O)C(Cl)=O.[NH3:31]>O1CCCC1.CN(C)C=O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:31])=[O:20])=[CH:16][CH:15]=2)[N:13]=1
Reactant: N
Reactant: O=C(O)c1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound (162) (0.45 g, 1.29 mmol) in tetrahydrofuran (12 ml) were added oxalyl chloride (0.17 ml, 2.59 mmol) and dimethylformamide (3 drops) under ice-cooling, and the mixture was stirred at room temperature for one hr. To this reaction mixture was added 28% aqueous ammonia (1.00 ml, 16.44 mmol) and the mixture was stirred at room temperature for one hr. and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate. The extracts were combined, washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethanol-ethyl acetate to give white crystals (0.45 g, quant.).
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58](ON2C3C=CC=CC=3N=N2)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O>[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58]([NH:1][C@@H:2]2[C:23](=[O:24])[N:4]3[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]4[N:15]([NH:16][CH:17]([CH3:18])[CH3:19])[N:14]=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 84.7 %

Procedure:
To a solution of 7β-amino-3-[(1-isopropylamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.35 g, 3.63 mmol) and triethylamine (0.735 mg, 7.26 mmol) in dimethylacetamide (17 ml) was added 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetate (3.05 g, 5.44 mmol). The mixture was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-isopropylamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.45 g, 84.8%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>C(Cl)Cl>[CH2:21]([S:23]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)(=[O:25])=[O:24])[CH3:22]
Reactant: NCCSc1cccc2nccn12
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCCSc1cccc2nccn12
Yield: 78.1 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 ml, 11 mmoles) in methylene chloride (100 ml) was added ethanesulfonyl chloride (0.95 ml, 10 mmoles) at room temperature with stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:5) to obtain 2.23 g of the desired product (78.2%, colorless crystals).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](N)=[O:10])=[CH:4][C:3]=1[CH3:12].Cl.[CH2:14]([OH:16])[CH3:15]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:16][CH2:14][CH3:15])=[O:10])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(CC(N)=O)ccc1F
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc(F)c(C)c1
Temperature: 85 °C
Reaction time: 10 h

Procedure:
2-(4-Fluoro-3-methylphenyl)acetamide (863 mg) was dissolved in saturated hydrochloric acid/ethanol (20 ml), and the reaction solution was stirred at 85° C. for 10 hours. The reaction solution was concentrated under reduced pressure and then diluted with ethyl acetate, followed by separation with water. The organic layer was washed with saturated aqueous sodium bicarbonate and brine and then dried over magnesium sulfate. 919 mg of the title compound was obtained by concentration under reduced pressure. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[OH:20].C(=O)(O)[O-].[Na+].O>CS(C)=O.Cl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[OH:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: N[C@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(N[C@H]2CCCC[C@H]2O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A solution of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (671 mg, 4.42 mmol, Small Molecules, Inc.) and sodium bicarbonate (991 mg, 11.8 mmol) in DMSO (14.7 mL), and water (2.1 mL) is heated at 130° C. for 48 h. After cooling to room temperature, the mixture is diluted with 1 N HCl and extracted twice with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane to furnish the title compound as an off-white solid (527 mg, 68%). LC-ES/MS m/z 265.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c[nH]nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccccc2)nc1C
Reaction time: 8 h
Yield: 71 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (5.1 g) synthesized in Example 1(3) was dissolved in dimethylformamide (50 mL), potassium carbonate (5.3 g) and benzylbromide (4.6 mL) were added to at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (5.9 g, 71%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[N:27]=[CH:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([NH:31][CH2:30][C:28]4[N:27]=[CH:26][N:25]([CH3:24])[CH:29]=4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:22][CH:23]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cn1cnc(CN)c1
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cn(C)cn1
Yield: 71 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,14-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with with (1-methyl-1H-imidazol-4-yl)methanamine, the title compound was obtained as a white solid in 71% yield: mp 225-226° C. (ethyl acetate/hexane): 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.55 (s, 1H), 7.41-7.32 (m, 2H), 7.08-6.97 (m, 2H), 6.91 (s, 1H), 6.78 (t, J=5.3 Hz, 1H), 4.96 (s, 2H), 4.53 (d, J=5.3 Hz, 2H), 3.70 (s, 3H), 2.64 (s, 3H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=4)=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:21][CH:22]=4)=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc3oc(-c4ccc(Cl)cc4)nc3c2)cn1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccc3oc(-c4ccc(Cl)cc4)nc3c2)cn1
Temperature: 80 °C
Reaction time: 40 h
Yield: 41.2 %

Procedure:
To 5-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)pyridin-2-amine (96.5 mg, 0.30 mmol) in dry pyridine (3 mL) at room temperature was added acetyl chloride (26 μL, 0.36 mmol), and stirred at 80° C. for 40 h. After cooling, the mixture was poured into water to give a precipitate, which was filtered off. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 45 mg (41%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[C:11]([OH:13])[C:10]([Cl:15])=[N:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)c1cncc(O)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cnc(Cl)c(O)c1
Temperature: 80 °C
Yield: 49.7 %

Procedure:
The compound of Example 52A (400 mg, 2.05 mmol) was dissolved in DMF (2 mL) and N-chlorosuccinimide (328 mg, 2.46 mmol) was added. The mixture was heated to 80° C. overnight, concentrated and purified by column chromatography to give the chloro pyridine (234 mg, 50%). MS (DCI) m/z 230, 232 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:35]([C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[CH2:45][OH:46])[CH:36]=[CH2:37].[H-].[Na+]>CN(C=O)C>[CH2:35]([C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[CH2:45][O:46][CH2:20][C:18]1[CH:19]=[C:15]2[N:14]=[C:13]([CH3:22])[C:12]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([N:8]3[CH2:9][CH2:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH3:34])[CH2:6][CH2:7]3)[N:16]2[N:17]=1)[CH:36]=[CH2:37]
Reactant: C=CCc1cc(F)ccc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(F)cc4CC=C)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (150 mg, 0.257 mmol) and (2-allyl-4-fluorophenyl)methanol (42.7 mg, 0.257 mmol) in DMF (5 mL) at 0° C. was added NaH (10.26 mg, 0.257 mmol). The reaction was stirred at 0° C. for 2 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(2-(((2-allyl-4-fluorobenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (70 mg, 0.112 mmol, 43.8% yield) as an oil. LCMS (M+1)=623.3.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Li]CCCC.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH3:1][CH:2]([CH3:5])[C:3]#[C:4][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cl
Reactant: C#CC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
Under an Ar atmosphere, to a mixture of 3-Methylbutyne (1.5 g, 22.0 mmol) in THF (15 ml) was added a solution of 2.5 M n-BuLi in hexanes (9.68 ml, 24.2 mmol) at −78° C. over 15 min, then the mixture was stirred at −78° C. for 5 min, and at −5˜−10° C. for 30 min. Ethyl chloroformate (2.63 g, 24.2 mmol) was added drop wise at −78° C., then the mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated aqueous NH4Cl under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by kugelrohr distillation (1˜3 mmHg 70˜80° C.) gave 2b (59%). 2b: colorless oil; 1H-NMR (CDCl3) δ 1.24 (6H, d, J=7.0 Hz), 1.31 (3H, t, J=7.2 Hz), 2.70 (1H, sep, J=7.0 Hz), 4.22 (2H, q, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12]Cl)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:7]2=[O:21].[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:9]1[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7](=[O:21])[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=c1c2cccc(Cl)c2nc(CCl)n1-c1ccccc1Cl
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2c(Cl)cccc2c(=O)n1-c1ccccc1Cl
Yield: 38.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2h (100 mg, 0.294 mmol), adenine (44 mg, 0.324 mmol), K2CO3 (45 mg, 0.324 mmol), and DMF (1 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 50 mg of a pale yellow solid (39%), mp 273.3-273.5° C. (discolors). 1H NMR (DMSOd6) δ: 8.11 (dd, J=1.3, 8.0 Hz, 1H); 8.08 (s, 1H); 8.05 (s, 1H); 8.00 (dd, J=1.3, 7.8 Hz, 1H); 7.79-7.83 (m, 2H); 7.63-7.66 (m, 2H); 7.56 (t, J=7.9 Hz, 1H); 7.21 (br s, 2H); 5.17 (d, J=17 Hz, 1H); 4.97 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 156.1, 152.8, 152.2, 150.2, 143.3, 142.0, 135.6, 133.1, 132.3, 131.9, 131.1, 131.0, 130.9, 129.4, 128.4, 126.0, 122.5, 118.4, 45.0. MS (ES): m/z 438.0 (M+). Anal. calcd. for C20H13Cl2N7O0.1CH4O0.6H2O(0.15KCl: C, 52.09; H, 3.18; N, 21.15. Found: C, 51.85; H, 2.93; N, 21.01.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[CH:10](O)=[O:11].S(S([O-])=O)([O-])=O.[Na+].[Na+].C>C(N)=O.O>[CH:10]([NH:1][C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:11]
Reactant: O=CO
Reactant: O=[N+]([O-])c1ncccn1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: NC=O
Solvent: O
Product: O=CNc1ncccn1
Reaction time: 0.29 h

Procedure:
The crude nitropyrimidine (25.32 g) from above was suspended in formamide (150 ml) and 90% formic acid (50 ml) and the suspension was warmed to 70° C. in a water bath. Sodium dithionite was carefully added to the warm suspension and then boiled for 15-20 minutes. The reaction mixture was diluted with hot water (300 ml), treated with charcoal and then boiled for an additional 20-25 minutes, filtered through celite, cooled and concentrated under reduced pressure to give formamido-pyrimidine which was collected by filtration, washed with acetone, and dried under vacuum at 56° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][CH:7]([CH3:9])[CH3:8])=[CH:4][CH:3]=1.C(O)(=O)C.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>O>[CH:7]([N:6]([C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:9])[CH3:8]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)Nc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)CC(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 500 ml reaction flask fitted with a condenser, drying tube, magnetic stirrer and therometer was charged with 89.5 g (0.528 mole) of 4-chloro-N-isopropylaniline, 200 ml of glacial acetic acid and 18.5 g (0.58 mole) of mercuric acetate. To the stirred solution there was added dropwise 48.8 g (0.58 mole) of diketene while the reaction temperature was maintained at 30°-5°. The reaction solution was allowed to stir overnight at ambient temperature. The solution was mixed with two liters of water and twice extracted with ether. The organic phase was washed with water and dried over sodium sulfate. After removing the solvent, the liquid residue weighed 134 g (100%). N.M.R. (CDCl3) ∂1.0 and 1.2 (isopropyl, doublet), 1.8 (CH3, enol), 2.1 (CH3, keto), 3.2 (CH2), 4.7-5.2 (CH, isopropyl), 7.1-7.5 (aromatic).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O/[N:30]=[C:31](\[NH2:39])/[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>CN(C=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][C:31]2[N:39]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[O:16][N:30]=2)[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N/C(Cc1cccnc1)=N\O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Cc3cccnc3)no2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
1-(Tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.29 g, 0.010 mmol) was treated with 1,1′-carbonyldiimidazole (1.62 g, 0.010 mmol) in DMF (5 mL) at ambient temperature for 30 min. Following this activation period, the crude (1Z)-N′-hydroxy-2-pyridin-3-ylethanimidamide (0.010 mmol) was added and the reaction mixture heated at 70° C. for 6 h followed by 120° C. for an additional 6 h. The reaction mixture was cooled and partitioned between EtOAc and water. The organic phase was separated, washed successively with saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give tert-butyl 4-[3-(pyridin-3-ylmethyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate. 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.53 (m, 1H), 7.67 (d, 1H, J=7.7 Hz), 7.28 (m, 1H), 4.20-4.05 (m, 2H), 4.08 (s, 2H), 3.08 (m, 1H), 2.94 (m, 2H), 2.04 (m, 2H), 1.87-1.73 (m, 2H), 1.47 (s, 9H). ES-LCMS m/z 367.36 (M+Na).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[C:2]=1[OH:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[C:10]([CH:1]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Oc1cc2ccccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4cc3O)c2cc1OC
Temperature: 130 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
Naphthalene-2,3-diol (1.00 g), 4-chloro-6,7-dimethoxyquinoline (691 mg), and 4-dimethylaminopyridine (1.14 g) were suspended in o-dichlorobenzene (20 ml), and the mixture was stirred at 130° C. for one hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (627 mg, yield 58%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[Br-:24].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.ClCCl>CO>[Br:24][CH:20]1[CH2:19][CH2:18][C:15]2=[CH:16][C:17]3[C:8]4[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][Br:1])=[CH:23][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:14]2[C:21]1=[O:22]
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.58 g, 6.95 mmol), pyridinium tribromide (2.56 g, 8.0 mmol), dichloromethane (22 mL) and methanol (2.5 mL) was stirred at about 20° C. for 3 hours to obtain a slurry. The precipitated product was filtered, washed with dichloromethane (10 mL) and dried in a vacuum oven at 40° C. to give 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.62 g, 84% yield). 400 MHz 1H NMR (CDCl3) δ 8.03-8.01 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74 (dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m, 1H), 2.59-2.46 (m, 2H).
Reaction SMILES: [CH2:1]=O.Cl.[I:4][C:5]1[CH:16]=[CH:15][C:8]2[C:9]([CH2:12][CH2:13][NH2:14])=[CH:10][O:11][C:7]=2[CH:6]=1>Cl.C=O>[I:4][C:5]1[CH:16]=[CH:15][C:8]2[C:9]3[CH2:12][CH2:13][NH:14][CH2:1][C:10]=3[O:11][C:7]=2[CH:6]=1
Reactant: NCCc1coc2cc(I)ccc12
Reactant: C=O
Agent: Cl
Product: Ic1ccc2c3c(oc2c1)CNCC3
Temperature: 70 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
Paraformaldehyde (8.9 g, 0.297 mol) was added to a solution of 2-(6-iodo-1-benzofuran-3-yl)ethanamine hydrochloride (80 g; 0.247 mol) in 1N HCl (500 mL) under N2. After 2 h stirring at 70° C., another portion of paraformaldehyde (740 mg) was added. The reaction mixture was cooled down to r.t., filtered, the resulting solid was washed with 1N HCl (100 mL), dried overnight under house vacuum to afford 76.7 g of the title product as a hydrochloric acid salt. 1H-NMR (400 MHz, CDCl3): δ 2.06 (bt, 2H), 2.92 (bt, 2H), 4.37 (s, 2H), 7.45 (d, 1H) 7.62 (dd, 1H), 8.05 (d, 1H), 10.04 (bs, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:22][C:14]1[NH:15][C:16]3[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5](=[O:11])[NH:6]2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-methyl-2-oxindole (147 mg), 3-methyl-indole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 4-methyl-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH:10]([OH:20])[CH2:11][C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1.[H][H]>C(O)C.CO.[Pt]=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH:10]([OH:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1
Reactant: OC(CC#Cc1cccnc1)CC#Cc1cccnc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CO
Product: OC(CCCc1cccnc1)CCCc1cccnc1
Yield: 98.9 %

Procedure:
A suspension of platinum oxide (280 mg) in absolute ethanol (1 mL) was diluted with absolute methanol (10 mL) followed by the addition of compound 1 (2.81 g, 10.73 mmol). The suspension was placed under 40 psi of hydrogen gas. After hydrogen consumption ceased, the hydrogen was replaced with nitrogen and the reaction was filtered and concentrated to provide 2.87 g of compound 2 as a viscous oil.