Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:29][C:30]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:17])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C=Nc1ccccc1
Product: O=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=O)Nc1ccccc1

Procedure:
The compound is prepared by a method analogous to that of Example 20 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carboxamide and phenyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
Cyanuric chloride (7.36 g, 39.9 mmol) was dissolved in acetone (120 ml), cooled to -15° C. and gradually added dropwise with morpholine (7.00 ml, 80.3mmol) dissolved in acetone (20 ml). This reaction mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using n-hexane and ethyl acetate (8: 2) as eluant, to obtain 6.33 g (yield: 67.5%) of 2,4-dichloro-6-morpholino-1,3,5-triazine as colorless crystals having melting point of 160.5° C.-161° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CC1O[N:29]=[C:28]([C:31]2C=CC=CC=2)[C:27]=1COC1C=CC(C(O)=O)=CN=1.C(N)(C)C>>[Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:29][CH:28]([CH3:31])[CH3:27])=[O:8]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)O)cc1Br
Solvent: CC(C)N
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)C)cc1Br
Yield: 86 %

Procedure:
As described for example 8b, 5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (240 mg, 0.6 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, was converted, using isopropylamine instead of methylamine, to the title compound (229 mg, 86%) which was obtained as an off white foam. MS: m/e=430.3/432.2 [M+H]+.
Reaction SMILES: [Na].[C:2]([C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][C:11]=1[Cl:12])([CH3:5])([CH3:4])[CH3:3].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:9]1[N:8]=[C:7]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])=[C:11]([Cl:12])[N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [Na]
Product: CC(C)(C)c1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred anhydrous benzyl alcohol (80 ml), was added pieces of sodium metal (1.73 g, 75 mmol). After the reaction completed, the mixture was cooled in an ice bath and 5-tert-Butyl-2,4,6-trichloro-pyrimidine (9 g, 37.5 mmol) was added. After 1 hr., the mixture was stirred at room temperature for overnight and evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography (eluent, ether:hexanes (1:19)) to afford 13 g (90%) of a white solid. m.p. 96° C.; 1H NMR (200 MHz, CDCl3) δ 1.50 (9H, s), 5.37 (2H, s), 5.41 (2H, s), 7.34-7.46 (10H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([O:18]C)=O)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH3:20]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([NH2:20])=[O:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Temperature: 80 °C
Yield: 53 %

Procedure:
A mixture of methyl 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (700 mg, 2.19 mmol) and 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated in an oil bath at 80° C. for 16 h. After cooled to RT, the solid was collected by filtration and washed with MeOH, to afford 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxamide (500 mg, 1.15 mmol, 53% yield). MS (ESI) m/z 306.96 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.18 (1H, br. s.), 8.33 (1H, br. s.), 7.79 (1H, br. s.), 7.71-7.77 (2H, m), 6.79 (1H, s), 6.52-6.60 (1H, m), 5.70 (2H, br. s.).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:23])[CH3:22])#[CH:13]>>[C:21]([N:20]1[C:15]2[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:13]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: C#Cc1ccccc1NC(C)=O
Reactant: COC(=O)c1ccc(I)cc1
Product: COC(=O)c1ccc(-c2cc3ccccc3n2C(C)=O)cc1
Yield: 59 %

Procedure:
The general procedure was used to convert methyl 4-iodobenzoate and N-(2-ethynylphenyl)acetamide to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 59% yield. 1H NMR (300 MHz, DMSO) δ 8.20-8.17 (d, J=8.2, 1H), 8.06-8.04 (d, J=8.2, 2H), 7.70-7.67 (d, J=8.3, 2H), 7.66-7.64 (d, J=7.7, 1H), 7.41-7.28 (m, 2H), 6.91 (s, 1H), 3.89 (s, 3H), 2.20 (s, 3H). 13C NMR (75 MHz, DMSO) δ 171.63, 166.71, 139.56, 139.00, 138.06, 130.21, 129.96, 129.78, 129.56, 126.06, 124.37, 124.33, 121.81, 116.10, 113.06, 53.12, 28.53. Anal. Calcd. for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found C, 73.50; H, 5.21; N, 4.54.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([F:22])=[CH:9][C:10]3[C:15](=[O:16])[N:14]([OH:17])[C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=3[N:21]=2)[CH2:3]1.F[C:24](F)(F)C([O-])=O>>[CH2:19]([N:12]1[C:11]2[N:21]=[C:7]([N:4]3[CH2:5][CH2:6][N:1]([CH3:24])[CH2:2][CH2:3]3)[C:8]([F:22])=[CH:9][C:10]=2[C:15](=[O:16])[N:14]([OH:17])[C:13]1=[O:18])[CH3:20]
Reactant: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCC(N)C3)nc21
Reactant: O=C([O-])C(F)(F)F
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCN(C)CC3)nc21

Procedure:
7-(3-Aminopyrrolidin-1-yl)-1-ethyl-6-fluoro-3-hydroxy-1H-pyrido[2,3-d]pyrimidine-2,4-dione, trifluoroacetate;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH2:24]([N:26](CC)CC)C>C(O)C>[CH3:20][NH:19][C:14]1[N:13]=[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:17]=[C:16]([NH:26][CH3:24])[N:15]=1
Reactant: CCN(CC)CC
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(Cl)cc2)n1
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(Cl)cc2)nc(NC)n1
Temperature: 140 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
0.62 g (0.0019 mol) of 4-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 10 ml of ethanol, treated with 1.67 g (0.025 mol) of methylamine hydrochloride and 6.2 ml (0.044 mol) of triethylamine and stirred in an autoclave at 140° C. for 18 hours. The mixture was freed completely from solvent, the residue was partitioned in ethyl acetate/water and the insoluble constituents were filtered off under suction. The filter cake was recrystallized in methanol/diethyl ether. There was obtained 0.28 g (45%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-4-chloro-benzenesulfonamide as white crystals; m.p. 272-273° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.[Br:14][C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1>CN(C)C=O.O>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:5][CH2:4][C:3]([OH:11])=[O:10])=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1ccc(Br)cc1
Reaction time: 0.08 h

Procedure:
A mixture of a 60% suspension of sodium hydride in mineral oil (4.8 g, 120 mmol) in N,N-dimethylformamide (50 mL) at about 5° C. was treated with diethyl malonate (36.4 mL, 240 mmol). The mixture was stirred for about 5 minutes, slowly treated with a solution of 4-bromobenzyl bromide (20.0 g, 80 mmol) in N,N-dimethylformamide (20 mL), stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated under high vacuum. The residue was dissolved in a mixture of acetic acid (46 mL), water (30 mL), and concentrated sulfuric acid (13 mL) and was heated to reflux for 18 hours. The reaction mixture was cooled, concentrated under high vacuum, and diluted with water. The formed crystalline solid was collected by filtration, washed with water and diethyl ether, and was dried under high vacuum to provide the desired product. MS (DCI-NH3): m/z 246, 248 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]=[C:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24]>C1COCC1>[C:11]1(=[CH:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH:23]=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1C=C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1C=C1CCCC1
Temperature: 25 °C

Procedure:
4-bromo-2-cyclopentylidenemethylanisole (738 mg, 2.5 mmol) in THF (20 ml) was cooled to -78° C. while stirring under nitrogen. n-Butyllithium (1 ml, 2.5M in Hexane, 2.5 mmol) was added dropwise over 1 minute. N,N-Dimethylformamide (0.5 ml) was added rapidly. The ice bath was removed an the reaction was warmed to room temperature. The reaction was diluted with ethyl acetate (100 ml) and was washed with water (50 ml) and brine (50 ml). The organic was dried over MgSO4, filtered and concentrated. The product was purified via flash chromatography. The yield of the title compound (440 mg, 1.8 mmol) was 72%.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:10][CH2:9]2)[C:6](=[O:11])[N:5]([CH:12]2[CH2:14][CH2:13]2)[C:4](=[O:15])[C:3]=1[N:16]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].NC1N(CC2CC2)C(=O)N(CC2CC2)C(=O)C=1.N([O-])=O.[Na+]>>[NH2:16][C:3]1[C:4](=[O:15])[N:5]([CH:12]2[CH2:14][CH2:13]2)[C:6](=[O:11])[N:7]([CH:8]2[CH2:10][CH2:9]2)[C:2]=1[NH2:1]
Reactant: Nc1c(N=O)c(=O)n(C2CC2)c(=O)n1C1CC1
Agent: Nc1cc(=O)n(CC2CC2)c(=O)n1CC1CC1
Agent: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Product: Nc1c(N)n(C2CC2)c(=O)n(C2CC2)c1=O
Yield: 84.9 %

Procedure:
The procedure similar to that described in Reference Example 1 was repeated except that 1.55 g (6.57 mmol) of Compound g prepared above and 2.86 g (16.4 mmol) of sodium hydrosulfite were employed in place of 6-amino-1,3-bis(cyclopropylmethyl)uracil and sodium nitrite, respectively. As a result, 1.24 g (yield: 75%) of Compound d was obtained as white powder.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)=[O:4].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH:2]([CH3:13])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=2)=[O:4])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1cc(C(=O)C(C)Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)ccc1O

Procedure:
12.15 g (0.05 mol) of 2-bromo-4'-hydroxy-3'-methylpropiophenone are dissolved in 25 ml of ethanol, 8.75 g (0.05 mol) of 4-benzylpiperidine diluted in 25 ml of ethanol, and then 5.4 g (0.05 mol) of sodium carbonate, are added and the mixture is heated under reflux for 1 and a half hours. The solvent is driven off and the residue is chromatographed on 100 g of silica using acetone as the eluant. This gives 18.4 g of a thick oil, which is used as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[O:13].[OH-].[K+].Cl>CS(C)=O.C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:12][OH:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1CCO
Temperature: 25 °C
Reaction time: 144 h
Yield: 23.8 %

Procedure:
To a solution of 4-fluoro-1-methyl-2-nitrobenzene (73.2 g, 0.47 mole) in DMSO (75 mL) was added paraformaldehyde (14.1 g, 0.47 mole), followed by potassium hydroxide (0.75 g) in ethanol (5 mL). The resulting reaction mixture was stirred at room temperature for six days and water (2 L) was added and the mixture neutralized with hydrochloric acid (2 N). The mixture was extracted with ethyl acetate (1 L) and the combined organic layers were washed with water (1 L), saturated sodium chloride (500 mL), dried (sodium sulfate) and concentrated to a yellow solid. Purification by flash column chromatography (silica gel, 1:1 methylene chloride:hexanes to methylene chloride) provided 20.7 g of the title compound as a light yellow oil. 1H NMR (CDCl3): 7.63 δ (dd, 1H); 7.40 δ (dd, 1H); 7.28 δ (dd, 1H); 3.90 δ (t, 3H); 3.10 δ (t, 2H); 1.55 δ (broad, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C:10]([C:17]#[N:18])=[CH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([CH3:23])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]([C:10]1([C:17]#[N:18])[CH2:23][CH:11]1[CH:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C=C(C#N)C(=O)OCc1ccccc1)CC
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCC(CC)C1CC1(C#N)C(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 66.4 %

Procedure:
To a solution of 2-cyano-4-ethyl-hex-2-enoic acid benzyl ester (3.76 g, 14.6 mmol) in 80 mL acetonitrile was added nitromethane (3.95 mL, 73 mmol), followed by DBU (2.18 mL, 14.6 mmol) resulting in an orange solution. The reaction was heated to 60° C. for 16 hours, then cooled and partitioned between Et2O and 1N HCl (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (5→10% EtOAc/hexanes) afforded 2.63 g (66%) of 1-cyano-2-(1-ethyl-propyl)-cyclopropanecarboxylic acid benzyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.22 (m, 2H), 1.86 (dd, J=9.0, 4.6 Hz, 1H), 1.72 (m, 1H), 1.45–1.57 (m, 4H), 1.42 (dd, J=8.3, 4.6 Hz, 1H), 1.14 (m, 1H), 0.93 (m, 6H). 13C NMR δ 168.21, 135.12, 128.88, 128.73, 128.16, 117.77, 68.25, 42.41, 36.72, 26.18, 25.97, 25.20, 19.33, 11.19, 10.84. LRMS: m/z 272.1 (M+1). IR (neat) 2245, 1734 cm−1. Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.44; H, 7.83; N, 5.22.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>COCCOC>[C:13]1([NH:12][C:10](=[O:11])[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:7]([OH:9])=[O:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: Nc1ccccc1
Solvent: COCCOC
Product: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
Cis-4-cyclohexene-1,2-dicarboxylic anhydride (7.6 g., 0.05 mole) was dissolved in 150 ml. 1,2-dimethoxyethane and 4.7 g. aniline (0.05 mole) was added. The reaction mixture was heated to reflux for one hour and allowed to stand overnight. The solvent was evaporated. The product then obtained was purified by pouring into 200 ml. of 10% hydrochloric acid solution. This was extracted with diethyl ether, dried over anhydrous magnesium sulfate, filtered and the solvent stripped off. There was obtained 7.3 g. of the title compound. The structure was confirmed by infrared analysis and n.m.r.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[C:3]=12
Reactant: CC(C)(O)CCBr
Reactant: Ic1ccnc2c[nH]nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)CCn1ncc2nccc(I)c21
Temperature: 120 °C

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (357 mg, 1.457 mmol), 4-bromo-2-methylbutan-2-ol (243 mg, 1.457 mmol) and Cs2CO3 (475 mg, 1.457 mmol) were combined in DMF (5 mL) and heated in a microwave at 120° C. for 40 minutes. The reaction was then cooled, filtered, and concentrated to give a residue which was purified by silica chromatography eluted with a step gradient of EtOAc in hexanes to give 4-(7-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)-2-methylbutan-2-ol which was dried and used immediately.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:7]=[CH:6][S:5][C:4]1=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:9]#[N:10].[CH2:18]([S:21](Cl)(=[O:23])=[O:22])[CH2:19][CH3:20].C(N(CC)CC)C.O>O1CCCC1.ClCCl>[CH2:18]([S:21]([O:1][N:2]=[C:3]1[CH:7]=[CH:6][S:5][C:4]1=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:9]#[N:10])(=[O:23])=[O:22])[CH2:19][CH3:20]
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1ccccc1C(C#N)=C1SC=CC1=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCS(=O)(=O)ON=C1C=CSC1=C(C#N)c1ccccc1C
Reaction time: 1 h
Yield: 70 %

Procedure:
In 490 g of tetrahydrofuran were dissolved 45 g (0.19 mol) of (3-(hydroxy)imino-3H-thiophen-2-ylidene)-(2-methylphenyl)-acetonitrile in Synthesis Example 1 and 27.0 g (0.19 mol) of commercially available propanesulfonyl chloride. To the solution cooled, 20.6 g (0.20 mol) of triethylamine was added dropwise such that the temperature might not exceed 10° C. The solution was allowed to ripen for 1 hour at room temperature, after which 150 g of water and 500 g of dichloromethane were added. The organic layer was separated, and washed with 150 g of water three times. The organic layer was concentrated in vacuum. Methanol was added to the concentrate for recrystallization, followed by filtration and drying. There were obtained crude yellow crystals. The crude yellow crystals were purified by silica gel column chromatography (eluent, dichloromethane). The elute was concentrated, followed by recrystallization from methanol, filtration and drying. There was obtained 77 g of yellow crystals (yield 70%).
Reaction SMILES: Br[C:2]1[S:27][C:5]2=[N:6][C:7]([CH3:26])=[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[CH:3]=1.O(C([N:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1)=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([CH3:26])[N:6]=[C:5]3[S:27][C:2]([C:38]4[CH:39]=[N:35][NH:36][CH:37]=4)=[CH:3][C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 110 °C

Procedure:
A mixture of ethyl 2-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 72) (402 mg, 0.82 mmol), 1-tert-butoxylcarbonyl-1H-pyrazole-4-boronic acid, pinacol ester (483 mg, 1.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (47.4 mg, 0.041 mmol) and potassium carbonate (340 mg, 2.46 mmol) in 1,4-dioxane (3 mL), DMF (1.5 mL) and water (0.75 mL) was heated at 110° C. for ca. 2 h. After cooling to RT, the reaction mixture was filtered through celite and the filtrate was concentrated. Purification by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in DCM, afforded the title compound (355 mg). LCMS (A) m/z: 477 [M+1]+, Rt 1.18 min (acidic).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].O>CN(C)C=O>[C:15]1(=[O:25])[N:19]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: CC(=O)c1ccc(OCCCBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
p-(3-Bromopropoxy)acetophenone (5.14 g.) and potassium phthalimide (3.75 g.) were dissolved in anhydrous N,N-dimethylformamide (50 ml.), and the solution was stirred at 70° C. for 2.5 hours. After the reaction mixture was allowed to cool, water (300 ml.) was poured thereto. The aqueous solution was extracted three times with ethyl acetate, and the extract was washed with ethyl acetate and then dried over magnesium sulfate. The ethyl acetate was removed by evaporation from the solution under reduced pressure, and the resultant residue was treated with ether to give p-(3-phthalimidopropoxy)acetophenone (5.75 g.).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]2([C:40]([F:43])([F:42])[F:41])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][N:25]4C(=O)C5C(=CC=CC=5)C4=O)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.NN>C(O)C>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([C:13]2([C:40]([F:41])([F:42])[F:43])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][NH2:25])=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 96.6 %

Procedure:
2-{[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoro-methyl)pyridin-3-yl]methyl}-1H-isoindole-1,3(2H)-dione (0.31 g) and hydrazine hydrate (0.035 ml) were added to ethanol (5 ml), and heated at 80° C. for 5 hours. The solvent was distilled off under reduced pressure, and then t-butyl methyl ether was added. The undissolved matters were removed by filtration, and the target compound (0.24 g) was obtained after concentration under reduced pressure.