Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH2:7][CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH3:19]>CN(C=O)C>[N:1]1([C:6]2[CH2:7][CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16](=[O:18])[NH2:19])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Reactant: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Reaction time: 4 h

Procedure:
To a suspension of 1,2-dihydro-3-(1-imidazolyl)-6-carboxy-naphthalene (500 mg) in DMF (10 ml) SOCl2 (2 ml) was added. Cooling in an ice bath, NH3 was passed through the reaction mixture, with stirring, for 4 hours. The reaction mixture was allowed to stand for 12 hours. The ammonium salt was filtered off and Et2O was added giving a precipitate which was chromatographed on silica gel with CHCl3 :CH3OH-CH3COOH (45:5:2.5) as eluant; 350 mg of 1,2-dihydro-3-(1-imidazolyl)-6-carbamoyl-naphthalene were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=1.[C:14]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[C:14]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[CH:13]=[CH:12][C:7]4[N:8]=[CH:9][S:10](=[O:11])[C:6]=4[CH:5]=3)[CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=S1C=Nc2ccc(CCBr)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=S1C=Nc2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc21

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.0 g (3.88 mmol) of 6-(2-bromoethyl)benzothiazolone, 822 mg (3.88 mmol) N-(1-naphthyl)piperazine, 410 mg (3.88 mmol) sodium carbonate, and 50 ml methylisobutylketone. The reaction was refluxed for 24 hours, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The resulting solid was treated with hot ethyl acetate to afford a white solid, m.p. 198°-220° C., 540 mg (36%).
Reaction SMILES: [Na].[N:2]#[C:3][NH2:4].[C:5]1([N:11]=[C:12]=[S:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)=[O:17]>CO.O>[NH2:2][C:3]1[N:4]=[C:12]([NH:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[S:13][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)=[O:17]
Reactant: N#CN
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: S=C=Nc1ccccc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: Nc1nc(Nc2ccccc2)sc1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
Following the procedure of Gewald et al., J. Prakt. Chem., vol. 35 (1967), pp. 97-104, sodium (188 mg, 8.20 mmol) was carefully dissolved in methanol (9 mL) at 0° C. and allowed to warm to ambient temperature. The resultant solution was added portionwise to a mixture of cyanamide (345 mg, 8.20 mmol) and phenyl isothiocyanate (0.98 mL, 8.2 mmol), whereupon heat evolved. 2-Bromo-3′-nitroacetophenone (2.00 g, 8.2 mmol) was added, and the resultant mixture stirred overnight at ambient temperature. The mixture was diluted with water (150 mL). A yellow-brown solid was filtered off, rinsed with water and a small amount of ether, dried under vacuum, and recrystallized from ethanol to give 2.17 g (52% yield) of the title compound in the form of dark brown crystals, melting point (mp) 186-187° C.
Reaction SMILES: [N:1]1([C:7]2[C:12]3[CH:13]=[CH:14][O:15][C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>ClCCCl.CO>[O:15]1[C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]4)[CH2:5][CH2:6]3)[C:12]=2[CH:13]=[CH:14]1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2occc2c(N2CCNCC2)n1
Solvent: ClCCCl
Solvent: CO
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of commercially available 4-piperazine-1-yl-furo[3,2-c]pyridine [CAS-Nr. 81078-84-4] (125 mg, 0.62 mmol) in 1,2-dichloroethane (1.25 ml) were added trans-N-[4-(2-oxo-ethyl)-cyclohexyl]-acetamide [CAS-Nr. 946599-01-5, WO 2007/093540] (124 mg, 0.68 mmol) and 3 drops of MeOH. The resulting yellow solution was stirred 18 h at room temperature before addition of Na(AcO)3BH (196 mg, 0.92 mmol). After stirring 18 h at room temperature the reaction mixture was partitioned between sat. aq. NaHCO3 sol. (50 ml) and EtOAc (50 ml). The aqueous layer was extracted with more EtOAc (2×25 ml). The combined organic layers were washed with H2O (40 ml) and brine (40 ml) and dried over MgSO4. After evaporation of the solvent, the crude product (yellow crystals) was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 95:5) to yield the title compound as light yellow crystals (95 mg, 42%), MS (ISP) m/z=371.2 [(M+H)+].
Reaction SMILES: BrCC.[CH:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:11](Br)[CH:12]=[CH2:13].Cl>CCOCC.Cl[Cu]>[CH2:4]=[CH:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C#CCCCCC
Reactant: C=CCBr
Agent: Cl[Cu]
Agent: Cl
Solvent: CCOCC
Solvent: CCBr
Product: C=CCC#CCCCCC
Yield: 70 %

Procedure:
A solution of bromoethane (43.6 g, 400 mmol) in Et2O (280 ml) was added dropwise to a suspension of Mg (9.6 g, 400 mmol) in Et2O (140 ml). After 3 hours a solution of 1-heptyne (35.0 g, 360 mmol) in Et2O (140 ml) was added dropwise to the reaction medium. After 90 minutes at reflux, CuCl (1.8 g, 18.2 mmol) was added to the cold reaction mixture and after 15 minutes a solution of allyl bromide (48.4 g, 400 mmol) in Et2O (140 ml) was added dropwise. After 18 hours at reflux, the cold reaction mixture was poured onto 10% aqueous HCl (320 ml) at 0° C. The aqueous phase was extracted with Et2O, then the organic phase was washed with H2O, dried (MgSO4), concentrated and distilled through a Vigreux column (65915 mbar) to afford the pure desired compound (70%).
Reaction SMILES: C[Si](C)(C)C#C[C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[C:9]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:8]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:7][C:6]=1[CH2:28][OH:29].[CH2:32]1COC[CH2:33]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:32]([CH:28]([C:6]1[CH:5]=[C:10]([C:11]([CH3:13])([CH3:14])[CH3:12])[C:9]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[C:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:7]=1)[OH:29])#[CH:33]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc(CO)c(C#C[Si](C)(C)C)c(C(C)(C)C)c1OCOCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C#CC(O)c1cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.5 g (40 mmol) of α-trimethylsilylethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol and 50 ml of THF are introduced into a round-bottomed flask and 40 ml (44 mmol) of tetrabutylammonium fluoride solution (1.1 M in THF) are added dropwise. The mixture is stirred at room temperature for one hour, the reaction medium is poured into water and extracted with ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and hexane (5/95 by volume). After evaporation of the solvents, 13.5 g (86%) of α-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol are collected in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][NH:19][C:13]=2[CH2:12]1)=[O:10].[H-].[Na+].I[CH3:29]>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:18][N:19]([CH3:29])[C:13]=2[CH2:12]1)=[O:10].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][C:14]2=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:18]([CH3:29])[N:19]=[C:13]2[CH2:12]1)=[O:10]
Reactant: CI
Reactant: O=C(c1cccc(Cl)c1Cl)N1CCc2c(-c3ccccc3)n[nH]c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2)c2c1CN(C(=O)c1cccc(Cl)c1Cl)CC2
Product: Cn1nc2c(c1-c1ccccc1)CCN(C(=O)c1cccc(Cl)c1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 2657.9 %

Procedure:
To a solution of 6-[(2,3-Dichlorophenyl)carbonyl]-3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (35 mg, 0.09 mmol) in DMF (0.5 mL) was added NaH (60%) (5 mg, 0.1 mmol). The reaction was allowed to stir at rt for 1 hr then iodomethane (0.005 mL, 0.09 mmol) was added. The reaction mixture was allowed to stir for 2 hours. After aqueous workup, the resulting mixture was extracted with ethyl acetate. The combined organic layers were dried and concentrated into a yellow residue which was purified via Basic HPLC (0-99% acetonitrile/water (NH4OH)) to afford the desired product 924 mg, 33%). MS (ESI): mass calcd. for C20H17C12N3O, 386.28. m/z found, 387.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH2:28][CH2:29][CH2:30][CH:31](Br)[CH3:32]>>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([C:20]([F:21])([F:22])[F:23])[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=1[C:9]([NH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[N:1]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH3:28])=[O:26]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: CC(Br)CCCBr
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1C

Procedure:
The title compound, MS: m/e=453.2 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1,4-dibromopentane. The two diastereomers were not separated.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:27][CH:28]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1c2n(c3c(-c4ccc(N)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (64 mg, 82%), MS (ISP) m/z=311.5 [(M+H)+], mp 254° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:3]1.O.NN.NN>CO>[NH2:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([OH:1])[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCCC[C@H](O)C1
Agent: NN
Solvent: CO
Solvent: O
Product: N[C@@H]1CCCC[C@H](O)C1
Reaction time: 8 h
Yield: 19.4 %

Procedure:
2-((1R,3S)-3-Hydroxycycloheptyl)-isoindoline-1,3-dione (1800 mg, 6.94 mmol) was dissolved in methanol (86.80 mL). Hydrazine monohydrate (0.354 mL, 7.29 mmol) was added to the solution and the resulting mixture was stirred overnight at reflux. An additional 0.2 eq (0.067 mL) of hydrazine was added and the mixture was refluxed for a second night. The reaction mixture was concentrated to a volume of a few milliliters and filtered. The solids were rinsed with 50 mL each of DCM and chloroform and the resulting filtrate concentrated under reduced pressure to afford the title compound (174 mg, 1.347 mmol, 19.40% yield) as an oil that was used without further purification. MS (ESI) m/z 130.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]1(=O)OC(C)C[O:6]1.[CH:12]1[C:17]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:15]=[C:14]([Cl:22])[CH:13]=1>CN(C=O)C>[Cl:22][C:14]1[CH:13]=[CH:12][C:17]([S:18]([NH:21][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])(=[O:20])=[O:19])=[CH:16][CH:15]=1
Reactant: CC1COC(=O)O1
Reactant: CCCN
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCCNC(=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
n-Propylamine (5.9 g., 0.1 mole.) and propylene carbonate (10.2 g., 0.1 mole.) were mixed and heated at 60° over night. To the resulting hydroxypropyl-n-propylcarbomate were added p-chlorobenzene sulfonamide (10.67 g., as sodium salt) and DMF (200 ml.) and the mixture was heated at 120° for 4 hours. After evaporation of the solvent the residue was taken up in water (200 ml.) and the solution adjusted to pH 8 by the addition of acetic acid. Unreacted p-chlorobenzene sulfonamide (2 g.) separated out and was collected. Further adjustment to pH 5 precipitated 1-(4-chloro-benzenesulfonyl)-3-n-propyl-urea (2 g.) whose infrared spectrum was identical with that of an authentic sample.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]3[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]3[N:15]=[C:16]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(Sc3ccc(Br)cc3)c2n1
Product: Brc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 8-(4-bromophenyl-thio)-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 205°-207° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:34][CH3:35])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:37]1C=C(S(Cl)(=O)=O)C=C(Cl)C=1>>[CH3:37][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=3)(=[O:24])=[O:25])=[C:16]([O:34][CH3:35])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)cc2c1CCN2S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 555.25 (M+H+.), was prepared in analogy to example 21, steps 1 to 6. Step 5 was performed using 3,5-dichloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)ncn1
Product: CC(C)(C)c1cc(Cl)ncn1
Yield: 78 %

Procedure:
Next, 4.7 g of 4-hydroxy-6-tert-butylpyrimidine obtained in Step 1 and 14 mL of phosphoryl chloride were put in a 50 mL three-neck flask, and the mixture was heated and refluxed for 1.5 hours. After the reflux, phosphoryl chloride was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane, and washed with water and then a saturated aqueous solution of sodium hydrogen carbonate. Anhydrate magnesium sulfate was added to the obtained organic layer for drying. This mixture was subjected to gravity filtration, and the filtrate was condensed to give a solid. This solid was purified by silica gel column chromatography. As a developing solvent, a mixed solvent of hexane and ethyl acetate in a ratio of 10:1 (v/v) was used. The obtained fraction was condensed to give 4-chloro-6-tert-butylpyrimidine (white solid, yield of 78%). A synthetic scheme of Step 2 is shown in (a-2) below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:33])[C:5]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[NH:26][C:25]=4[CH:32]=3)[N:14]=2)=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:50]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)#[N:51]>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>[CH3:10][NH:9][C:7]([C:6]1[CH:11]=[C:2]([C:55]2[CH:56]=[CH:57][C:52]([C:50]#[N:51])=[CH:53][CH:54]=2)[CH:3]=[C:4]([F:33])[C:5]=1[NH:12][C:13]1[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[NH:26][C:25]=3[CH:32]=2)[N:14]=1)=[O:8]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CNC(=O)c1cc(-c2ccc(C#N)cc2)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl
Temperature: 90 °C
Yield: 43.7 %

Procedure:
5-Bromo-2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (55.0 mg, 0.103 mmol) was dissolved in toluene (4.00 mL, 37.6 mmol) and ethanol (4.00 mL, 68.5 mmol). Tetrakis(triphenylphosphine)palladium(0) (11.9 mg, 0.0103 mol) was added followed by 1.00 M sodium carbonate in water (412 uL) and 4-cyanophenylboronic acid (21.2 mg, 0.144 mmol). The reaction was heated at 90° C. overnight and then concentrated under reduced pressure. The residue was taken up in DCM (10 mL) and washed with 1 M Na2CO3 (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-HPLC using a gradient of 20-45% AcN/water containing 0.1% TFA as the eluting solvent to obtain 4-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-4′-cyano-5-fluoro-biphenyl-3-carboxylic acid methylamide as a white foam (25 mg, 44%). LCMS (m/e) 556 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.54 (s, 1H), 9.40-9.30 (m, 2H), 8.80-8.71 (m, 1H), 8.21 (s, 1H), 8.08-7.98 (m, 4H), 7.95 (d, 1H, J=12.1 Hz), 7.89 (s, 1H), 7.27 (d, 1H, J=8.1 Hz), 7.16-7.10 (m, 1H), 6.93 (d, 1H, J=8.1 Hz), 2.77 (d, 3H, J=4.2 Hz), 2.60-2.43 (m, 2H), 2.02-1.94 (m, 4H); 19F-NMR (d6-DMSO, 400 MHz) δ −75.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.Cl.[N:29]1([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)[Cl:57]>CCOCC.CO.C(Cl)(Cl)Cl>[ClH:57].[CH3:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]([C:4]1[CH:3]=[C:2]([O:1][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:11]2[C:10]3[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: ClCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CC(C)CC1

Procedure:
2.5 g. (6.76 mmole) of 1-Hydroxy-3-(3-methyl-2-octyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran was combined with 1.41 g. (6.76 mmole) of γ-piperidinobutyric acid hydrochloride and 1.48 g. (7.16 mmole) of dicyclohexylcarbodiimide in 125 ml. of methylene chloride and stirred at room temperature for 16 hours. The by-product of dicyclohexylurea was removed by filtration and the filtrate was evaporated to give a light brown residue. The residue was dissolved in ether and the small amount of solid which appeared was removed by filtration. The ether was removed on a rotary evaporator and the gummy residue which remained was triturated several times with small quantities of hexane. The material was thoroughly dried to give 2.8 g. (74%) of product as a colorless powder. The material was pure by thin layer chromatography (10% MeOH/CHCl3); the infrared and nmr spectra are consistent with the desired product.
Reaction SMILES: C1(C2OC(C(F)(F)F)=C(C(NC3C=CC(C4C=CC(C([C@@H]5CCC[C@H]5C(O)=O)=O)=CC=4)=CC=3)=O)N=2)C=CC=CC=1.[C:41]1([C:47]2[O:48][C:49]([C:78]([F:81])([F:80])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([CH:69]5[CH2:74][CH2:73][CH2:72][CH2:71][CH:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:57][CH:56]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(C2OC(C(F)(F)F)=C(C(O)=O)N=2)C=CC=CC=1.NC1C=CC(C2C=CC(C([C@H]3CCCC[C@H]3C(O)=O)=O)=CC=2)=CC=1>>[C:41]1([C:47]2[O:48][C:49]([C:78]([F:80])([F:81])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([C@H:69]5[CH2:74][CH2:73][CH2:72][CH2:71][C@H:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:59][CH:60]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(-c2ccc(C(=O)C3CCCCC3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Nc1ccc(-c2ccc(C(=O)[C@H]3CCCC[C@H]3C(=O)O)cc2)cc1
Agent: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(-c2ccc(C(=O)[C@H]3CCCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of racemic trans-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid above, racemic 2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic cis-2-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product was separated by chiral SFC to afford (1R,2S)-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer). [α]D: +11.7° in DMSO. LCMS calcd for C31H25F3N2O5 (m/e) 562, obsd 563 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[CH:18][CH:19]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[CH:18][N:17]([CH2:24][C:25]([CH3:27])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:26])[N:16]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(CCl)c1ccccc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(-c2ccn(CC(C)(C)c3ccccc3)n2)sc1C(=O)NCc1ccc(F)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)thiazole-5-carboxylic acid 4-fluoro-benzylamide and (2-chloro-1,1-dimethyl-ethyl)-benzene as describe in Example 83 and isolated as a white solid (0.046 g, 33% yield). 1H NMR (400 MHz, CDCl3) δ 7.22-7.35 (m, 7H), 7.02-7.08 (m, 1H), 6.69 (d, J=2 Hz, 1H), 6.62 (d, J=2 Hz, 1H), 5.96-6.03 (bm, 1H), 4.57 (d, J=4 Hz, 2H), 4.28 (s, 2H), 2.73 (s, 3H), 1.40 (s, 6H); MS (M+H)+=449.2; Rt=1.64 min; HRMS (M+H)+=449.18.