Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](OCC)=[O:17])=[CH:11][C:10]=1[CH3:21])#[N:8]>O1CCCC1.O>[NH2:8][CH2:7][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=1[CH3:21]
Reactant: CCOC(=O)c1cc(C)c(C#N)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CO)cc(C)c1CN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 233.3 %

Procedure:
To a solution of aluminum lithium hydride (2.1 g) in tetrahydrofuran (20 ml) was added a solution of ethyl 4-cyanomesitylenate (2.9 g) in tetrahydrofuran (30 ml) at 0° C. and the mixture was refluxed under heating for 6 hr. To this reaction mixture was added 50% (v/v) tetrahydrofuran in water under ice-cooling. This mixture was stirred at room temperature for 30 min and the catalyst was filtered off using Celite. The solvent was evaporated and the obtained residue was recrystallized from methanol-isopropyl ether to give the title compound (5.5 g) as white crystals.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6]([OH:14])([CH3:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C.[OH-].[K+]>C(O)C>[OH:14][C:6]([CH3:13])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][C:4]([OH:15])=[O:3]
Reactant: CCCCCCC(C)(O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)(O)CC(=O)O
Yield: 83.2 %

Procedure:
Ethyl-3-hydroxy-3-methyl-n-nonanoate (25 g) was refluxed for 3 hours with a 10% solution of potassium hydroxide in dry ethanol (210 ml). The ethanol was evaporated in vacuo and the residue was treated with water (100 ml). The aqueous solution was washed with ether then was acidified (ice-bath cooling) with dilute hydrochloric acid. The oil that separated was extracted into ether. The ether solution was washed with brine then was dried over magnesium sulphate and evaporated to give a light yellow oil. This was vacuum distilled to yield 3-hydroxy-3-methyl-n-nonanoic acid as a clear syrup (18.1g).
Reaction SMILES: CO[C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:19]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4].O.[NH2:32][NH2:33]>C(O)C>[N:25]1([CH2:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:9]4[NH:10][C:11]5[CH:12]=[N:13][C:5]([C:3]([NH:32][NH2:33])=[O:4])=[CH:6][C:7]=5[C:8]=4[CH:17]=3)=[CH:23][CH:22]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: NN
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (425 mg, 1.06 mmol) and hydrazine hydrate (1.29 mL, 26.5 mmol) in ethanol (4.6 mL) was heated under reflux for 1 h under a nitrogen atmosphere. The solution was allowed to cool to ambient temperature and the resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford a yellow solid (337 mg, 79%). The solid was used without purification.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([O:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:8]1>[Pd].CO.ClCCl.O>[CH3:5][O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([O:13][C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:8]1
Reactant: CO[C@@H]1CCC[C@H](Oc2ncccc2[N+](=O)[O-])C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CO[C@@H]1CCC[C@H](Oc2ncccc2N)C1

Procedure:
Ammonium formate (7.25 g) was added to a suspension of 2-(cis-3-methoxy-cyclohexyloxy)-3-nitro-pyridine (5.80 g) and 10% palladium on charcoal (400 mg) in methanol (40 ml) at room temperature and the mixture was heated to reflux for 30 min until LCMS indicated complete conversion of the starting material. The mixture was diluted with dichloromethane (100 ml) and water (40 ml), filtered through celite, and the filtercake was washed with dichloromethane (30 ml). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was submitted to column chromatography (silica gel, petrol ether/ethyl acetate 70:30) to give the desired product.
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[N:4]=1)[NH2:2].[C:13]([CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[C:17](OCC)=[O:18])(=O)[CH3:14]>>[CH3:14][C:13]1[C:16]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[C:17]([OH:18])[N:1]([C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=3[N:4]=2)[N:2]=1
Reactant: CCOC(=O)C(Cc1ccc(-c2ccccc2)cc1)C(C)=O
Reactant: Cc1ccc2[nH]c(NN)nc2c1
Product: Cc1ccc2[nH]c(-n3nc(C)c(Cc4ccc(-c5ccccc5)cc4)c3O)nc2c1

Procedure:
Using 2-hydrazino-5-methyl-1H-benzimidazole (4) obtained in Example 1, step 3 and ethyl 2-acetyl-3-(4-phenylphenyl)propanoate (33), and by a method similar to that in Example 1, step 4, 3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-4-[(4-phenylphenyl)methyl]-1H-pyrazol-5-ol (34) was obtained.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[N:5]([CH3:24])[C:4]1=[O:25])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[N:5]([CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1cccc(O)c1
Yield: 72 %

Procedure:
(3R)-3-Ethyl-7-fluoro-4-(3-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to give an oil which was purified via Biotage Horizon® (SiO2, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) to yield (3R)-3-ethyl-7-fluoro-4-(3-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (72%). [α]D25=−281° (c=0.0098 G/ML, CHCl3); MS (ESI) m/z 329 ([M+H]+); MS (ESI) m/z 327 ([M−H]−) HRMS: calcd for C18H17FN2O3.0.10H2O, 329.9234; found (ESI+), 329.12884; Anal. Calcd for C18H17FN2O3 0.10H2O: C, 65.49; H, 5.25; N, 8.49. Found: C, 65.29; H, 4.93; N, 8.33.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-tert.butoxycarbonylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[NH:19][NH2:20].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([NH:20][NH:19][C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])[CH2:3][OH:4]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 15 h

Procedure:
Z-Ser-OH (10.0 g) and 6.2 g of t-butyl carbazate were dissolved in 150 ml of DMF and the solution was ice-cooled. HONB (8.0 g) and 9.3 g of DCC were added and the mixture was stirred for 15 hours. The formed DCU was filtered off and the filtrate was concentrated. The residue was extracted into AcOEt and the AcOEt solution was washed with 4% aqueous NaHCO3 and 10% aqueous citric acid, dried over Na2SO4 and concentrated. Ether was added and the crystals was collected by filtration. Yield 7.3 g (50.4%), mp 95°-98° C., [α]D26 -6.2° (c=0.8, DMF), Rf1 0.62.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1.[S:18]1[C:22]2[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:27]([C:24]2[CH:25]=[CH:26][C:21]3[N:20]=[CH:19][S:18][C:22]=3[CH:23]=2)=[O:28])=[CH:9][CH:8]=1
Reactant: NCc1ccc(OCc2cccc(F)c2)cc1
Reactant: O=C(O)c1ccc2ncsc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(OCc2cccc(F)c2)cc1)c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 4-(3-fluorobenzyloxy)-benzylamine described in Preparation Example 6 (129 mg, 0.558 mmol) and benzothiazole-6-carboxylic acid (100 mg, 0.558 mmol) in tetrahydrofuran (5 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (296 mg, 0.670 mmol) and triethylamine (93 μl, 0.670 mmol), and the solution was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water, and then, dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (148 mg, 68%) was obtained as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:26]1[CH2:29][CH2:28][CH2:27]1.CN(C=O)C>CCOC(C)=O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([N:26]4[CH2:29][CH2:28][CH2:27]4)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C1CNC1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1c(Cc2ccc(-n3cccn3)cc2)c(N2CCC2)nc2ccc(Br)cc12
Temperature: 100 °C

Procedure:
3-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (2.50 g, 5.77 mmol, Intermediate 4: step c), azetidine (988 mg, 17.3 mmol), and DMF (30 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The vessel was then cooled and contents were transferred to a separatory funnel with EtOAc dilution, then extracted three times with deionized water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-20% hexane/ethyl acetate) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:9])([CH3:8])[C:6](=[O:10])[C:5]([CH3:12])([CH3:11])[C:4](=[O:13])[C:3]=1[C:14]([C:16]1[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=1)=[O:15].[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:26][C:17]1[C:16]([C:14]([C:3]2[C:4](=[O:13])[C:5]([CH3:12])([CH3:11])[C:6](=[O:10])[C:7]([CH3:9])([CH3:8])[C:2]=2[Cl:1])=[O:15])=[CH:21][CH:20]=[C:19]([C:22]([F:23])([F:24])[F:25])[N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Cl)C(C)(C)C(=O)C(C)(C)C1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2CBr)=C(Cl)C(C)(C)C1=O

Procedure:
0.39 g (1 mmol) of 5-chloro-2,2,6,6-tetramethyl-4-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)cyclohex-4-ene-1,3-dione and 0.20 g (1.1 mmol) of N-bromsuccinimide are refluxed in the presence of a catalytic amount of dibenzoyl peroxide in 10 ml of carbon tetrachloride. After the reaction has subsided, the resulting succinimide is removed by filtration and the crude product is purified by column chromatography (mobile phase: ethyl acetate/hexane 1:4). This gives pure 4-(2-bromomethyl-6-trifluoromethylpyridine-3-carbonyl)-5-chloro-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione of melting point 94.5-95° C.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[O:4].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reaction time: 8 h
Yield: 84 %

Procedure:
500 mg (2.27 mmole) 6-Nitro-1H-indole-2-carboxylic acid methyl ester was dissolved in 4 mL neat N1,N1-dimethyl-ethane-1,2-diamine, was kept at 55° C. overnight and was evaporated. The oily residue was triturated with n-hexane to give 528 mg (84%) yellow solid which was no further purified. MS: 277.13 (calcd for M+H+: 277.13)
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)OC1C=CC=CC=1)#[N:2].[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][NH2:33])[N:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C.ClCCl>CN1CCCC1=O>[Cl:25][C:26]1[N:27]=[CH:28][N:29]=[C:30]([N:32]2[C:1]([NH2:2])=[N:3][C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[N:33]2)[CH:31]=1
Reactant: NNc1cc(Cl)ncn1
Reactant: N#CNC(=Nc1ccc(N2CCOCC2)cc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1cc(Cl)ncn1
Temperature: 220 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A mixture of N-cyano-N′-(4-morpholinopheny)-O-phenylisourea (8.76 g, 27.2 mmol, 4-chloro-6-hydrazino-pyrimidine (4.12 g, 28.5 mmol) and di-iso-propylethylamine (18.9 mL, 109 mmol) in N-methyl-pyrrolidinone (50 mL) was heated in the microwave apparatus at 220° C. for 5 min, cooled, poured into ice-water, stirred 0.5 h and filtered to obtain crude product (9.30 g). Purification by flash chromatography (SiO2) eluted with 2:98 methanol:dichloromethane provided the title compound (3.91 g, 39% yield) as a yellow powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([Cl:17])[N:5]=[C:4]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:3]=1.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].[Cl-].[Na+]>CN(C)C=O>[Cl:17][C:6]1[N:5]=[C:4]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:3]=[C:2]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: NCC(F)(F)F
Reactant: Fc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2Cl)c(F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2NCC(F)(F)F)c(F)c1
Yield: 88.3 %

Procedure:
A solution of 4,6-dichloro-2-(1H-imidazol-1-yl)-5-(2,4,6-trifluorophenyl)pyrimidine (35 mg, 0.10 mmol) and 2,2,2-trifluoroethylamine (50 mg, 0.5 mmol) in 2 mL of N,N-dimethylformamide is stirred at room temperature for 1 h. A saturated sodium chloride solution is added, and the product is extracted with ehtyl acetate. The organic solution is washed with saturated sodium chloride (×4), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of 20% ethyl acetate in hexanes to 50% ethyl acetate in hexanes. Concentration provides 6-chloro-2-(1H-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine as a light tan solid (36 mg, mp 168-170° C.). MS: m/z 408.2 (M+H).
Reaction SMILES: C(Br)(Br)[Br:2].N[C:6]1[C:10]([CH:11]2[CH2:13][C:12]2([Br:15])[Br:14])=[CH:9][N:8]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:7]=1.N(OC(C)(C)C)=O>C(#N)C>[Br:2][C:6]1[C:10]([CH:11]2[CH2:13][C:12]2([Br:15])[Br:14])=[CH:9][N:8]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:7]=1
Reactant: Nc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1(Br)Br
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: FC(F)(F)c1cc(Cl)c(-n2cc(C3CC3(Br)Br)c(Br)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromoform (2 ml) was added to a stirred solution of the title compound of Example 8 (0.25 g) in acetonitrile (2 ml) and the mixture cooled to about 0° C. t-Butyl nitrite was added dropwise, then the reaction mixture allowed to warm to room temperature, stirred for 1 hour at room temperature and then for 1 hour under reflux, allowed to cool and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using mixtures of hexane:ether (19:1 then 9:1) as eluants, to provide the title compound as a colourless gum. δ (CDCl3): 1.85 (t,1H), 2.25 (dd,1H), 2.70 (dd,1H), 7.25 (s,1H), 7.70 (s,2H). MS (thermospray): M/Z [M+H] 554.5; C13H6Br3Cl2F3N2 +H reqires 554.75.
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[O:26])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:7][CH2:6]1)(O)=[O:2].[NH:35]1[C:39]([NH2:40])=[N:38][N:37]=[N:36]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CN(C=O)C>[NH:35]1[C:39]([NH:40][C:1]([CH2:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[F:34])=[O:26])[CH:20]=4)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)=[O:2])=[N:38][N:37]=[N:36]1
Reactant: O=C(O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Reactant: Nc1nnn[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1)Nc1nnn[nH]1

Procedure:
A DMF (4 mL) solution of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester (188 mg) obtained in Example 2, 1H-tetrazol-5-ylamine (54 mg), BOP reagent (212 mg), and diisopropylethylamine (0.10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with 1 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was concentrated and vigorously stirred in water/isopropyl ether. The obtained solid was heated to reflux in methanol and collected by filtration. The title compound (99 mg, 46%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16]Cl.[Na+].[I-].O>[OH-].[K+].CC(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCc1cc(I)ccc1Br
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Brc1ccc(I)cc1COc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Phenol (13 g) dissolved in 4 M KOH solution (60 mL) is added to 4-bromo-3-chloromethyl-1-iodo-benzene (41.0 g) dissolved in acetone (50 mL). NaI (0.5 g) is added and the resulting mixture is stirred at 50° C. overnight. Then, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19].C([O-])([O-])=O.[K+].[K+].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29]>CC(C)=O.O.CN(C)C(Cl)=S>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:19][C:28](=[S:29])[N:27]([CH3:31])[CH3:26]
Reactant: CN(C)C(=S)Cl
Reactant: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=S)Oc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 91.1 %

Procedure:
Place 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (64.3 g, 219 mmol) in acetone (450 mL) and water (200 mL) with K2CO3 (91.8 g, 664 mmol) and dimethylthiocarbamoyl chloride (31.5 g, 255 mmol). Stir at ambient temperature for 1.25 h. Add additional dimethylthiocarbamoyl chloride (3 g, 24 mmol) and stir for an additional 1.75 h at ambient temperature. Add more dimethylthiocarbamoyl chloride (0.7 g, 5.7 mmol) and water (150 mL) to the mixture and stir for 0.5 h at ambient temperature. Slowly add water (500 mL) to the reaction over 2 h to promote crystallization and stir the resulting slurry at ambient temperature for 1.5 h. Collect the solid by filtration to give the desired intermediate (76 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH3:10])[CH:4]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:5]([CH3:10])[CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(N)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(NC(=O)C(C)(C)C)c(C)c1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 4-methoxy-2-methylphenylamine (15.0 g, 109 mmol) and triethylamine (13.3 g, 131 mmol) in anhydrous THF (350 mL) at 0° C. was added pivaloyl chloride (14.1 mL, 13.8 g, 114 mmol). A white precipitate formed and the suspension was stirred for additional 30 min before water (10 mL) was added. The mixture was stirred for 30 min, THF evaporated and the residue was mixed with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and evaporated to an oil (23.5 g, 97%): LC/MS (+APCI) m/z 222 (M+H).