Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]=[CH:8][N:9]3[C:14]([S:15][CH3:16])=[N:13][N:12]=[C:10]3[CH2:11][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]=[CH:8][N:9]3[C:14]([S:15]([CH3:16])=[O:27])=[N:13][N:12]=[C:10]3[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Cc1nnc(SC)n1C=C2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc2c(c1)Cc1nnc(S(C)=O)n1C=C2

Procedure:
By a procedure similar to that described in Example 17, 9-methoxy-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine was reacted with m-chloroperbenzoic acid to obtain 9-methoxy-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from methanol), m.p. 176°-177° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([Cl:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of 1-(4-nitro-phenyl)-cyclopentanecarboxylic acid (8.85 g) in dry dichloromethane (100 mL) was treated with oxalyl chloride (5.0 mL) and catalytic amount dry dimethylformamide (5 drops). The mixture was stirred at room temperature, under anhydrous conditions, for 16 hours then evaporated to give the title compound as an off white solid (100%), which was used without further purification.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3][CH2:2]1.Cl[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>O>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[NH:7][C@H:4]1[CH2:5][CH2:6][C@H:1]([NH2:8])[CH2:2][CH2:3]1
Reactant: Clc1ncccn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: N[C@H]1CC[C@H](Nc2ncccn2)CC1
Temperature: 160 °C

Procedure:
A stirred mixture of trans-1,4-cyclohexanediamine (1.50 g, 13.1 mmol) and 2-chloropyrimidine (500 mg, 4.37 mmol) was heated at 160° C. for 2 h then cooled to RT. The mixture was diluted with water, filtered, and the aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to afford 22A (235 mg, 28%). MS (ES): m/z=193 [M+H]+.
Reaction SMILES: BrC1C=CC(Br)=CC=1C1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)=[N:12][N:13]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33]([NH:13][NH:12][C:11](=[O:10])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1)=[O:34]
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)ccc3Br)o2)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)cc(Cl)c2)cc1
Yield: 60 %

Procedure:
By the general method for the synthesis of 2-(2,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (1) in Example 3, the reaction of 3,5-dichlorobenzoyl chloride (20.0 g, 0.010 mole) with 4-octoxybenzoyl hydrazide (25.24 g, 0.010 mole) gave the intermediate 3,5-dichloro-N′-[4-(octyloxy)benzoyl]benzohydrazide (25 g, 60% yield). Cyclocondensation of the intermediate 3,5-dichloro-N′-[4-(octyloxy)benzoyl]-benzohydrazide (16.0 g) with POCl3 (83 mL) gave the required 2-(3,5-dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (4) (11.16 g, 73% yield).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=O)C.[OH-].[Li+].Cl>C1COCC1.O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[CH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C(=Cc2ccc(C)cc2)C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C=C(C(=O)O)c2ccc(O)cc2)cc1
Yield: 82.4 %

Procedure:
To a solution of compound 37 (20.16 g, 68.1 mmol) in 100 mL THF was added a solution of lithium hydroxide (5.7 g, 237.5 mmol) in 100 mL water. The reaction was allowed to stir at room temperature for 16 h after which 5% HCl in water was added to pH=1. The yellow solid was filtered and recrystallized out of toluene, washed with hexane and dried under vacuum to yield a white solid (14.27 g, 82.5%). 1H NMR (400 MHz, DMSO-d6) δ 12.46 (br s, 1H), 9.47 (br s, 1H), 7.63 (s, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 2.22 (s, 3H).
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:5].[F:31][C:32]([F:43])([F:42])C1C=CC(C(Cl)=O)=CC=1>>[F:31][C:32]([F:43])([F:42])[C:29]1[CH:30]=[CH:2][C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:5])=[CH:27][CH:28]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccccc1F
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccc(C(F)(F)F)cc1
Yield: 74 %

Procedure:
According to the method used for synthesis of the compound 28a, the titled compound (592 mg) is synthesized by using tert-butyl((2-trimethylstannylphenyl)-(2-(3-m-tolylureido)acethyl)amino)acetate (1.0 g) and 4-trifluoromethylbenzoylchloride (364 mg). Yield 74%.
Reaction SMILES: [I:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][NH:7][C:8](=[O:40])[C@@H:9]([NH:16][C:17](=[O:39])[C@@H:18]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([S:35](=[O:38])(=[O:37])[NH2:36])=[CH:31][CH:30]=2)=[S:27])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[C:12]([CH2:11][CH2:10][C@H:9]([NH:16][C:17](=[O:39])[C@@H:18]([NH:25][C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([S:35](=[O:37])(=[O:38])[NH2:36])=[CH:33][CH:34]=1)=[S:27])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:42][CH:41]=1)=[O:40])([OH:14])=[O:13]
Reactant: COC(=O)CC[C@H](NC(=O)[C@H](CCC(=O)OC)NC(=S)Nc1ccc(S(N)(=O)=O)cc1)C(=O)NCc1ccc(I)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NS(=O)(=O)c1ccc(NC(=S)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)NCc2ccc(I)cc2)cc1
Yield: 25.9 %

Procedure:
A solution of (S)-methyl 5-(4-iodobenzylamino)-4-((S)-5-methoxy-5-oxo-2-(3-(4-sulfamoylphenyl)thioureido)pentanamido)-5-oxopentanoate (0.200 g, 0.27 mmol) and lithium hydroxide (48 mg) in methanol (3.0 mL) and water (1.0 mL) was stirred at room temperature for overnight. The reaction mixture was purified by HPLC to give the title product (49.4 mg) as a yellow solid. MS (ESI), 728 (M+Na)+.
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([O:19][CH3:20])[CH:9]=2)([CH3:3])[CH3:2].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:6]2[C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:29])=[N:14][C:13]3[C:8](=[CH:9][C:10]([O:19][CH3:20])=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=3)[N:7]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(OS(=O)(=O)C(F)(F)F)nc2cc1OC
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1OC
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-7-methoxy-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (2.5 g, crude) in dioxane (5.0 mL) and water (3 drops) was added (4-fluorophenyl)boronic acid (2.40 g, 17.15 mmol), Pd(PPh3)4 (320 mg, 0.28 mmol), and K3PO4 (3.58 g, 16.87 mmol) with stirring for 1.5 h at 95° C. under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-(isopropyl(methyl)amino)-7-methoxyquinoxaline-6-carboxylate as a light yellow solid (0.9 g, 36% 2 steps).
Reaction SMILES: C(C1C[C:9](C#N)([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:12]=2)CCC1=O)(OC)=O.[H-].[Na+].C(C(C1C=CC(OC(F)F)=C(OCC2CC2)C=1)(CCC(OC)=O)CCC(OC)=[O:37])#N>COCCOC>[CH:23]1([CH2:22][O:21][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=2[O:17][CH:18]([F:20])[F:19])[CH:9]=[O:37])[CH2:25][CH2:24]1
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC(F)F)c(OCC3CC3)c2)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 60 °C

Procedure:
2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one To a suspension of sodium hydride (80% dispersion in mineral oil, 11.6 g, 388 mmol) in dry 1,2-dimethoxyethane (700 mL) under an argon atmosphere was added a solution of crude dimethyl 4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pimelate (41 g) in dry 1,2-dimethoxyethane (700 mL). The resulting mixture was heated at 60° C. for 1 h, cooled to room temperature, quenched with dilute aqueous hydrochloric acid and concentrated The residue was diluted with water, was acidified to pH 3 and was extracted twice with methylene chloride. The organic extract was washed with acidic water, was dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with methylene chloride, followed by trituration with cold ether provided a solid (17.7 g, 43% from 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde): m.p. 115°-116° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[O:10])[CH:2]=1.[BH4-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)[OH:10])[CH:2]=1
Reactant: O=C(CCc1cccnc1)c1ccc2c(c1)CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCc1cccnc1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a solution of [2-(3-pyridyl)ethyl]-(5,6,7,8-tetrahydronaphthalen-2-yl)ketone (3.02 g) in MeOH (50 ml) was added NaBH4 (0.45 g) and the mixture was stirred at room temperature for 30 minutes. After removal of the solvent, the residue was extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated to give the titled compound (1.56 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH3:21])[N:17]=[C:16]([NH2:18])[C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:10](=[O:20])(=[O:19])[CH2:9]1.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:27]([O-:29])=[O:28])=[CH:4][C:3]=1[C@@:8]1([CH3:21])[N:17]=[C:16]([NH2:18])[C:11]2([CH2:12][CH2:13][CH2:14][CH2:15]2)[S:10](=[O:20])(=[O:19])[CH2:9]1
Reactant: C[C@@]1(c2ccccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
(R)-8-(2-Fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (172 mg, 554 μmol, Eq: 1.00) was dissolved in conc. sulfuric acid (2.72 g, 1.48 ml, 27.7 mmol, Eq: 50), then at 0° C. fuming nitric acid (52.4 mg, 37.1 μl, 831 μmol, Eq: 1.5) was added dropwise. The light brown solution was stirred at 0° C. for 2 hours. The reaction mixture was poured on ice and basified with 3 N NaOH followed by extraction with dichloromethane. The organic layer was separated, dried over Na2SO4, filtered and evaporated to dryness to give the crude and pure (R)-8-(2-fluoro-5-nitro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (210 mg, 591 μmol, 107% yield) as an off-white foam. MS (ISP): m/z=356.5 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)n1c(=O)n(CCC(=O)OC)c2ccccc21
Temperature: 25 °C
Yield: 64.3 %

Procedure:
To a stirred solution of 1-Isopropenyl-1,3-dihydro-benzimidazol-2-one (5 g, 28.7 mmol) in DMF (20 ml) was added methyl acrylate (2.8 ml, 31.6 mmol) followed by benzyltrimethylammonium hydroxide (Triton B, 40 wt % in MeOH, 3.2 ml). The resulting solution was stirred at ambient temperature until the reaction was complete. After this time the reaction was poured into water and ethyl acetate. The layers were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 30% ethyl acetate/hexanes). The product-containing fractions were combined and concentrated to give 4.8 g (64%) of the desired product.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH2:8][O:9][C:10](/[CH:12]=[CH:13]/[CH2:14]P(OCC)(OCC)=O)=[O:11].[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=O.Cl>O1CCCC1.O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]([CH3:23])=[CH:14][CH:13]=[CH:12][C:10]([O:9][CH2:8][CH3:7])=[O:11])=[CH:27][CH:28]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=C(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A stirred solution of 25.3 grams (0.230 mole) of potassium tert.-butoxide in 250 mL of tetrahydrofuran was cooled to 0 ° C., and a solution of 56.5 grams (0.230 mole) triethyl 4-phosphonocrotonate in 50 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature at about 0°-10 ° C. The complete addition required about 30 minutes. The reaction mixture was then stirred for one hour at 0°-5° C., and then 26.6 grams (0.180 mole) of 4-methoxyacetophenone was added in one portion. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was made acidic with an aqueous 2N hydrochloric acid solution and diluted with about 200 mL of water. The mixture was extracted with two 250 mL portions of diethyl ether. The combined extracts were washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was taken up in 150 grams of silica gel, and the solvent was removed under reduced pressure. The silica gel mixture was placed on top of a column of silica gel, and the mixture was eluted with 10% ethyl acetate in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.9 grams of ethyl 5-(4-methoxyphenyl)-2,4-hexadienoate. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[OH:14][C:11]1([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
A solution the compound prepared in Example 250 (0.68 g) in ethanol (11 mL) was treated with hydrazine monohydrate (0.208 mL), followed by 10% palladium-carbon (0.238 g). The mixture was refluxed for 18 hours. After allowing mixture to cool to room temperature, the catalyst was filtered off and washed with methanol. The filtrate was evaporated in vacuo to obtain the title compound (0.510 g) having the following physical data.
Reaction SMILES: [OH-].[K+].[N:3]#[C:4][NH2:5].[F:6][C:7]([F:28])([F:27])[C:8]1[CH:26]=[CH:25][C:11]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.Cl>O.CC(C)=O>[C:4]([NH:5][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]2[CH:25]=[CH:26][C:8]([C:7]([F:28])([F:6])[F:27])=[CH:9][CH:10]=2)=[CH:24][CH:23]=1)[CH3:22])#[N:3]
Reactant: N#CN
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)NC#N
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
10.4 g (0.1575 mole) of 85% potassium hydroxide are dissolved in 75 ml of water. 3.5 g (0.0825 mole) of cyanamide are added at 20° C. and the clear, colourless solution is cooled to 10° C. Then a solution of 25.8 g (0.075 mole) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride in 15 ml of acetone is added dropwise such that the temperature does not exceed 15° C. After the reaction mixture has been stirred for 45 minutes at this temperature, 9 g (0,09 mole) of 37% aqueous hydrochloric acid are added dropwise at 5° C. The product precipitates as an oil which crystallises on standing over 30 minutes. The colourless crystals are isolated by filtration, washed with water, dried over phosphorous pentoxide, affording 24.9 g (95.0% of theory) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid N-cyanamide with a melting point of 125°-127° C.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH2:4][F:5].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:19][C:14]2[C:15]([O:17][CH3:18])=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(C(CF)CF)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(C(CF)CF)CC2

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (140 mg, 66%). LCMS (m/e) 573 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.96 (s, 1H), 7.32 (s, 1H), 6.67 (s, 1H), 5.34 (d, 1H, J=7.3 Hz), 5.24 (d, 1H, J=7.0 Hz), 4.77-4.64 (m, 2H), 4.64-4.52 (m, 2H), 4.03-3.93 (m, 1H), 3.89 (s, 3H), 3.31-3.10 (m, 2H), 2.97-2.82 (m, 8H), 2.80 (s, 3H), 2.31-2.16 (m, 2H), 1.92-1.78 (m, 2H), 1.50-1.32 (m, 4H).
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]([C:11]1[C:12]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[N:13][N:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23]([OH:25])=[O:24])=[C:16]([F:30])[C:15]=12)=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:16]1[C:15]2[N:14]([N:13]=[C:12]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:11]=2[C:9](=[O:10])[NH:8][CH3:6])[CH:19]=[CH:18][C:17]=1[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: Cc1ccc(C(=O)O)cc1-c1ccn2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12

Procedure:
To a solution containing 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.070 g, 0.13 mmol) and dichloromethane (8.0 mL) was added TFA (0.84 mL, 10.9 mmol) at room temperature. The solution was maintained for 15 min and concentrated to dryness to afford 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as an off white solid which was used without further purification. LCMS retention time: 1.825 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 444 (MNa+).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[O:16][C:17]([CH:20]=O)=[CH:18][CH:19]=4)[CH:11]=[C:10]([C:22]([NH:24][CH2:25][C:26]4[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37].CCN(C(C)C)C(C)C.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[O:16][C:17]([CH2:20][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:19]=4)[CH:11]=[C:10]([C:22]([NH:24][CH2:25][C:26]4[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)o3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CS(=O)(=O)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CNCCS(C)(=O)=O)o3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reaction time: 3 h

Procedure:
To a stirred solution 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-methyl)-6-(5-formylfuran-2yl)-1H-indazole-4-carboxamide (0.09 g, 0.19 mmol) in methanol (2 mL), 2-(methylsulfonyl)ethanamine (0.072 g, 0.581 mmol) and DIPEA (0.05 g, 0.39 mmol) was added at room temperature and reaction stirred for 3 h. Then NaBH3CN (0.012 g, 0.196 mmol) was added and reaction stirred at room temperature for 18 h. On completion, methanol was removed under reduced pressure and then water was added to the residue. The aqueous phase was extracted with 10% MeOH/DCM and the combined organic layers were dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)-1H-indazole-4-carboxamide. LCMS: 566.90 (M+1)+; HPLC: 90.05% (@ 254 nm) (Rt; 5.253); 1H NMR (MeOD, 400 MHz) δ 8.31 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 6.92 (s, 1H), 6.44 (s, 1H), 6.13 (s, 1H), 5.18-5.42 (m, 1H), 4.59 (s, 2H), 4.57 (s, 2H), 3.91 (s, 2H), 3.16 (t, 2H, J=6.4 Hz), 3.02 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 2.19-2.23 (m, 2H), 2.11-2.14 (m, 2H), 1.98 (m, 2H), 1.80 (m, 2H).