Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][O:6][C:7]1([CH3:25])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([O:17][C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:9]=2[O:8]1.C1(C)C=CC=CC=1>CCCCCC>[CH3:1][NH:2][C:3]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([O:17][C:14]2[CH:15]=[CH:16][C:9]3[O:8][C:7]([O:6][CH3:5])([CH3:25])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[CH:19][CH:20]=1)=[O:4]
Reactant: CN=C=O
Reactant: COC1(C)CCc2cc(Oc3ccc(N)cc3)ccc2O1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CNC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(C)(OC)O3)cc1
Reaction time: 6 h
Yield: 97 %

Procedure:
Methyl isocyanate (0.16 g) was added at room temperature to a solution composed of 0.4 g of 4-(2-methoxy-2-methyl-2,3-dihydro-6-benzopyranyloxy)aniline and 3.0 ml of toluene, and the mixture was stirred for 6 hours. Addition of n-hexane to the mixture yielded crystals which were collected by filtration to give the desired product as white crystals (yield not less than 97%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:13])=[N+:10]([O-])[CH:11]=1)=[O:5])[CH3:2].[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:13][C:9]1[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)c1ccc(C)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc(COC(C)=O)nc1
Yield: 59.2 %

Procedure:
A mixture of 13.7 g of 5-ethoxycarbonyl-2-methyl-pyridine-1-oxide and 15 g of acetic anhydride was stirred under reflux. Excess acetic anhydride was removed under a reduced pressure, and the residue was purified by distillation under a reduced pressure (110° C./0.1 mmHg) to obtain 10.0 g of ethyl 6-acetoxymethylnicotinate. ##STR7##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Nc1ccccc1S
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1N
Reaction time: 0.5 h

Procedure:
2-Aminothiophenol (6.26 g, 50 mmol) was added to a mixture of sodium hydride (2.0 g of 60% oil dispersion, 50 mmol) in DMF (100 ml) at 0° under nitrogen. After stirring for 30 minutes at 0°, 2-fluoro-5-nitrobenzonitrile (8.3 g, 50 mmol) in DMF (20 ml) was added and the mixture kept at room temperature overnight. The reaction mixture was evaporated and azeotroped with toluene, then the residue was partitioned between chloroform and water and the layers separated. Drying (sodium sulphate) and evaporation of the organic layer gave a residue which was separated from chloroform as bright yellow crystals (10.1 g, Rf 0.52 in 1:1 ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:11][C:12]2[NH:13][CH2:14][CH2:15][N:16]=2)[CH:3]=1.[Br:17]Br.N>CC(O)=O>[Br:17][C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: BrBr
Reactant: Clc1cc(NC2=NCCN2)cc2[nH]cnc12
Agent: N
Solvent: CC(=O)O
Product: Clc1cc(NC2=NCCN2)c(Br)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
To a solution of 7-chloro-5-(2-imidazolin-2-ylamino)benzimidazole (0.61 g, 2.6 mmol) in 10 ml of AcOH was added 0.3 ml of Br2. Resulting reaction mixture was stirred for 12 h at 25° C. and concentrated in vacuo, yielding an oil, which was subjected to column chromatography (NH3 sat'd 30% MeOH/EtOAc) to yield 0.23 g (0.85 mmol, 33%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.12 g (12%) of the product as a light yellow solid: mp 244-246° C.; Anal. Calc. for C10H9N5BrCl. 1.0C4H4O4.0.5H2O requires C, 37.77; H, 3.17; N,18.35. Found: C, 37.75; H, 3.08; N, 18.21.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[NH2:27][C@@H:28]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([NH:27][C@@H:28]3[C@@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]3)=[O:22])[C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H](N)C1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccccc3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3R,4R)-3-amino-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]2[CH2:15][CH:16]([CH3:18])[O:17][C:13]=2[C:12]([Cl:19])=[CH:11][CH:10]=1.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22]>O1CCOCC1>[Cl:19][C:12]1[C:13]2[O:17][CH:16]([CH3:18])[CH2:15][C:14]=2[C:9]([N:8]=[C:21]=[O:22])=[CH:10][CH:11]=1
Reactant: CC1Cc2c(N)ccc(Cl)c2O1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1Cc2c(N=C=O)ccc(Cl)c2O1

Procedure:
6.07 g of triethylamine was added to a mixture of 9.18 g of 32A, 11.87 g of trichloromethyl chloroformate and 250 mL of dioxane, and the mixture was refluxed for 6 hours. The mixture was cooled, filtered, and the filtrate was stripped of solvent, to give 7-chloro-2,3-dihydro-4-isocyanato-2-methylbenzofuran (34A), as a brown liquid.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].I[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([C:3]1[N:7]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: ICCCc1ccccc1
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2CCCc2ccccc2)cc1
Yield: 9.4 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54 mmol) was alkylated according to the procedure of Example 40 using potassium tert-butoxide (1.08 mL of a 1 M solution, 1.08 mmol) and 1-Iodo-3-phenylpropane (0.093 mL, 0.60 mmol) to afford the title compound (0.020 g, 10%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OCC)(=O)CC(C)=O>>[OH:4][CH:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6]
Reactant: CC(=O)CC(=O)OCC(C)C
Solvent: CCOC(=O)CC(C)=O
Product: CC(C)COC(=O)CC(C)O
Yield: 52 %

Procedure:
Isobutyl 3-hydroxybutyrate was prepared following the procedure as described in step 1) of Preparation Example 2, except for that isobutyl acetoacetate was used to replace for ethyl acetoacetate. Yield 52%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:10](#[N:13])[CH:11]=[CH2:12]>O.C(OCC)(=O)C>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:12][CH2:11][C:10]#[N:13]
Reactant: CNc1ccccc1O
Reactant: C=CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1ccccc1OCCC#N
Yield: 378.3 %

Procedure:
A solution of 2-methylaminophenol (0.74 g, 6.0 mmol), Triton B (60 μL, 40% in water) and acrylonitrile (4.0 mL, 60 mmol) was refluxed for 16 hrs. The mixture was diluted with ethyl acetate. The organic layer was then washed with water and brine, and was dried over MgSO4. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to give 3-(2-methylamino-phenoxy)-propionitrile (4.0 g) as a brown oil. [M+H]+ 177.1; tR=0.715 min (method 1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:16](Cl)=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH2:27]>>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:15]2[C:16]([OH:27])=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2cc3ccccc3nc2Cl)CCN(Cc2ccccc2)CC1
Reactant: O
Agent: Cl
Product: Oc1nc2ccccc2cc1C1=CCN(Cc2ccccc2)CC1

Procedure:
15.5 g (43.9 mmol) 1-benzyl-4-(2-chloro-quinolin-3-yl)-piperidin-4-ol were refluxed for 8 h in 150 mL of a 6M aqueous hydrochloric acid solution. 100 mL water were added dropwise to the reaction mixture and the precipitated solid was suction filtered, dried and then stirred into 150 mL of a 15%, aqueous potassium carbonate solution. After the precipitate had been suction filtered the product was obtained as a free base and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:27][CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:25]=O)=[CH:23][CH:24]=1)=[O:19])[CH3:13].N1C=CC=C1C(OCC)=O>>[CH2:27]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:25]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:23][CH:24]=1)=[O:19])[CH3:28]
Reactant: CCN(CC)CCNC(=O)c1ccc(C=O)[nH]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: CCOC(=O)c1ccc[nH]1
Product: CCN(CC)CCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(Br)cc32)[nH]1
Yield: 38 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (212 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-diethylaminoethyl)amide (prepared from ethyl pyrrole-2-carboxylate by method A, B and then C) to give 162 mg (38%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:21]([Cl:36])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Na]>O.CC(O)C>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:23][C:18]([NH:16][C:10]2[C:7]3[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=3[C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[N:19][CH:20]=1
Reactant: CCN1CCc2c(N)ccc(OC)c2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CCN1CCc2c(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc(OC)c2CC1
Temperature: 120 °C

Procedure:
3-Ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamine (50.01 mg, 0.2270 mmol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (77.0 mg, 0.227 mmol) and 10-camphorsulfonic acid (79.1 mg, 0.340 mmol) were charged to 2 ml IPA in a microwave tube. The reaction was heated to at 120° C. for 40 minutes. Pour reaction into water (50 ml) and saturated sodium bicarb (90 ml) and extract 3 times with 25 ml portions of methylene chloride. Dry combined organic over magnesium sulfate, filter and evaporate to a brown oil (87 mg). The crude reaction was purified on silica gel (12 g Isco column) using a gradient of 0-20% methanol in methylene chloride and then isocratic 20% methanol in methylene chloride to yield N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as an off white foam. 1H-NMR (CDCl3) δ 7.88 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.38 (s, 1H), 5.18 (br s, 1H), 3.81 (s, 3H), 3.10 (br s, 2H), 2.72 (s, 3H), 2.68-2.49 (m, 6H), 2.18-2.00 (m, 2H), 1.82-1.69 (m, 2H), 1.40-1.18 (m, 4H), 1.07 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].[OH-].[Na+]>O.CO>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCCC(CCCC(CC#CCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(O)CCCC(CC#CCCCC(=O)O)S(C)(=O)=O

Procedure:
Methyl 8-methylsulfonyl-12-acetoxy-5-heptadecynoate (41.6 g., 0.10 mole) is added to a solution of sodium hydroxide (12.0 g., 0.3 mole) in water (120 ml.) and methanol (600 ml.). The resulting solution is heated at 55°-60° C. for 24 hours. Most of the methanol is removed by evaporation in vacuo. The residue is diluted with water and extracted with ether. The aqueous solution is acidified with concentrated hydrochloric acid. The product which separates is taken up in ether, washed with water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a viscous yellow oil. Purification is effected by column chromatography on silica gel with 2% methanol in chloroform as eluant. The title compound is obtained as a nearly colorless viscous oil.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:13]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[Br:13][CH2:2][C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccsc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccsc1
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a solution of 3-acetylthiophene (3.73 g) in diethyl ether (60 mL) was added aluminum chloride (386 mg), and the mixture was stirred for 5 min. Bromine (1.55 mL) was slowly added at room temperature to this mixture, and the mixture was further stirred for 2 hr. Aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether to give the title compound as white crystals (yield 3.93 g, 65%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CN([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(N(CC)CC)C>C(OCC)C>[CH2:20]([O:19][C:17]([C:16]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=2)=[N:2][O:1][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C=CN(C)C
Reactant: O/N=C(\Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1conc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.6 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (50 g, 241 mmol) in diethylether (1 L) was added a solution of ethyl 3-(N,N-dimethylamino)acrylate (87 mL, 601 mmol) and triethylamine (49 mL, 349 mmol) in diethylether (1 L). The resulting mixture was then stirred for 14 h at room temperature and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title product (50.2 g, 88%) which was obtained as a light yellow solid. MS: m/e=236.1 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[S:14][C:15]([C:18]([O-:20])=O)=[CH:16][N:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[N:22]1[CH:23]=[CH:24][N:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][C:26]=12.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[N:22]1[CH:23]=[CH:24][N:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:18]([C:15]3[S:14][C:13]([CH:10]4[CH2:9][CH2:8][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:12][CH2:11]4)=[N:17][CH:16]=3)=[O:20])=[CH:27][C:26]=12
Reactant: O=C([O-])c1cnc(C2CCN(c3ccccc3)CC2)s1
Reactant: NCc1ccn2ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NCc1ccn2ccnc2c1)c1cnc(C2CCN(c3ccccc3)CC2)s1
Reaction time: 8 h

Procedure:
Lithium 2-(1-phenylpiperidin-4-yl)thiazole-5-carboxylate (28.8 mg, 0.098 mmol), imidazo[1,2-a]pyridin-7-ylmethanamine (17.31 mg, 0.118 mmol), 4-methylmorpholine (49.6 mg, 0.490 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (55.9 mg, 0.147 mmol) were combined in a vial with dichloromethane (2.5 ml) and the reaction was stirred overnight. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate. The organic layers were dried with sodium sulfate, filtered, and concentrated. Trituration of the crude material with dichloromethane provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.21 (t, J=5.9 Hz, 1H), 8.49 (dd, J=7.0, 0.9 Hz, 1H), 8.34 (s, 1H), 7.91-7.88 (m, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.43-7.38 (m, 1H), 7.26-7.16 (m, 2H), 7.01-6.93 (m, 2H), 6.84 (dd, J=7.0, 1.7 Hz, 1H), 6.81-6.72 (m, 1H), 4.48 (d, J=5.9 Hz, 2H), 3.81-3.73 (m, 2H), 3.24-3.01 (m, 1H), 2.90-2.78 (m, 2H), 2.19-2.09 (m, 2H), 1.90-1.73 (m, 2H); MS (ESI(+)) m/e 418 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH:16]=O)=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.Cl.[NH2:19]O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:19])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=Cc1cnn2c(-c3cccnc3)ccnc12
Reactant: NO
Agent: Cl
Solvent: CCO
Product: N#Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.01 mole of 7-(3-pyridyl)pyrazolo-[1,5-a]pyrimidine-3-carboxaldehyde and 0.011 mole of hydroxylamine hydrochloride in 25 ml. of ethanol is heated on a steam bath for 3 hours. The solvent is removed and to the residue is added 25 ml. of acetic anhydride. The mixture is heated at reflux temperature for 6 hours and the solvent is removed in vacuo. The residue is partitioned between dichloromethane and sodium bicarbonate solution and the organic layer is separated, dried over magnesium sulfate, and the solvent removed to give the product of the example, m.p. 258°-260° C.
Reaction SMILES: C(O[C:4](=[O:17])/[C:5](/[C:15]#[N:16])=[CH:6]\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1)C.C(OC(=O)/C(/C#N)=C/NC1C=CC(I)=CC=1)C.CCOCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[I:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]([C:15]#[N:16])[C:4]2=[O:17]
Reactant: CCOC(=O)/C(C#N)=C\Nc1ccc(I)cc1
Agent: CCOC(=O)/C(C#N)=C/Nc1ccc(I)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: N#Cc1c[nH]c2ccc(I)cc2c1=O
Temperature: 260 °C
Yield: 85 %

Procedure:
A mixture of (Z)-2-cyano-3-(4-iodo-phenylamino)-acrylic acid ethyl ester and (E)-2-cyano-3-(4-iodo-phenylamino)-acrylic acid ethyl ester (example 14a, 150 g, 0.44 mol) in diphenylether (1500 mL) was refluxed at 260° C. for 12 h. After cooling, ether was added. The solid was collected by filtration, washed with ether and dried to obtain 6-iodo-4-oxo-1,4-dihydro-quinoline-3-carbonitrile (110.5 g, 85%) as a black solid. LC-MS m/e 297 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].N1C=CC=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)C(Nc1ccc(Cl)cc1)C(=O)OCC
Reaction time: 8 h
Yield: 34.8 %

Procedure:
p-Chloroaniline (2 g) was dissolved in dry benzene (20 ml), and diethyl bromomalonate (3.8 g) and then dry pyridine (1.3 ml) were added. The mixture was refluxed with stirring overnight. The solvent was distilled off under reduced pressure, and then water was added. The mixture was extracted with chloroform twice. The chloroform layers were washed with water twice and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue (3.34 g) was purified by silica gel column chromatography using benzene as an eluent to give 1.56 g (yield 35%) of diethyl p-chloroanilinomalonate having the following NMR data.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:18]([NH:26][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Temperature: 100 °C

Procedure:
To a stirred solution of 1-fluoro-2-nitrobenzene (14.1 g, 0.1 mol) and triethylamine (14 ml, 0.1 mol) in DMF (150 ml) was added phenethylamine (12.1 g, 0.1 mol). The mixture was now heated to 100° C., and the reaction was monitored by TLC. After the reaction was completed (2 h) the solvent was removed by evaporation in vacuo. The residue was partitioned between 0.5N aqueous HCl (100 ml) and ether (100 ml). The organic phase was washed with water, dried and evaporated to give the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH:5]=[CH:6]2)[C@@H:3]1[C:9]([NH2:11])=[O:10]>CO.[Pd]>[NH2:1][C@@H:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)[C@@H]1[C@H](N)[C@H]2C=C[C@@H]1C2
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1N
Reaction time: 8 h

Procedure:
A solution of (+/−)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide (707 mg, 4.65 mmol) in methanol (23 ml) was evacuated and purged with nitrogen and treated with palladium on carbon (74.2 mg, 0.070 mmol). The resulting suspension was evacuated and purged with a hydrogen balloon and stirred under the hydrogen overnight. The mixture was filtered through celite, washed with methanol, and dried to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[C:16]([CH:20]3[CH2:22][CH2:21]3)[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2cc(Br)cnc2Cl)c1C
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cc(C3CC3)cnc2Cl)c1C
Yield: 63.7 %

Procedure:
To 1-(5-bromo-2-chloropyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2 g) in Reference Example 29 (1), cyclopropylboronic acid (724 mg), tetrakis(triphenylphosphine)palladium (0) (670 mg) and 2 M sodium carbonate aqueous solution (8.7 ml) was added tetrahydrofuran (12 ml), and stirred under reflux. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution under ice-cooling, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 1-(2-chloro-5-cyclopropylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.13 g) as a white solid. MS (ESI) m/z: 306 (M+H)+.