Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].C([O-])(O)=O.[Na+].[C:21](=O)([O:30]N1C(=O)CCC1=O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:11][C:12]([NH:15][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:13])[CH3:14]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)COc1cccc(N)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a solution of 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile (Example Dd, 30.5 g, 148.6 mmol) in THF/H2O (1:1, 400 mL) was added NaHCO3 (24.7 g, 294 mmol), followed by benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (44.0 g, 176 mmol) at room temperature. The reaction was stirred at room temperature for 4 h then the organic layer was separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine and dried over MgSO4. After filtration, the solvent was evaporated and the crude oil was purified by chromatography on silica gel (eluent: 0-60% EtOAc in hexane) to give the title compound as yellow oil (44.8 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 6H), 4.02 (s, 2H), 4.96 (s, 2H), 5.98 (s, 2H), 6.14 (d, J=8.0 Hz, 1H), 6.32 (dd, J=0.8, 8.4 Hz, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.38-7.21 (m, 6H). MS 340 (MH+).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1([C:27]#[N:28])[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:26][C:22]1[CH:21]=[C:20]([S:17]([N:14]2[CH2:13][CH2:12][C:11]([NH:10][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])([C:27]#[N:28])[CH2:16][CH2:15]2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N#CC1(N)CCN(S(=O)(=O)c2cccc(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#CC1(NC(=O)C2CCCCC2)CCN(S(=O)(=O)c2cccc(Cl)c2)CC1
Reaction time: 2.5 h

Procedure:
A solution of cyclohexanecarbonyl chloride (118 μL, 0.880 mmol) in chloroform (0.25 mL) was added to a mixed solution of 4-amino-1-(3-chloro-benzenesulfonyl)-piperidine-4-carbonitrile (120 mg, 0.400 mmol) in chloroform (1.25 mL) and a saturated aqueous sodium carbonate solution (1.25 mL), and the mixture was vigorously stirred at room temperature for 16 hours. Cyclohexanecarbonyl chloride (51 μL) was further added and the mixture was stirred for 2.5 hours. The organic layer and the aqueous layer were then separated, and the aqueous layer was further extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was washed with n-hexane to give cyclohexanecarboxylic[1-(3-chloro-benzenesulfonyl)-4-cyano-piperidin-4-yl]-amide as a white solid. This was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:4][CH:3]=1.C(Cl)Cl.[S:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2.Cl>N1C=CC=CC=1>[F:1][C:2]1[C:7]([NH:8][C:27]([C:26]2[S:22][C:23]3[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=3[CH:25]=2)=[O:28])=[C:6]([CH3:9])[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:4][CH:3]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1N
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A 200-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.45 g, 13.7 mmol), methylene chloride (85 mL), and pyridine (3 mL) and cooled to 0° C. To the resulting solution, benzo[b]thiophene-2-carbonyl chloride (2.7 g, 13.7 mmol) was. The reaction was warmed to room temperature and stirred for 1 h. After this time, aqueous HCl (1M, 50 mL) was added to the reaction. The separated aqueous layer was extracted with dichloromethane (2×25 mL). The combined organics were washed with aqueous HCl (1M, 2×50 mL), water (1×50 mL) and brine (50 mL), dried over sodium sulfate; filtered and concentrated under reduced pressure. The resulting crude white solid (5.6 g, 99% yield) was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[CH3:47][N:48]=[C:49]=[O:50]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][C:49]([NH:48][CH3:47])=[O:50])=[C:3]([CH3:39])[CH:4]=2)=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: CN=C=O
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added methyl isocyanate (0.023 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature and for 2 hours at ambient temperature. Methyl isocyanate (0.03 ml) was further added thereto, and the mixture was stirred overnight at ambient temperature. The mixture was partitioned between dichloromethane and water, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[3-methyl-4-(N'-methylureido)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline (150 mg) as an amorphous powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[S:8]1[CH2:14][C:12](=[O:13])[NH:11][C:9]1=S.CCN(C(C)C)C(C)C>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:9]1[S:8][CH2:14][C:12](=[O:13])[N:11]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCc1cccs1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2cccs2)=N1

Procedure:
Similar procedure as described in example 15a was used, starting with thiophen-2-ylmethyl-amine, rhodanine, mercuric chloride and DIEA to give 2-(thiophen-2-ylmethyl-amino)-thiazol-4-one. LC-MS m/e 259 (MH+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[Cl:17])=[C:4]([CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[O:21][C:20]2=[O:39])[CH:3]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:48]>ClCCl>[F:37][C:35]([F:36])([F:38])[C:27]1[CH:26]=[C:25]([C@H:22]2[O:21][C:20](=[O:39])[N:19]([CH2:18][C:4]3[CH:3]=[C:2]([Br:48])[CH:7]=[CH:6][C:5]=3[C:8]3[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=3[Cl:17])[C@H:23]2[CH3:24])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=1
Reactant: BrC(Br)Br
Reactant: CC(C)c1ccc(Cl)c(-c2ccc(N)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CC(C)c1ccc(Cl)c(-c2ccc(Br)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-3-[(4-amino-2′-chloro-5′-isopropylbiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (100 mg, 0.175 mmol) in bromoform (0.5 mL) and dichloromethane (1 mL) was added t-butyl nitrite (23 μL, d=0.867, 90% pure, 0.193 mmol). The resulting mixture was stirred at 50° C. for 1 h. An aliquot indicated completion of the reaction. The reaction crude was deposited on 2 prep-TLC plates eluted by dichloromethane to afford the title compound. LC-MS: 635.80 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 6:4 mixture of rotamers δ 7.84-7.88 (m, 1H), 7.67-7.74 (m, 2 H), 7.60-7.63 (m, 1 H), 7.51-7.57 (m, 1 H), 7.38-7.42 (m, 1 H), 7.19-7.23 (m, 1 H), 7.11-7.16 (m, 1 H), 7.09 (d, J=2.3 Hz, 0.6 H), 7.03 (d, J=2.3 Hz, 0.4 H), 5.66 (d, J=8.0 Hz, 0.4 H), 5.55 (d, J=8.0 Hz, 0.6 H), 4.86 (d, J=15.6 Hz, 0.6H), 4.70 (d, J=15.6 Hz, 0.4H), 3.77-4.00 (m, 2 H), 2.87-2.95 (m, 1 H), 1.20-1.28 (m, 6 H), 0.53 (d, J=6.6 Hz, 1.2H), 0.45 (d, J=6.4 Hz, 1.8 H).
Reaction SMILES: CSC.B.[C:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])(O)=[O:6]>C1COCC1>[Cl:18][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:5][OH:6])=[CH:17][C:13]=1[CH2:14][OH:15]
Reactant: O=C(O)Cc1ccc(Cl)c(C(=O)O)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of borane dimethyl sulfide complex (2M in THF, 6.50 mL) was added portionwise over 5 minutes to a solution of 5-(carboxymethyl)-2-chlorobenzoic acid [Aromatic Intermediate 7, step b] (1.37 g) in dry THF (20 mL) at room temperature. The resulting effervescing solution was stirred at room temperature for 1.5 hours, then heated to reflux for 1 hour. The cooled mixture was quenched by the portionwise addition of methanol (5 mL) over 5 minutes. The solution was stirred at room temperature for 2 hours and then purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a colourless oil. Yield 0.933 g.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:30])=[C:27]([CH:29]=1)[NH2:28]>>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:28][C:27]3[CH:29]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=3[CH3:30])=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(Cl)cc1N
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Product: Cc1ccc(Cl)cc1Nc1ncc(C(=O)NCC2CCCCC2)c(C(F)(F)F)n1
Yield: 54.3 %

Procedure:
In a manner similar to Example 243, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-ioxan (1 ml) and 5-chloro-2-methyl aniline (Aldrich) (110 mg) were reacted to give the title compound (36 mg)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>C(O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[NH:6][C:5]3=[O:12])=[CH:22][CH:21]=1
Reactant: O=C1NC(=O)c2cc(O)ccc21
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1NC(=O)c2cc(OCc3ccc(F)cc3)ccc21
Temperature: 80 °C
Yield: 46.8 %

Procedure:
A mixture of 5-hydroxy-isoindole-1,3-dione (200 mg, 1.0 mmol), potassium carbonate (178 mg, 1.05 mmol), 4-fluorobenzylbromide (204 mg, 1.05 mmol) in ethanol (5 mL) was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was filtered and evaporated. The residue was purified by chromatography (SiO2, heptane-CH2Cl2 2:3 then CH2Cl2— 2N NH3-MeOH 99:1: to 95:5) to afford the title compound (127 mg, 38%) as an off-white solid. MS: m/e=271.1 (M+).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S:14]([NH:17][CH2:18][CH3:19])(=[O:16])=[O:15])[N:11]([CH2:20][CH3:21])[C:10]=2[CH:22]=1)([O-:5])=[O:4].[CH2:23](Br)[CH3:24].O>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S:14]([N:17]([CH2:23][CH3:24])[CH2:18][CH3:19])(=[O:16])=[O:15])[N:11]([CH2:20][CH3:21])[C:10]=2[CH:22]=1)([O-:5])=[O:4]
Reactant: CCNS(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2n1CC
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)S(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2n1CC
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
2.6 g (0.11 mol) of sodium hydride are added to a solution of 29.8 g (0.1 mol) of 6-nitro-1,N-diethyl-1H-benzimidazole-2-sulfonamide in 100 ml of dimethylformamide. The solution is stirred for one hour at 40° C., 10.8 g (0.1 mol) of ethyl bromide are added and the mixture is stirred for 12 hours at 50° C. It is poured into water and the product is filtered off and washed with water. The precipitate is recrystallized from ethanol to give 25.6 g (78%) of 6-nitro-1,N,N-triethyl-1H-benzimidazole-2-sulfonamide melting at 90°-1° C.
Reaction SMILES: C([NH:9][CH:10]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1)[C:11]([OH:13])=[O:12])(=O)C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[NH2:9][CH:10]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(NC(C(=O)O)c1ccc2c(c1)CCO2)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NC(C(=O)O)c1ccc2c(c1)CCO2
Yield: 60 %

Procedure:
The α-benzamido(2,3-dihydro-5-benzofuranyl)acetic acid (100 mg) is dissolved in 20 ml of methanol and 40 ml of water. Then 20 mg of a palladium on carbon catalyst is added and the mixture subjected to hydrogen pressure of 10 to 40 pounds/in2 for 4 hours. The mixture is filtered to remove the solid and the methanol is evaporated to give the title compound in about 60% yield. NMR(DMSO-D6)ppm(δ)7.95(s,1);6.7(m,3); 4.8(s,1);4.42(t,2);2.95(t,2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CN=C1[C:24](C1NC=CN=1)=[O:25]>C1COCC1>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:24]1=[O:25]
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COC(=O)c1cccc2[nH]c(=O)n(CC(OC)OC)c12
Yield: 59.5 %

Procedure:
The solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (0.7 g, 2.4 mmol) from Step C of Example 13 in THF (23 mL) with di(1H-imidazol-2-yl)methanone (0.4 g, 2.6 mmol) was refluxed overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude material which was purified by column chromatography (silica gel, 0% to 100% ethyl acetate in hexanes) to afford methyl 3-(2,2-dimethoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.4 g, 60%): 1H NMR (300 MHz, DMSO-d6) δ 11.29 (s, 1H), 7.30 (dd, J=7.8, 1.2 Hz, 1H), 7.17 (dd, J=7.8, 1.5 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 4.31 (t, J=5.4 Hz, 1H), 4.23-4.22 (m, 2H), 3.85 (s, 3H), 3.18 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2].[C-]#[N:21].[Na+]>CN(C)C=O>[C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[N:21])=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CCCc1c(OCCCCBr)ccc(C(C)=O)c1O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC#N)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
A solution of 30.0 g. (91.1 mmoles) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl bromide and 4.91 g. (100.2 mmoles) of sodium cyanide in 225 ml. of dimethylformamide was heated to 75°-85° C. for about 17 hours. The reaction mixture was cooled to room temperature, filtered, and evaporated in vacuo at 75° C. Cold 0.1N hydrochloric acid was added to the residue, and the residue was extracted into ethyl acetate. The ethyl acetate layer was twice washed with 0.1N hydrochloric acid, dried over sodium sulfate, and evaporated in vacuo to yield 21.02 g. of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butane nitrile as a dark amber oil which crystallized as it cooled.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]Br>CC(O)=O>[Br:11][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH2:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1Br
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 4-nitro-phenylamine (50 g, 0.36 mol) in AcOH (500 mL) was added Br2 (60 g, 0.38 mol) dropwise at 5° C. The mixture was stirred for 30 min at that temperature. The insoluble solid was collected by filtration and basified with saturated aqueous NaHCO3 to pH 7. The aqueous phase was extracted with EtOAc (300 mL×3). The combined organic layers were dried and evaporated under reduced pressure to obtain compound 2-bromo-4-nitroaniline (56 g, 72%), which was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:12]([CH3:22])[C:13](=[O:21])[CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH3:20])=[O:18].[Br:23]N1C(=O)CCC1=O>>[Br:23][C:14]1[C:13](=[O:21])[N:12]([CH3:22])[C:11]([NH:10][C:3]2[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(SC)cc1F
Product: COC(=O)c1cc(Br)c(=O)n(C)c1Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of methyl 2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate was added N-bromosuccinimide. The reaction mixture was stirred at room temperature for 25 minutes and then quenched with saturated sodium bisulfite. The reaction mixture was diluted with H2O and partitioned between EtOAc/diethyl ether and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave methyl 5-bromo-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25].[Cl-].[NH4+]>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][C:22](=[O:26])[O:23][CH2:24][CH3:25])[CH:8]=1
Reactant: COc1ccc(C2=Cc3ccc(OC)cc3CC2)c(N)c1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1cc(OC)ccc1C1=Cc2ccc(OC)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenylamine (400 mg) in tetrahydrofuran (10 ml) and N,N-diisopropylethylamine (0.5 ml) was added ethyl chlorocarbonate (0.2 ml) on an ice bath, and the solution was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added thereto, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide ethyl [5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenyl]carbamate (445 mg). This compound (438 mg) was used according to an analogous synthetic method to Example 337 described below to provide the title compound (286 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH:44][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nn1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)nn3)nc2n1C1CCCC1
Yield: 58 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (98 mg, 0.336 mmol), was combined with 3-(6-amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (112 mg, 0.336 mmol) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7 H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (115 mg, 0.195 mmol) in 58% yield. MS m/z 590.6 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:34]([O:36]CC)=[O:35])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[C:14]3[C:15]([CH3:18])=[N:16][NH:17][C:13]=3[N:12]3[N:19]=[CH:20][C:21]([C:22]4[CH:23]=[N:24][C:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:26][CH:27]=4)=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.C1COCC1.O[Li].O.Cl>O>[CH3:1][C:2]1([C:34]([OH:36])=[O:35])[CH2:3][CH2:4][CH:5]([CH2:8][C:9]2[C:14]3[C:15]([CH3:18])=[N:16][NH:17][C:13]=3[N:12]3[N:19]=[CH:20][C:21]([C:22]4[CH:23]=[N:24][C:25]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:26][CH:27]=4)=[C:11]3[N:10]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(C)CCC(Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]nc(C)c23)CC1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1n[nH]c2c1c(CC1CCC(C)(C(=O)O)CC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 80 °C
Reaction time: 96 h

Procedure:
To a 20 mL scintillation vial was charged ethyl 1-methyl-4-((3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)methyl)cyclohexanecarboxylate (Int-6c, 0.03 mmol). To this residue was added 2:1 THF:H2O (1.5 mL) and LiOH.H2O (20 mg). The resulting solution was stirred at 80° C. for 4 days. After 4 days, the reaction was brought to pH 3 with 1N HCl(aq). The reaction was reduced in vacuo and the residue was purified via reverse-phase preparatory HPLC to 1-methyl-4-((3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)methyl)cyclohexanecarboxylic acid (3). (M+H=481.27, retention time=4.01 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.C(OB([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)O)CCC>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:44]3[CH:43]=[CH:42][C:41]([CH:6]([CH2:7][CH3:8])[CH3:11])=[CH:46][CH:45]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: CCCCOB(O)c1ccccc1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: CCC(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.8 g, 3.3 mmol) was coupled with 4-sec butyl-phenyl boronic acid (750 mg, 4.0 mmol) according to general procedure G to give {-4-[2-(4′-sec-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.