Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][N:9]([CH3:12])[CH2:10][CH2:11][C:5]=2[C:4]=1[N+:21]([O-:23])=[O:22].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:20]=[CH:19][C:6]2[CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][N:9]([CH3:12])[CH2:10][CH2:11][C:5]=2[C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCN(C)CC2c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCc2c(ccc(O)c2[N+](=O)[O-])C(c2ccccc2)C1
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
0.40 g (0.00128 mol) 7-methoxy-3-methyl-6-nitro-l-phenyl-2,3,4,5-tetrahydro1H-3-benzazepine was dissolved in 6 ml dry dichloromethane. The solution was cooled to -20° C. and 1.5 ml boron tribromide was added dropwise. The reaction mixture was stirred at -20° C. for 15 min and at room temperature for 2.5 h. Then, the mixture was concentrated in vacuo and the residue was hydrolized by careful addition of methanol. 10 ml water was added and the solution was heated to reflux for 0.5h. The cooled solution was adjusted to pH 8.5 by addition of NaHCO3 -solution and extracted with dichloromethane. Evaporation of the solvent yielded the compound as a yellow powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][S:15]([O-:18])(=O)=[O:16])[CH:9]=[CH:10][C:11]=1[Cl:12].[Na+].C1C=CC=CC=1>CN(C)C=O>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][S:15]([Cl:3])(=[O:18])=[O:16])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CCc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=S(=O)(Cl)CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
Thionyl chloride (1.15 mL, 15.83 mmol) was added dropwise to a suspension of sodium 2-(3,4-dichloro-phenyl)-ethanesulfonate (3.17 g, 11.47 mmol) in a mixture of anhydrous benzene (50 mL) and anhydrous N,N-dimethylformamide (1 mL) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and was then heated at 80° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The solids were washed with benzene and the combined filtrates were concentrated in vacuo. The residue was taken up in hexane and the resulting suspension was heated at 50° C. for 30 min. After cooling to room temperature, a solid was collected by filtration to give 2.20 g (70% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=[CH:16][CH:15]=4)[C:6]=3[N:7]=[C:2]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3cccc4ccccc34)c2n1
Product: c1ccc2c(CSc3ncnc4c(N5CCOCC5)nc(N5CCNCC5)nc34)cccc2c1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-4-morpholino-8-(1-naphthylmethyl-thio)-pyrimido [5,4-d]-pyrimidine (m.p.: 206°-209° C.) and piperazine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]2[CH2:15][CH2:16][CH2:17][C:10]=2[N:9]=1>C(O)C>[Cl:7][C:8]1[N:13]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:11]2[CH2:15][CH2:16][CH2:17][C:10]=2[N:9]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Solvent: CCO
Product: Clc1nc2c(c(N3CCOCC3)n1)CCC2
Reaction time: 13 h
Yield: 85 %

Procedure:
Morpholine (0.32 mL, 3.7 mmol) was added to a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (0.5 g, 2.65 mmol) in anhydrous ethanol (5 mL) and stirred at a temperature in the range of 65° C. to 85° C. for 10 to 16 hours. Thereafter, the mixture was concentrated under reduced pressure and the crude was diluted with anhydrous ether. After standing at a temperature in the range of 5° C. to 10° C. for 2 hours, the precipitated solid was filtered and washed with ether. The solid was recrystallized from ethyl acetate to afford the title compound as a pale yellow solid (0.54 g, 86% yield).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[CH:10][C:8](=[O:9])[N:7]([CH2:13][CH:14]=[CH2:15])[C:5]1=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.Cl.[N:21]([O-])=[O:22].[Na+]>O>[CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([N:21]=[O:22])[C:8](=[O:9])[N:7]([CH2:13][CH:14]=[CH2:15])[C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCn1c(N)cc(=O)n(CC=C)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCn1c(N)c(N=O)c(=O)n(CC=C)c1=O
Reaction time: 4 h
Yield: 86.7 %

Procedure:
1,3-Diallyl-6-aminouracil (5 g) was suspended in 400 ml of water in a 1 L round bottom flask with overhead stirring. Acetic acid (6.7 ml of a 20% solution) was added, followed by intermittent addition of 2 ml of concentrated hydrochloric acid and a sodium nitrite solution (1.53 g in 7 ml water). After 4 hours, this solution was filtered, washed with water, collected and dried in a vacuum oven at 80° C. for 20 hours to yield 4.54 g of 1,3-diallyl-5-nitroso-6-aminouracil as a purple solid, m.p. 170°-180° C. (87% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:33]([O:34][CH3:35])[CH3:32])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a stirred solution of 10.0 g of 3-bromo-4-chlorobenzoic acid in 275 ml of anhydrous dichloromethane at OOC were added 7.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.5 ml of triethylamine followed by 3.9 g of N,O-dimethylhydroxylamine hydrochloride. After stirring overnight at room temperature the mixture was washed with 200 ml of water and then with 200 ml of a 1M solution of hydrochloric acid. The organic solution was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a cream solid.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14].C1(C)C=CC=CC=1>O>[Cl-:10].[CH3:11][N:12]([CH2:8][P+:3]([CH2:1][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])([CH2:4][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[CH2:6][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 97.2 %

Procedure:
A mixture of THPC (9.53 g, 0.05 mol), 1,3-dimethylurea (17.62 g, 0.20 mol), and toluene (75 ml) was heated to reflux in an apparatus fitted with a Dean-Stark trap for azeotropic removal of the water. The mixture was held at reflux until the evolution of water ceased; 3.7 ml (0.20 mol) was collected in 1 hr., and no more passed over in the next hr. The product, which had separated during the reaction as a mass of white solids, was broken up, triturated under toluene, filtered, and dried, giving 22.88 g (97.2%) of tetrakis(1,3-dimethylureidomethyl)phosphonium chloride (I, R=R'=CH3, R"=H, X=Cl) as a white crystalline solid, mp 187°-189° C. dec. Two recrystallizations from 2-propanol (8 ml/g), followed by drying under vacuum for 2 hr at 56° C. (acetone), gave a 1:1 solvate of the product and 2-propanol, mp 194°-194.5° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:13]C(=O)[NH:11][CH:10]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>C(O)C>[NH2:11][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[OH:13]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)c(F)c2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Yield: 74.8 %

Procedure:
To a solution of (4RS,5SR)-5-(3,4-difluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (3.5 g, 9.8 mmol) in ethanol (60 ml) was added 8N aqueous sodium hydroxide solution (6.1 ml, 49 mmol) and the mixture was heated under reflux for 6 hrs. The reaction solution was concentrated, diluted with water (300 ml), and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (2.43 g, 75%).
Reaction SMILES: [NH4+]=[S:2].C(O)C.[CH2:6]([N:10]1[C:14]([C:15]#[N:16])=[C:13]([CH2:17][OH:18])[N:12]=[C:11]1[N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[C:7]#[C:8][CH3:9]>C(OCC)(=O)C>[CH2:6]([N:10]1[C:14]([C:15](=[S:2])[NH2:16])=[C:13]([CH2:17][OH:18])[N:12]=[C:11]1[N:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C(N)=S
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10 ml of a 50% aqueous solution of ammonium sulfide was added to a 50 ml ethanol solution of 3.596 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-hydroxymethyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 16 hours. 400 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 3.221 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (4:1).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: [H][H]
Reactant: CC(C)(C)C=Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)CCc1ccccc1N

Procedure:
1 g (4.87 mmol) of 1-[3,3-dimethylbut-1-en-1-yl]-2-nitrobenzene are stirred in 20 ml of methanol with 0.26 g of palladium/carbon (10%) at 40° C. under 60 bar of hydrogen pressure for 24 hours. Subsequently, the solution is filtered with suction through Celite and the filtrate is concentrated by rotary evaporation. This gives 0.8 g (58% of theory) of an oil. Purity (GC-MS): 63%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:11](=[O:36])[N:12]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)=[O:4].[CH3:37][C:38]([CH3:54])([CH3:53])[C:39]([O:41][NH:42][C:43]([CH:45]([CH2:49][CH:50]([CH3:52])[CH3:51])[C:46](O)=[O:47])=[O:44])=[O:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:46](=[O:47])[CH:45]([C:43](=[O:44])[NH:42][O:41][C:39](=[O:40])[C:38]([CH3:53])([CH3:37])[CH3:54])[CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:7][N:6]1[C:11](=[O:36])[N:12]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)=[O:4]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1C[C@@H](N)C[C@H]1C(=O)OC
Reactant: CC(C)CC(C(=O)O)C(=O)NOC(=O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1C[C@@H](NC(=O)C(CC(C)C)C(=O)NOC(=O)C(C)(C)C)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
(2S,4S)-4-Amino-1-{pentyl-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]carbamoyl}-pyrrolidine-2-carboxylic acid methyl ester (2.0 g, 3.0 mmol) and 2-(2,2-dimethyl-propionyloxycarbamoyl)-4-methylpentanoic acid (1.2 g, 1.4 equiv) were dissolved in DMF (20 mL). DIPEA (2 mL, 3.5 equiv) was added, followed by HATU (1.4 g, 1.2 equiv). The mixture was stirred for 16 hours at room temperature and then partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was re-extracted with EtOAc (100mL). The combined organics were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, and evaporated to afford the title compound (2.2 g, 3 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C38H52N8O7, 732.9. found 733.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:34])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:34])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([OH:29])=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(NC(=O)OC(C)(C)C)C3(C)C)c(C(N)=O)cnn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C1(C)C
Temperature: 70 °C
Yield: 112.1 %

Procedure:
A solution of ethyl 4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (10.62 g, 22.42 mmol) and 1 N NaOH (120 mL) in THF (100 mL) and MeOH (100 mL) was heated to 60° C. for 16 hrs. and then the reaction mixture was added 120 ml of 1 N NaOH solution and heated to 70° C. for 8 hrs. The reaction mixture was added 120 ml of 1 N NaOH solution and heated to 70° C. for 8 hrs which was concentrated to remove THF and MeOH. The aqueous layer was acidified with conc. HCl solution until pH about 4 at 0-5° C. The solid was collected to give 4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (11.2 g, 76% yield). HPLC retention time=3.020 min., LC/MS (M+H)+=446.3.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH:13]([C:16]1[CH:17]=[C:18]([OH:24])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([CH:13]([CH3:15])[CH3:14])[CH:17]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: COc1ccc(O)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(C)C

Procedure:
4-Chloro-3,5-dimethylnitrobenzene (2.12 g), 1.9 g of 3-isopropyl-4-methoxyphenol, and 1.74 g of potassium carbonate are heated 18 hrs at 125° in 25 ml dimethylsulfoxide. The mixture is poured into ethyl acetate and extracted once with water and five times with brine. The ethyl acetate is dried, filtered, and stripped to yield an oil which is chromatographed on silica gel with 97:3 hexane:ethyl acetate to afford 3,5-dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)-nitro benzene NMR (CDCl3): δ1.1 (6H,d), 2.2 (6H,s), 3.3 (1H,m), 3.7 (3H, s) 6.3 (1H,d of d), 6.6 (1H,d), 6.7 (1H, d), 8.0 (2H, s).
Reaction SMILES: CO[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1.[OH:20]C1C=CC(OC2C=CC(C(F)(F)F)=CN=2)=CC=1>C(O)(=O)C.Br>[OH:20][C:18]1[CH:19]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: COc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccccc1Oc1ccc(C(F)(F)F)cn1

Procedure:
2-p-Methoxyphenoxy-5-trifluoromethylpyridine (10.5 g) in glacial acetic acid (100 ml) and 48% hydrobromic acid (50 ml) were stirred and heated under reflux for 71/2 hours. The solution was then evaporated and the remaining oil treated with sodium bicarbonate solution and shaken with ether (2×300 ml). The ether extract was shaken with 2-molar sodium hydroxide solution (200 ml) and then water (150 ml). The aqueous layers were combined, acidified with 2-molar hydrochloric acid and extracted with ether (2×300 ml). The ether extract was dried and evaporated to give a brown oil identified as 2-p-hydroxyphenoxy-5-trifluoromethylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:20][CH3:21])=[C:11]([CH:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]3=[O:19])[N:12]=2)=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]=3[O:19][CH3:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)CCC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC)CCC1=O
Temperature: 40 °C
Yield: 58.3 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-cyclopentane-1,3-dione (650 mg, 2.03 mmol) in acetone (10 ml) was added potassium carbonate (553 mg, 4 mmol), followed by iodomethane (248 μl, 4 mmol), and the reaction heated to 40° C. for 6 hours. The solvent was then removed from the crude reaction mixture under reduced pressure and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (395 mg).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([CH3:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].C([N:42](CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C=C(N)C=CC1=2)(=O)C>>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([CH3:37])[C:34]([NH2:42])=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(Br)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(N)cc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 26 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate following the procedure of Example 26, Steps 1-2 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-amino-2,3,4,5-tetrahydrobenzo[b]azepine 1-carboxylate. CI MS 546 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.[NH2:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40].[H-].[Na+]>CN(C=O)C>[OH:40][CH2:39][CH:38]([NH:37][C:23]1[N:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=1)[CH2:41][OH:42]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Reactant: NC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(NC(CO)CO)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and 2-aminopropane-1,3-diol (1.0 equiv.) in DMF (0.05M) was added 60% sodium hydride (1.0 equiv.) at 0° C. The reaction was allowed to warm to room temperature and stir for 24 hours. LCMS analysis indicated the formation of the desired product. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(3-(2-((1,3-dihydroxypropan-2-yl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 28% yield. LCMS (m/z) (M+H)=532.1, Rt=0.68 min. 1H NMR (400 MHz, <cd3od>) δ ppm 2.45 (s, 3H) 3.64-3.71 (m, 1H) 3.79 (s, 10H) 3.85-3.91 (m, 1H) 4.53-4.59 (m, 1H) 4.63-4.69 (m, 1H) 6.67 (s, 1H) 7.44 (d, J=7.43 Hz, 1H) 7.51 (d, J=7.83 Hz, 1H) 7.56 (t, J=8.02 Hz, 1H) 7.93 (d, J=8.22 Hz, 1H) 7.96-8.01 (m, 3H) 8.16 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1B(O)O>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(Br)cc12
Reactant: Cc1ccncc1B(O)O
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: CN(C)C=O
Product: Cc1ccncc1-c1cnc2c(c1)c(C=O)nn2C1CCCCO1
Temperature: 90 °C

Procedure:
To a heterogeneous solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XI) (0.21 g, 0.67 mmol) and K3PO4 (0.212 g, 1 mmol) in DMF (5 mL) and water (0.5 mL) was added 4-methyl-pyridine-3-boronic acid (LVI) (0.101 g, 0.74 mmol). The solution was purged with nitrogen by using nitrogen/vacuum cycle (3×). Pd(PPh3)4 (23 mg, 0.02 mmol) was added to the solution and again purged with nitrogen. The solution was heated at 90° C. for 4 h under nitrogen. The solution was filtered through a pad of Celite while it was still hot. The Celite was washed with DCM (3×). The combined filtrate was concentrated under vacuum. The residue was dissolved in DCM, and washed subsequently with saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (LVII). The crude product was used directly for step 2 without further purification. ESIMS found for C18H18N4O2 m/z 323.4 (M+H).