Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(F)cn2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(F)cn2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (69 mg) in ethyl acetate (1.5 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 31 mg, 51%).
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][C:15]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:16][C:17]([O:19]CC)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CNC>O>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6](/[CH:14]=[C:15](/[C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)\[CH2:16][C:17]([OH:19])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)C=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: CNC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2/C=C(\CC(=O)O)c2ccc(F)cc2)CCN(C)C1
Temperature: 100 °C

Procedure:
A mixture of ethyl 4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)but-2-enoate (50 mg, 0.123 mmol; prepared according to General Method 5) and 40% aqueous N,N-dimethylamine (1 mL) was heated overnight at 100° C. The reaction mixture was cooled to RT, diluted with water (5 mL) and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was triturated with ether to obtain a pale yellow solid. 1H NMR (CD3OD, freebase) δ (ppm): 7.65 (m, 2H), 7.30 (d, 1H), 7.20 (m, 3H), 7.05 (d, 1H), 6.90 (d, 1H), 4.35 (m, 2H), 3.50 (m, 2H), 3.20 (m, 4H), 3.0 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[CH3:20])[C:16](=[O:21])[NH:15][CH:14]=[CH:13]3)[CH2:5][CH2:4]1.[CH2:22](N(CC)CC)[CH3:23].C(=O)C.[BH4-].[Na+].Cl>CO>[CH2:22]([NH:2][C@@H:3]1[CH2:4][CH2:5][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[CH3:20])[C:16](=[O:21])[NH:15][CH:14]=[CH:13]3)[CH2:7][CH2:8]1)[CH3:23]
Reactant: Cc1cc2c(=O)[nH]ccc2cc1O[C@H]1CC[C@@H](N)CC1
Reactant: CCN(CC)CC
Agent: CC=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CCN[C@H]1CC[C@@H](Oc2cc3cc[nH]c(=O)c3cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
0.2 g (0.65 mmol) of 6-(cis-4-amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one hydrochloride (138), 69 mg (0.68 mmol) of triethylamine and 35 mg (0.78 mmol) of acetaldehyde were stirred in 13 ml of dry methanol for 4 h at 5° C. After addition of 37 mg (0.97 mol) of sodium borohydride the mixture was stirred overnight at room temperature. Since incomplete conversion of the starting amine was observed the same amounts of actetaldehyde and sodium borohydride were added again sequentially within 2 h. After further stirring for 2 hours the reaction mixture was acidified with concentrated hydrochloric acid and the methanol was evaporated. The aqueous residue was washed with ethyl acetate and then saturated with potassium carbonate and extracted with methylene chloride to give 145 mg of 6-(cis-4-ethylamino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one (139). Rt=0.89 min (Method A). Detected mass: 301.20 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:11]([O-])(=O)=O.[K+].ClCCl>Cl.O>[Cl:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:10]
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(O)c1Cl
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
73 g (0.52 mol) of 3-nitrophenol are dissolved in 2 liters-of 6N hydrochloric acid while heating. The mixture is cooled in an ice bath to 28°-30° C. 32 g (0.26 mol) of potassium chlorate in 500 ml of water are added over 1.5 hours and then, at the end of the addition, the mixture is left stirring for 30 minutes at 28°-30° C. The mixture is cooled to 15° C. and 1 liter of dichloromethane is added. The layers are separated and the organic phase is washed with water. The organic phase is dried and evaporated. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane/methanol (80/20) mixture. Recrystallization is carried out from toluene. 29 g of product are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:36])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=3[S:20](=[O:34])(=[O:33])[N:19]=2)[C:8]1=[O:35].[OH-].[Na+:40]>O>[CH3:1][C:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:36])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O-:17])=[C:9]([C:18]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=3[S:20](=[O:34])(=[O:33])[N:19]=2)[C:8]1=[O:35].[Na+:40]
Reactant: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A suspension of the product of Example 37C (0.302 g) in water (10 mL) was treated with 0.997N sodium hydroxide solution (0.545 mL, 0.540 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.308 g, 98%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.58 (m, 1 H) 0.73 (m, 9 H) 0.95 (m, 5 H) 1.38 (m, 3 H) 1.71 (m, 1H) 2.13 (m, 1 H) 2.94 (m, 3 H) 7.32 (m, 3 H) 7.46 (m, 3 H) 8.04 (m, 1 H) 9.88 (m, 1 H) 15.46 (m, 1 H). MS (ESI−) m/z 558 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:26])[C:24]#[N:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:27]=[N+:28]=[N-:29].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:24]3[NH:29][N:28]=[N:27][N:25]=3)[CH3:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C#N)CCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1nnn[nH]1
Yield: 68.2 %

Procedure:
3 g of (RS)-7(4,5-diphenyl-2-oxazolyl)-2-methylheptanenitrile in 30 cm3 of dimethylformamide are treated with twice 1.7 g of sodium azide and twice 3.6 g of triethylamine hydrochloride under the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 2 cm in diameter containing 78 g of silica gel (50 to 200μ). The column is eluted, collecting 200 cm3 fractions, with 1 liter of diisopropyl ether and then with 1.6 liters of a diisopropyl ether/ethyl acetate (95:5 by volume) mixture. The fractions from the last eluent mixture are concentrated to dryness under reduced pressure (0.2 kPa). 2.3 g (68%) of (RS)-5-[7-(4,5-diphenyl-2-oxazolyl)-2-heptyl]-1H-tetrazole are obtained in the form of a yellowish oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:17]>C(O)C.[C].[Pd]>[ClH:17].[OH:16][CH2:15][C:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OCC1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OCC1(O)CCNCC1
Reaction time: 8 h

Procedure:
500 mg of 1-benzyl-4-(hydroxymethyl)piperidin-4-ol (synthesized according to the method described in J. Med. Chem., 1988, 486-491) was dissolved in 10 ml of ethanol, 300 mg of 10% palladium carbon and 0.38 ml of concentrated hydrochloric acid were added thereto, and the mixture was subjected to hydrogenation at room temperature overnight. The reaction mixture was filtrated to remove precipitates, the precipitates were washed with ethanol and water, and the filtrate was concentrated under reduced pressure. The obtained residue was turned into powder by adding diethylether to obtain 374 mg of the objective compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[C:18]([F:23])[CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]4=[O:24])=[C:18]([F:23])[CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)c(F)c2)cn1)c1ccc(Cl)s1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)c(F)c2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 13.3 %

Procedure:
A mixture of 5-chloro-N-((1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (83 mg, 0.14 mmol), 2-hydroxypyridine 1-7 (30 mg, 0.31 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture was heated at 130° C. in a sealed tube for 4 h. It was then purified by HPLC to give the titled compound (8 mg). MS 429.0 and 431.0 (M+H, Cl pattern).
Reaction SMILES: [P:1](=[S:17])(Cl)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.[NH2:19][NH2:20].NN>>[P:1](=[S:17])([NH:19][NH2:20])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: NN
Solvent: O
Product: NNP(=S)(Oc1ccccc1)Oc1ccccc1
Yield: 84 %

Procedure:
O,O-Diphenyl phosphorochloridothioate, (PhO)2P(S)Cl, (38 g, 0.13 mole) was added slowly to hydrazine hydrate, (25 g of 60% solution ≅0.47 mole hydrazine) at 65°-75° C. The mixture was allowed to cool slowly and the solid product was then recovered by filtration, washed with water and dried. Recrystallization from benzene/petroleum ether (1:1) gave 30.5 g product (84% yield) melting at 59°-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Cl[C:30]1C=CC(OC(C2C=CC(OC3C=CC(Cl)=CC=3)=CC=2)C(OC)=O)=CC=1C.CN(C)P(N(C)C)(N(C)C)=O.CI>O1CCCC1.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[CH3:30]
Reactant: COC(=O)C(C)(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C(Oc1ccc(Cl)c(C)c1)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(Oc1ccc(Cl)c(C)c1)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.015 mole of lithium N,N-diisopropylamide (prepared as in example 55) in tetrahydrofuran is chilled to -65° C. to -75° C. To the solution is added methyl (4-chloro-3-methylphenoxy)[p-(p-chlorophenoxy)phenyl]acetate in tetrahydrofuran. To the mixture is added 5 ml of hexamethylphosphoramide and while chilling to -65° C. to -75° C., 4.26 g of methyl iodide is added. After 1 hr., the mixture is allowed to warm to room temperature and stirr overnight. The mixture is poured into water and extracted with ether. The ether extracts are washed with 10% hydrochloric acid, water, saturated NaHCo3, saturated NaCl solution and dried (MgSO4). Evaporation of the solvent under reduced pressure gives the product as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][O:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH2:17]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:21]3[C:20]([CH3:22])=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][C:14]=4[C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c(OCC(=O)c3ccc(C(C)C)cc3)c1)CCC2
Solvent: CO
Product: Cc1cc2c(c3occ(-c4ccc(C(C)C)cc4)c13)CCC2
Yield: 77 %

Procedure:
Using 1-(4-isopropylphenyl)-2-((6-methyl-2,3-dihydro-1H-inden-4-yl)oxy)ethanone obtained in Reference Example 180, the title compound was synthesized in the same manner as in Reference Example 143. Yield 77%. Melting point: 70-72° C. (methanol).
Reaction SMILES: C(CC([N:6]1[CH2:9][CH:8]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]4[CH:39]=[CH:38][C:29]5[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=5[CH:27]=4)[CH:19]=3)=[C:13]([CH3:40])[CH:12]=2)[CH2:7]1)=O)#N.[OH-].[Li+]>O1CCCC1.CO>[NH:6]1[CH2:9][CH:8]([O:10][C:11]2[CH:12]=[C:13]([CH3:40])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]4[CH:39]=[CH:38][C:29]5[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=5[CH:27]=4)[CH:19]=3)=[C:15]([CH3:17])[CH:16]=2)[CH2:7]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)CC#N)C5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OC2CNC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
(S)-Methyl 2-(6-((4′-((1-(2-cyanoacetyl)azetidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 16c (80 mg, 0.15 mmol) was dissolved in 2 mL of a mixture of the solvents of tetrahydrofuran and methanol (V/V=1:1), followed by addition of 1M aqueous lithium hydroxide solution (1 mL, 1 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-2-(6-((4′-(azetidin-3-yloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 16 (65 mg, yield 95.6%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8].[ClH:19]>[Pt](=O)=O>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(F)c2)c1
Agent: O=[Pt]=O
Agent: Cl
Product: COC(=O)C1CCNC(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
Methyl 2-(3,4-difluorophenyl)isonicotinate (5.821 g, 23.36 mmol) was dissolved in hydrogen chloride (1.25 M in MeOH) (37.4 mL, 46.72 mmol) and stirred at room temperature for 30 min. The solvent was evaporated in vacuo. The remaining HCl salt was redissolved in MeOH (20 mL), platinum(IV) oxide (0.159 g, 0.70 mmol) was added and the reaction mixture hydrogenated in a Büchi hydrogenator at 5 bar and room temperature for 6 h. The catalyst was filtered off, washed with MeOH and the filtrate evaporated in vacuo to yield methyl 2-(3,4-difluorophenyl)piperidine-4-carboxylate hydrochloride (6.10 g, 90%) as a pale solid. MS m/z 256 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:8])([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:4][CH2:3][C:2]([F:8])([F:1])[CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])(=[O:18])=[O:17]
Reactant: OCCC(F)(F)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC(F)(F)COS(C)(=O)=O
Reaction time: 8 h

Procedure:
To a stirred mixture of 2,2-difluoro-1,4-butanediol (12.97 g, 103 mM), dry pyridine (65 mL) and dichloromethane (200 mL) is slowly added a solution of methanesulfonylchloride (23.6 g) in dichloromethane (50 mL). Stirring is continued overnight. The reaction mixture is washed with 2N HCl (twice), followed by 10% aqueous NaHCl3 until neutral, and then with water. The organic layer is dried (MgSO4) and upon evaporation of the solvents, a slightly yellow oil is obtained. Crystallization is induced by scratching the oil with dry ether, to yield the compound 1,4-bis-methanesulfonyloxy-2,2-difluorobutane as white crystals: 22.3 g (77%).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:40]=[CH:39][C:19]3[C:20](=[O:38])[CH2:21][C:22]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[O:23][C:18]=3[C:17]=2[CH2:41][CH2:42][CH3:43])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:40]=[CH:39][C:19]3[C:20](=[O:38])[CH2:21][C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[O:23][C:18]=3[C:17]=2[CH2:41][CH2:42][CH3:43])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1c(OCCCOc2cccc3ccccc23)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Product: CCCc1c(OCCCOc2cccc3ccccc23)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O

Procedure:
The title compound was prepared by the method of Example 22 substituting the title product of Example 28 (549 mg) for the title product of Example 21 to give, after crystallization from ethyl acetate, 141 mg, m.p. 164°-167° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:31][C:32]1[N:33]=[CH:34][N:35]([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][C:38]=2[O:44][CH3:45])[CH:36]=1>>[Cl:31][C:32]1[N:33]=[CH:34][N:35]([C:37]2[CH:43]=[CH:42][C:40]([NH:41][C:2]3[N:3]=[C:4]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:22][CH2:23]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:39][C:38]=2[O:44][CH3:45])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Product: COc1cc(Nc2nc3c(c(N4CCN(C(=O)OC(C)(C)C)CC4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Yield: 62.1 %

Procedure:
tert-butyl 4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (Preparation Hl) (117 mg, 0.270 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (60.4 mg, 0.270 mmol) were combined as per Example 26 to give tert-butyl 4-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (104 mg, 0.168 mmol, 62.1% yield) crude without purification. LC-MS (M+H)+=620.4.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1ccccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 65A (0.014 g, 0.046 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.020 g, 49% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(m, 9H), 0.89(m, 9H), 1.62-1.48(m, 2H), 2.31(s, 3H), 2.34-2.24(m, 1H), 2.62-2.53(m, 1H), 2.68-2.65(m, 2H), 2.84-2.73(m, 2H), 2.97-2.88(m, 1H), 3.22-3.12(m, 1H), 3.50(s, 3H), 3.70-3.62(m, 1H), 3.87-3.83(d, J=9.93 Hz, 1H), 4.08(s, 1H), 4.43-4.12(m, 4H), 4.55-4.52(d, J=7.72 Hz, 1H), 6.65-6.62(d, J=9.56 Hz, 1H), 7.01-6.99(m, 3H), 7.09-7.08(m, 2H), 7.24-7.20(m, 5H), 7.32-7.29(m, 1H), 7.49-7.46(d, J=9.56 Hz, 1H), 7.91-7.82(m, 5H), 8.64-8.63(d, J=4.41 Hz, 1H).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCO
Agent: Cl
Product: CCCCCCCCOP(=O)(Cl)Cl
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
Phosphoryl trichloride (3113 g; 20.3 moles) is placed in a 5-liter flask fitted with a condenser and mechanical stirrer, and cooled down to about 10° C. (external ice bath). Octanol (2380 g; 18.3 moles; 0.9 equivalents with respect to POCl3) is added at a rate such that the reaction temperature remains below 15° C. The reaction is exothermic and the HCl gas that evolves during this reaction is vented out with a flow of nitrogen through an aspirator operated with a slight vacuum of about 0.5 inches of mercury. When addition of alcohol is completed (2-3 hours), the ice bath is removed and the reaction mixture is allowed to warm to room temperature and then warmed to 60°-70° C. and stirred at this temperature for 1.5 hours to drive out most of the HCl gas. The product, octyl phosphorodichloridate, is obtained as a clear light yellow free-flowing liquid.