Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:19]([OH:22])(=O)=[O:20])[C:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=2)=[CH:5][CH:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:31])=O>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:19]([Cl:31])(=[O:22])=[O:20])[C:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(-c2cc(S(=O)(=O)O)c3ccncc3c2)cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(-c2cc(S(=O)(=O)Cl)c3ccncc3c2)cc1
Temperature: 62.5 °C
Reaction time: 0.5 h
Yield: 115.2 %

Procedure:
To a slurry of 7-(4-methoxy-phenyl)-isoquinoline-5-sulfonic acid (12.13 g, 38.5 mmol) in 1,2-dichloroethane (200 mL) and DMF (2.99 mL, 38.5 mmol) add oxalyl chloride (26.8 mL, 308 mmol) dropwise. Mechanically stir the slurry under nitrogen atmosphere while heating at 60-65° C. for 4 hr. Cool the slurry to −10° C. Wait for 30 min then filter. Wash the yellow solid with 20% ether/dichloromethane and dry under a nitrogen atmosphere affording the title compound (14.8 g) as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH2:24][CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[N:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH2:24]([C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1)[CH3:25]
Reactant: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-ethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.89) (0.30 g, 0.739 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.180 g, 0.813 mmol) according to the general procedure VI. Obtained as a white solid (0.050 g, 16%). MS (ISP) 421.1 [(M+H)+]; mp 209° C.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][N:5]=[C:6]([C:26](=[N:28][O:29][CH3:30])[CH3:27])[C:7](=[N:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19][N:20]=[CH:21][C:22]([O:24]C)=O)[CH3:8]>O1CCCC1>[CH3:1][NH:2][C:22](=[O:24])[CH:21]=[N:20][O:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][N:9]=[C:7]([CH3:8])[C:6](=[N:5][O:4][CH3:3])[C:26](=[N:28][O:29][CH3:30])[CH3:27]
Reactant: CN
Reactant: CON=C(C)C(=NOC)C(C)=NOCc1ccccc1CON=CC(=O)OC
Solvent: C1CCOC1
Product: CNC(=O)C=NOCc1ccccc1CON=C(C)C(=NOC)C(C)=NOC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2 ml of 40% strength aqueous methylamine solution are added to a solution of 0.6 g (1.5 mmol) of methyl [2-(2,3-bismethoxyimino-1-methylbutylideneaminooxymethyl)phenyl]methoxyiminoacetate in 10 ml of tetrahydrofuran, and the mixture is stirred for 12 hours at room temperature. For working up, the reaction mixture is evaporated in vacuo, taken up in 20 ml of diethyl ether, washed using 20 ml of water, dried over sodium sulfate and evaporated in vacuo. This gives 0.6 g (98%) of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: Nc1cccc(Br)c1
Product: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1F

Procedure:
3-Bromoaniline is coupled with 4-chloro-7-fluoro-6-nitroquinazoline, to produce 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline, which is reacted thereafter with the sodium salt of 3-(4-morpholinyl)-1-propanol, as described hereinabove, to produce 4-[(3-bromophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-nitroquinazoline. The morpholino-substituted 6-nitroquinazoline is then reduced to the corresponding 6-aminoquinazoline, which is further reacted with bistributyltin, iodine-123, iodine-124 or iodine-131 and acryloyl chloride, as described hereinabove, to yield the final iodine-123 labeled, iodine-124 labeled or iodine-131 labeled product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:19]([NH2:20])=[N:18][C:12]3[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: Cc1cc(C)cc(-c2cc3cnc(N)nc3nc2N)c1
Reactant: CC(C)(C)N=C=O
Product: Cc1cc(C)cc(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1

Procedure:
The title compound was prepared from 0.3 g of 6-(3,5-dimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 94 and 0.14 mL of tert-butyl isocyanate according to Example 2. The product is purified by MPLC eluting with 1:1 CHCl3 :EtOAc; mp 180°-182° C., CIMS (1% ammonia in methane): m/z (relative intensity) 365 (MH+ +1, 16), 366 (MH+ +2, 3), 84 (100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:29](Cl)(=[O:38])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:29](=[O:38])[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and hydrocinnamoyl chloride.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[CH:13][CH:12]=1)[C:2]#[CH:3].Cl.O1CCOCC1>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:2]#[CH:3]
Reactant: C#CCOCCOCCOc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C#CCOCCOCCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)phenylcarbamate (I-7a: 1.91 g, 5.69 mmol) in CH2Cl2 (14.24 mL) was added 4N HCl in dioxane (14.24 mL, 56.9 mmol). The mixture was stirred at room temperature for 2 hours, concentrated in vacuo, followed by the addition of aqueous saturated sodium bicarbonate. The mixture was then extracted twice with ethyl acetate, dried over MgSO4, filtered, and concentrated in vacuo. 4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)aniline (I-7b) was used as is for next step. LC-MS (M+1) 236.1, t=0.87 minute.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22]Br.O>CN(C)C=O>[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22][N:10]1[C:11]([CH3:13])=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1
Reactant: COC(=O)CCC(=O)CBr
Reactant: Cc1cc(-c2ccc(Cl)cc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)Cn1nc(-c2ccc(Cl)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
3-(4-Chloro-phenyl)-5-methyl-1H-pyrazole (1.84 g, 9.6 mmol) was dissolved in dimethylformamide (20 ml) followed by the addition of sodium hydride (60% dispersion in oil, 384 mg, 9.6 mmol). The reaction was stirred at room temperature for 15 min, followed by the addition of 5-bromo-4-oxo-pentanoic acid methyl ester (2 g, 9.6 mmol). The reaction was stirred at room temperature for a further 30 min, before the addition of water (200 ml). The solution was then extracted with ethyl acetate (2×150 ml). The organics were dried over magnesium sulfate and concentrated in vacuo. The crude product was then purified by column chromatography (120g column, DCM to 90% DCM/EtOAc over 50 mins) to give 5-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-oxo-pentanoic acid methyl ester (1.84 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:31]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=1)([CH3:34])([CH3:33])[CH3:32].CC(C)([O-])C.[Na+].C(C1C=C(C(C)C)C=C(C(C)C)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1)(C)C>O1CCOCC1>[C:31]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[CH:39][CH:38]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Temperature: 105 °C
Yield: 12.3 %

Procedure:
To a mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (227 mg, 0.55 mmol), 4-bromobenzoic acid tert-butyl ester (170 mg, 0.66 mmol), sodium tert-butoxide (106 mg, 1.1 mmol) and (2′,4′,6′-triisopropyl-1,1′-biphenyl-2-yl)dicyclohexylphosphine (X-PHOS, 38 mg) in dioxane (5 mL) bubbled with argon was added tris(dibenzylideneacetone)dipalladium Pd2(dba)3 (23 mg). The mixture was heated at 105° C. for 2 hrs. Solvents were evaporated and the residue was extracted with ethyl acetate and 0.1N hydrochloric acid. The organic layer was dried and concentrated. The residue was crystallized from ethyl acetate to give a pale yellow solid as 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid tert-butyl ester (40 mg).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][C:14]=1O)#[N:8].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][C:14]=1[O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])#[N:8]
Reactant: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1
Reactant: CSCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(-c2ccc(OCCCSC)c(C#N)c2)c1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
In 5 ml of THF were dissolved 63 mg of 3-(methylthio)-1-propanol and 100 mg of methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate, and the resulting solution was heated at 0° C. for 10 minutes in the presence of 0.15 ml of tributylphosphine and 149 mg of 1,1′-(azodicarbonyl)dipiperidine. Then, the reaction solution was warmed to room temperature and stirred all day and night. After removal of the solvent, water was added and extraction with ethyl acetate was performed. The resulting organic layer is washed with brine and then dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain 92 mg of methyl 2-{3-cyano-4-[3-(methylthio)propoxy]phenyl}isonicotinate. (2) Then, 92 mg of the compound was dissolved in a mixed solution of 3 ml of methanol and 3 ml of THF, and 0.32 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 60° C. for 1 hour. After being cooled, the reaction solution was diluted with diisopropyl ether and an aqueous layer was separated. The aqueous layer was neutralized with 1M hydrochloric acid and then extracted with ethyl acetate. After washing with brine, the organic layer was dried and concentrated under reduced pressure to obtain 81 mg of 2-{3-cyano-4-[3-(methylthio)propoxy]phenyl}isonicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11][NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.Cl.[CH:23](O)=O>C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11][N:12]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH3:23])=[CH:4][CH:3]=1
Reactant: Clc1ccc(COc2cccc(CNCC3CC3)c2)cc1
Reactant: O=CO
Agent: C=O
Agent: Cl
Product: CN(Cc1cccc(OCc2ccc(Cl)cc2)c1)CC1CC1
Temperature: 25 °C

Procedure:
In a mixture of 150 ml of formic acid and 150 ml of 37% formaldehyde was dissolved 80 g of 3-(4-chlorobenzyloxy)-N-cyclopropylmethylbenzylamine. The solution was refluxed with heating, for 3 hours. The reaction mixture was cooled to room temperature, and 150 ml of concentrated hydrochloric acid was added thereto. The mixture was subjected to vacuum distillation to remove the solvent. The resulting residue was treated with chloroform-aqueous sodium hydroxide solution. The resulting chloroform layer was separated, washed with water, dried with anhydrous sodium sulfate, and subjected to vacuum distillation to remove the solvent, whereby 86 g of 3-(4-chlorobenzyloxy)-N-cyclopropylmethyl-N-methylbenzylamine was obtained as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(O)cc1
Reactant: CCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OCC(CC)CC)cc1
Temperature: 25 °C

Procedure:
To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), K2CO3 (anhydrous, 10 g) and 1-bromo-2-ethyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude product obtained was taken to next step without purification. Yield 2.8 g.(94%); (M+H)+297.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[CH:18][S:19][C:13]=2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11]1.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1.CCCCCC.O1CCCC1>[OH:31][CH:24]([C:18]1[S:19][C:13]2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11][N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)Cc1nn(C)c(=O)c2ccsc12
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3ccccc3)sc12
Temperature: 25 °C

Procedure:
A solution of lithium diisopropylamide (13.6 mmol) in tetrahydrofuran/hexane (2:1, 22 ml) was added dropwise to a solution of 5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (example 6 step b, 2.00 g) in tetrahydrofuran (24 ml) at −70° C. under nitrogen. Benzaldehyde (2.00 ml) was added and after 15 minutes, the mixture was warmed to room temperature. 1M Hydrochloric acid (50 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The organic extracts were washed twice with 1M hydrochloric acid, twice with saturated sodium hydrogen carbonate solution, then with brine, dried, filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate:isohexane (1:3 then 1:2 then 1:1), to give the title compound (2.48 g) of which 0.5 g was purified by preparative normal-phase HPLC with gradient ethanol/dichloromethane elution to gave the title compound (0.38 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][N:34]=2)[C:23]([Cl:40])=[CH:22][N:21]=1>>[Cl:40][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Reactant: Cc1cccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Product: Cc1cccnc1-c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 58 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine) was combined with (2,5-Dichloro-pyrimidin-4-yl)-[2-(3-methyl-pyridin-2-yl)-phenyl]-amine to yield 5-Chloro-N*4*-[2-(3-methyl-pyridin-2-yl)-phenyl]-N*2*-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-pyrimidine-2,4-diamine (93.00 mg, 58% yield) as an off white powder. 1H-NMR (CDCl3) δ 9.45 (s, 1H), 8.58 (d, J=4.8 Hz, 1H), 8.39 (d, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.38 (m, 3H), 7.24 (m, 2H), 7.02 (d, J=8.0 Hz, 1H) 6.87 (m, 1H), 3.24 (m, 7H), 2.34 (s, 3H), 1.31 (m, 3H). LC/MS (ESI+)=553 (M+H). MP=130.5° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccnc4)cc23)CC1
Yield: 32.6 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (100 mg, 0.24 mmols), 3-pyridinylboronic acid (88.5 mg, 0.72 mmols), potassium carbonate (197 mg), and Pd(PPh3)4 (28 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (33 mg, 38%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[O:16][CH3:17])[C:5](=O)[CH3:6].Cl.[NH2:21]O>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:21][O:18][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[O:16][CH3:17])=[O:19]
Reactant: COC(=O)C(C(C)=O)C(=O)c1ccc(Br)cc1OC
Reactant: NO
Agent: Cl
Product: COC(=O)c1c(C)noc1-c1ccc(Br)cc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 3 using 2-(4-bromo-2-methoxy-benzoyl)-3-oxo-butyric acid methyl ester and hydroxylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[C:8]([C@H:17]([NH:27][C:28](=[O:43])[CH2:29][N:30]2[C:38]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=3[C:32]([C:39]([F:42])([F:41])[F:40])=[N:31]2)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[N:9][C:10](S(C)(=O)=O)=[N:11][CH:12]=1>ClCCl>[Br:6][C:7]1[C:8]([C@H:17]([NH:27][C:28](=[O:43])[CH2:29][N:30]2[C:38]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=3[C:32]([C:39]([F:42])([F:41])[F:40])=[N:31]2)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[N:9][C:10]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:11][CH:12]=1
Reactant: COCCN
Reactant: CS(=O)(=O)c1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Solvent: ClCCl
Product: COCCNc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reaction time: 8 h

Procedure:
2-Methoxyethylamine (0.086 ml, 1 mmol) was added at room temperature to a solution of compound 11H (62 mg, 0.1 mmol) in dichloromethane (5 mL). Stirring was continued at 45° C. for overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography using an ethyl acetate/hexanes eluent to yield the title compound. MS (m/z) 618.00 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH2:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C1C[O:35][CH2:34][CH2:33]1.C(Cl)(=O)C>C(N(CC)CC)C>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH:29][C:34](=[O:35])[CH3:33])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reactant: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(6-aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (50 mg, 0.12 mmol) and THF (5 mL) is added acetyl chloride (50 mg) and triethylamine (50 mg). The solution is stirred at rt for 10 min before being partitioned between EtOAc and water. The organic layer is washed further with brine. The organic layer is then dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound. MS (ESI) m/z 470.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.61 (d, J=1.01 Hz, 1 H), 8.34 (d, J=9.09 Hz, 1 H), 8.05 (s, 1 H), 7.93 (d, J=3.54 Hz, 1 H), 7.89 (d, J=7.83 Hz, 1 H), 7.56 (t, J=7.96 Hz, 1 H), 7.39-7.45 (m, 2 H), 7.09 (dd, J=8.97, 2.40 Hz, 1 H), 6.88 (s, 1 H), 6.73 (d, J=3.79 Hz, 1 H), 4.40 (s, 2 H) 2.01 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Reactant: NCCc1ccc(O)cc1
Solvent: COCCOC
Product: Nc1nc(NCCc2ccc(O)cc2)c(F)c(-c2ccco2)n1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester and tyramine in DME. ES-MS m/e (%): 315 (M+H+, 100).