Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([F:17])=[C:11]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=1)C1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([F:17])=[C:11]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=1
Reactant: CC(C)(C)Nc1nc(NCc2ccccc2)c(C#N)cc1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)Nc1nc(N)c(C#N)cc1F
Yield: 86 %

Procedure:
To 500 mg of 2-benzylamino-6-t-butylamino-3-cyano-5-fluoropyridine were added 3 ml acetic acid and 0.5 ml ethanol, and then, 10 microspatulas of palladium black, and the mixture was stirred under hydrogen atmosphere at 60° C. for 2 days. The catalyst was removed with a membrane filter, and the solvent of the filtrate was distilled off. To the residue was added chloroform, and the mixture was washed with aqueous solution of sodium hydrogencarbonate. The organic layer was collected, dried over magnesium sulfate. The solvent was distilled off to obtain 300 mg of the title compound.
Reaction SMILES: [CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]2[CH2:23]1.C1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[CH2:23][C:24]4[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=4[C:26]([OH:28])=[O:27])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1

Procedure:
A solution of 2.1 g of (E)-3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]benzeneamine, 1.25 g of homophthalic anhydride and 30 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 2.31 g of (E)-2-[2-[3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]phenyl=amino]-2-oxoethyl]benzoic acid; m.p. 189°-190° C. from tetrahydrofuran.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:39])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:35]4[CH2:38][CH2:37][CH2:36]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.Cl[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.[F-].[Cs+]>COCCOC.CCOC(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>[CH:1]1([CH:4]([O:6][C:7](=[O:39])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:35]4[CH2:38][CH2:37][CH2:36]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([C:41]3[N:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:2][CH2:3]1
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3n2C2CCC2)cc1)C1CC1
Reactant: Clc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(-c4ncccn4)cc3n2C2CCC2)cc1)C1CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
A mixture of {4-[3-cyano-1-cyclobutyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (0.2 g, 0.38 mmol), 2-chloropyrimidine (39 mg, 0.34 mg), Pd(PPh3)4 (22 mg, 0.095 mmol) and cesium fluoride (0.116 g, 0.76 mmol) in DME (2.0 mL) was stirred at 100° C. for 16 h. The mixture was then diluted with EtOAc (20 mL), washed with water and brine, dried over Na2SO4, concentrated and purified on silica gel (CH2Cl2/EtOAc) to provide [4-(3-cyano-1-cyclobutyl-6-pyrimidin-2-yl-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (0.15 g, 82%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].Cl.C(OCC)(=O)C>C(O)C.N1C=CC=CC=1>[OH:33][N:32]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24]
Reactant: O=C(c1ccccc1)c1ccccc1SSc1ccccc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccccc1SSc1ccccc1C(=NO)c1ccccc1
Yield: 35.9 %

Procedure:
The [2-(2-benzoyl-phenyldisulfanyl)-phenyl]-phenyl-methanone (0.55 g, 1.2 mmol) was diluted with ethanol (5 mL) and anhydrous pyridine (5 mL). Hydroxylamine hydrochloride (1 g, 14 mmol) was added and the solution was refluxed for 90 minutes. The solution was cooled and poured into cold aqueous HCl (1N). Ethyl acetate was added, the layers were separated, and the organic portion was washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated to dryness and the residue was triturated with 75% hexane/25% ethyl acetate to give the title compound (0.19 g, 32%) as a white solid, mp 191-193° C.;
Reaction SMILES: [SH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[OH-].[K+].O.Cl[C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=1>CC(C)=O>[CH3:24][O:23][C:17]1[N:18]=[C:19]([O:21][CH3:22])[N:20]=[C:15]([S:1][CH:2]([CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:5])=[O:4])[N:16]=1
Reactant: O=C(O)C(S)C1CCCC1
Reactant: COc1nc(Cl)nc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1nc(OC)nc(SC(C(=O)O)C2CCCC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.1 %

Procedure:
To a mixture solution of 6.0 g of 2-mercapto-2-cyclopentyl acetic acid, 4.2 g of potassium hydroxide and 50 ml of water, a solution of 30 ml of acetone and 6.6 g of 2-chloro-4,6-dimethoxy S-triazine was added at a temperature of from 0° to 5° C. for 20 mimutes. Then, the reaction mixture was stirred at room temperature for 1.5 hours. Acetone was removed by distillation under reduced pressure, and the residue was extracted with ethyl ether. The ethyl ether layer was removed, and the aqueous layer was adjsuted to pH 2 to 3 with a 5% hydrochloric acid aqueous solution and extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried. Then, ethyl acetate was removed by distillation under reduced pressure to obtain a white solid. The solid was recrystallized from isopropyl ether and n-hexane to obtain 4.5 g of the desired product.
Reaction SMILES: C(OC([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:41][C:42]2[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:28][CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[F:50][C:48]([F:49])([F:51])[C:46]1[CH:47]=[C:42]([CH:43]=[C:44]([C:52]([F:53])([F:54])[F:55])[CH:45]=1)[CH2:41][N:22]([C@@H:12]1[C:13]2=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=[C:21]2[NH:8][CH2:9][CH2:10][CH2:11]1)[C:23]1[N:24]=[N:25][N:26]([CH2:28][CH2:29][N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN3C(=O)c4ccccc4C3=O)n2)c2cc3c(cc21)COC3
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-9-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (Example 106, Step 1) (0.39 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL). After stirring at room temperature for 3 h, quench the reaction with concentrated sodium carbonate, dilute with dichloromethane (20 mL), and water (20 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (10-50%) to provide the title intermediate as a colorless foam. MS (ES+): 730 (M+59).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24]C(C)([O-])C.[K+].[C:30]([N:33]1[CH2:37][CH2:36][C:35]2([C:45]3[C:40](=[CH:41][CH:42]=[C:43](C=O)[CH:44]=3)[N:39]([C:48]([NH:50][C:51]3[S:52][C:53]([Cl:56])=[CH:54][N:55]=3)=[O:49])[CH2:38]2)[CH2:34]1)(=[O:32])[CH3:31].[Cl-].[NH4+]>O1CCCC1.O>[C:30]([N:33]1[CH2:37][CH2:36][C:35]2([C:45]3[C:40](=[CH:41][CH:42]=[C:43]([CH:24]=[CH:4][O:3][CH3:2])[CH:44]=3)[N:39]([C:48]([NH:50][C:51]3[S:52][C:53]([Cl:56])=[CH:54][N:55]=3)=[O:49])[CH2:38]2)[CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(C)(C)[O-]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(C=O)cc12
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)Nc1ncc(Cl)s1
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (0.63 g, 1.85 mmol) was dissolved in tetrahydrofuran (4 mL). Thereafter, potassium tert-butoxide (0.21 g, 1.85 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred for 10 minutes. Thereafter, a tetrahydrofuran solution (3 mL) of the 1′-acetyl-N-(5-chlorothiazol-2-yl)-5-formylspiro[indoline-3,3′-pyrrolidine]-1-carboxamide (100 mg, 0.247 mmol) obtained in Step 2 of Example 401 was added to the reaction solution, and the thus obtained mixture was then stirred at room temperature for 1 hour. Thereafter, a saturated aqueous solution of ammonium chloride and water were added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to obtain 1′-acetyl-N-(5-chlorothiazol-2-yl)-5-(2-methoxyvinyl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (83 mg, 78%) in the form of a yellow amorphous product.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=1)([CH3:5])[CH3:4].[H-].[Na+].F[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(O)(=O)C>[CH3:4][C:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=1)([CH3:5])[CH2:2][O:1][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)CO)ccn1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(C(C)(C)COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a stirred solution of the alcohol (59) (1.11 g, 4.17 mmol) in DMF (10.0 mL) at 0° C. under nitrogen was added sodium hydride (350 mg, 8.75 mmol) in a single portion. The mixture was warmed to RT for 30 min and was then sonicated, flushed with nitrogen and re-cooled to 0° C. A solution of 1-fluoro-4-nitronaphthalene (14) (797 mg, 4.17 mmol) in DMF (4.0 mL) was added over 5 min and the reaction mixture allowed to warm to RT and after 30 min glacial acetic acid (1.0 mL) was added. The reaction mixture was poured onto saturated aqueous NaHCO3 solution and extracted twice with EtOAc. The combined organic extracts were washed three times with water and with brine and then dried (MgSO4), and evaporated in vacuo. The residue was triturated from EtOAc and washed with ether (20 mL) to afford the title compound (60) as a yellow solid (1.23 g, 64%): m/z 438 (M+H)+ (ES+).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C1C=CC=CC=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CCOCC>[C:1]1([CH:18]2[CH2:19][CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncccc2c1
Reactant: [Li]c1ccccc1
Agent: Br[Mg]Cc1ccccc1
Solvent: CCOCC
Product: c1ccc(C2CCc3ccccc3N2)cc1

Procedure:
By the 3-step method of Preparation E, substituting 1M phenyllithium in ether for the benzylmagnesium bromide solution, quinoline (25 g, 0.194 mol) was converted to present title product, 22.4 g, as an oil.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[OH-].[Na+].[CH3:9][CH:10]([CH3:18])[CH2:11][C:12](=O)[CH2:13][C:14](=O)[CH3:15]>O>[CH2:11]([C:12]1[CH:13]=[C:14]([CH3:15])[N:3]=[C:1]([N:4]2[C:14]([CH3:15])=[CH:13][C:12]([CH2:11][CH:10]([CH3:18])[CH3:9])=[N:5]2)[N:2]=1)[CH:10]([CH3:18])[CH3:9].[CH2:11]([C:12]1[CH:13]=[C:14]([CH3:15])[N:3]=[C:1]([N:4]2[C:12]([CH2:11][CH:10]([CH3:18])[CH3:9])=[CH:13][C:14]([CH3:15])=[N:5]2)[N:2]=1)[CH:10]([CH3:18])[CH3:9]
Reactant: CC(=O)CC(=O)CC(C)C
Reactant: N=C(N)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(CC(C)C)nc(-n2nc(C)cc2CC(C)C)n1
Product: Cc1cc(CC(C)C)nc(-n2nc(CC(C)C)cc2C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50 %
Yield: 4 %

Procedure:
To aminoguanidine hydrochloride (1.59 g, 14.4 mmol), water (5 ml), sodium hydroxide (576 mg, 14.4 mmol), and 6-methyl-2,4-heptanedione (manufactured by Tokyo Chemical Industry, purity: 97.0% or higher) (4.50 g, 31.6 mmol) were added, and then stirred at 80° C. for 8 hours. To the reaction mixture, water (30 ml) was added, and the extraction was carried out with ethyl acetate (10 ml). The extract was washed with saturated brine, dried with anhydrous sodium sulfate, and then concentrated. The obtained residue (3.83 g) was subjected to silica gel column chromatography (80 g of silica gel, chloroform to chloroform:methanol=100:1) to obtain 4-isobutyl-2-(3-isobutyl-5-methylpyrazol-1-yl)-6-methylpyrimidine (181 mg, 4%) and 4-isobutyl-2-(5-isobutyl-3-methylpyrazol-1-yl)-6-methylpyrimidine (2.05 g, 50%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.CCOC(C)=O.N1C=CC=CC=1>C(Cl)(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:10]([I:29])=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(I)c([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1

Procedure:
From (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (made as described in International Patent Specification No. WO 94/14742) (1.82 g, 4.88 mmol) in CHCl3 (50 ml)m, silver triflate (1.26 g, 4.88 mmol) and iodine (1.24 g, 4.88 mmol). Chromatography (SiO2;EtOAc) afforded the title comgound (2.2 g) as a colourless gum. (Found C, 59.23; H, 5.32; N, 2.67. C23H26NO2I requires C, 60.13; H, 5.25; N, 2.81) δH (CDCl3) 1.5-1.9 (8H, m,CH2)4), 3.25 (1H, d, J 5 Hz, CH2pyridine), 3.27 (1H, d, J 5 Hz, CH2 pyridine), 3.74 (3H, s, OCH3), 4.6-4.7 (1H, m, OCH), 4.64 (1H, t, J 8 Hz, CH phenyl), 6.74 (1H, s, C6H2), 7.01 (2H, d, J 5 Hz, H3, H5 pyridine), 7.24 (1H, s, C6H2), 7.25-7.4 (5H, m, C6H5), and 8.39 (2H, d. J 5 Hz, H2, H6 pyridine). m/z 500 (M+, 100%), 406 (25) and 212 (14).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C=O)C.O>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)[CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(-c3cccc(CCl)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: C1CCNC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnn2c(-c3cccc(CN4CCCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1 h
Yield: 44.7 %

Procedure:
The product from step 1 (60 mg, 0.13 mmol) was dissolved in 1 mL of DMF and K3PO4 (33 mg, 0.16 mmol) was added. The mixture was treated with pyrrolidine (0.15 mL, 1.55 mmol) and stirred for 1 hour. The mixture was diluted with water (10 mL) and stirred for 10 minutes. The precipitate was collected and purified by preparative HPLC eluting with 10%-90% acetonitrile/water (0.1% TFA) to provide 29 mg (54%) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13]([NH2:15])=O)=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13]#[N:15])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C(N)=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C#N

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide with triphosgen/triethylamine in THF. mp 105-107° C., 1H NMR(CDCl3) d 6.90(s,2H), 6.26(brs,1H), 6.05(s,1H), 4.24(m,1 H), 2.28(s,3H), 2.25(s,3H), 2.17(s,6H), 1.72(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:7]=1.Br[CH2:25][C:26]([CH3:28])=[CH2:27].C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:27][C:26]([CH3:28])=[CH2:25])[CH:12]=2)[CH:7]=1
Reactant: C=C(C)CBr
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=C(C)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
N-(3-Methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (34 mg, 0.11 mmol), 3-bromo-2-methylprop-1-ene (11 μl, 0.11 mmol), cesium carbonate (69 mg, 0.21 mmol) and DMA (210 μL) were combined in a vial and stirred at 100° C. for 1.25 hours. The reaction mixture was diluted with EtOAc, washed with aqueous sodium bicarbonate, then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude N-(3-methyl-5-(1-(2-methylallyl)-1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine as a yellow oil. MS ESI calcd. for C19H19F3N5 [M+H]+ 374. found 374.
Reaction SMILES: O1CCCC1.[C:6]1([S:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([S:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Sc2ccccc2)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Sc3ccccc3)nc2)no1
Temperature: 50 °C
Reaction time: 4 h
Yield: 23.5 %

Procedure:
To a tetrahydrofuran (5 mL) solution of (6-phenylsulfanyl-pyridin-3-yl)acetohydroximoyl chloride (149 mg, 0.54 mmol) described in Manufacturing Example 97-1-4 and 3-ethynyl-pyridin-2-ylamine (15 mg, 0.13 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (80 μL, 0.57 mmol), which was stirred for 4 hours at 50° C. under nitrogen atmosphere. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) and then further purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (11 mg, 23%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]([CH3:26])([CH3:25])[C@H:9]2[NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([Cl:24])=[CH:19][CH:18]=3)=[O:14])=[CH:5][CH:4]=1)#[N:2].[C:27](C1C=C2C(CC(C)(C)C2NC(C2NC3C(C=2)=CC(Cl)=CC=3)=O)=CC=1)#N.C([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Cl:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:27])[C:15]([C:13]([NH:12][C@H:9]1[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=3)[CH2:7][C:8]1([CH3:26])[CH3:25])=[O:14])=[CH:23]2
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC1(C)Cc2ccc(C#N)cc2C1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1c(C(=O)N[C@H]2c3cc(C#N)ccc3CC2(C)C)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of Example 2 N-(6-cyano-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-chloro-1H-indole-2-carboxamide (30 mg, 0.083 mmol) and K2CO3 (34 mg, 2.48 mmol) in DMF (0.3 mL) was added methyl iodide (6 μL, 0.091 mmol) and the resulting mixture was stirred at rt for 16 h. Water (˜5 mL) was added dropwise followed by stirring for an additional 30 min. The precipitated solid was collected by vacuum filtration, rinsed with additional water (˜5 mL) and dried in vacuo to afford the title product as a white solid (26 mg). HPLC Ret. time: 3.79 min. LCMS MH+ (m/z) 378.30. 1H NMR: (DMSO-d6, 400 MHz): 8.72 (d, 1H), 7.71 (s, 1H), 7.68 (d, 1H), 7.65 (s, 1H), 7.58 (d, 1 H), 7.44 (d, 1 H), 7.26 (dd, 1 H), 7.18 (s, 1H), 5.34 (d, 1H), 4.00 (s, 3H), 2.52-2.48 (m, 2 H), 1.21 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:24]#[N:25].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][C:24]#[N:25])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzyl chloride (0.66 g) in N,N-dimethylformamide (20 mL) was added potassium cyanide (0.40 g), and the mixture was stirred at 60° C. for 18 hours. The reaction mixture was cooled to room temperature, and to the mixture was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1-3/1) to give [4-(2-Benzyloxybenzyl)phenyl]-acetonitrile (0.54 g).