Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:13]=[O:14])=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(-c2ccccc2C=O)cc1

Procedure:
Methyl (4-bromophenyl)acetate (5.9 g), (2-formylphenyl)boronic acid (5.0 g) and potassium carbonate (10.8 g) were combined in a mixture of toluene and methanol [9:1] (50 mL). The resulting mixture was degassed by bubbling nitrogen though for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (1.5 g) was added and the reaction heated to reflux for 12 hours, under nitrogen. The reaction mixture was filtered through a pad of Celite, the filter pad was washed with ethyl acetate and the combined filtrates evaporated. Purification on silica, eluting with a gradient 0 to 10% ethyl acetate in iso-hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:15]([OH:17])=O)=[CH:5][N:6]=[C:7]2[O:12][CH2:13][CH3:14].CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1.O>C(O)(=O)C>[CH2:13]([O:12][C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]3[N:1]4[C:20]([C:15](=[O:17])[C:4]([C:3]=23)=[CH:5][N:6]=1)=[CH:24][CH:23]=[CH:22]4)[CH3:14]
Reactant: CCOc1ncc(C(=O)O)c2c(N)cccc12
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ncc2c(=O)c3cccn3c3cccc1c23
Temperature: 20 °C

Procedure:
A solution of 5-amino-4-carboxy-1-ethoxyisoquinoline (50.8 g) and 2,5-dimethoxytetrahydrofuran (32 cc) in acetic acid (250 cc) is kept at a temperature between 90° and 95° C. for 35 minutes, whilst stirring. The solution is cooled to about 20° C. and then poured into water (1250 cc). The yellow crystals which precipitate are filtered off and washed with water (5 × 50 cc). After drying under reduced pressure (1 mm Hg) at 20° C., crude 4-ethoxy-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (52.7 g) is obtained. After recrystallisation from ethanol, the pure product melts at 188° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH:29]3[CH2:33][CH2:32][CH2:31][O:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCC1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCCO1

Procedure:
Prepared similarly to Intermediate 213 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1>>[NH2:37][C:23]1[N:24]=[CH:25][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:27][C:22]=1[CH3:21]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cnc(N)c(C)c3)ccn2c1=O

Procedure:
Methyl 8-(6-amino-5-methylpyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (96.2 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[N:25]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[N:29][C:24]2=[N:23][CH:22]=1)CCC>>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:27]=[CH:26][N:25]2[C:21]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10]#[N:11])[CH:3]=3)=[CH:22][N:23]=[C:24]2[N:29]=1
Reactant: N#Cc1ccccc1-c1cc(Cl)ccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccn1
Yield: 13.7 %

Procedure:
2-(4-Chloropyridin-2-yl)benzonitrile (65 mg, 0.3 mmol) was coupled with 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.6 mmol) as described in Example 1 to give 2-[4-(7-trifluoromethyl-imidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile (15 mg) as a white solid: δH (400 MHz, DMSO) 7.62 (1H, d, J 7.0), 7.69 (1H, m), 7.88 (1H, m), 7.93 (1H, dd, J 5 and 2), 8.04 (2H, m), 8.27 (1H, d, J 1), 8.60 (1H, s), 8.92 (1H, dd, J 5 and 1), 9.60 (1H, d, J 8); m/z (ES+) 366 (M++H).
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]1[CH:6]=[C:7]([NH2:21])[C:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])=[CH:9][CH:10]=1>C(O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]2[N:11]([C:12]3[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=3[CH3:18])[C:2]([NH2:1])=[N:21][C:7]=2[CH:6]=1
Reactant: N#CBr
Reactant: Cc1cc(C)c(Nc2ccc(F)cc2N)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(-n2c(N)nc3cc(F)ccc32)c(C)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A solution of cyanogen bromide (2.67 g, 25.2 mmol) in anhydrous ethanol (10 mL) was added at 0° C. to a solution of 4-fluoro-N1-(2,4,6-trimethyl-phenyl)-benzene-1,2-diamine (4.74 g, 19.4 mmol) in anhydrous ethanol (20 mL) under nitrogen. The reaction mixture was warmed up to room temperature for 10 min, then was heated at 155° C. for 40 min with a flow of nitrogen to remove ethanol. Upon cooling to room temperature, the resulting solids were transferred to a separatory funnel via dichloromethane (70 mL), and washed sequentially with 1 N sodium hydroxide (2×35 mL), water and brine. The organic layer was dried over anhydrous sodium sulfate and solvents were removed in vacuo to afford the title compound as a red solid (5.11 g, 98% yield). The purity of this compound was determined to be 95% by LC/MS. 1H NMR (CDCl3, 300 MHz) δ 7.12 (dd, J=9.7, 2.4 Hz, 1H), 7.06 (s, 2H), 6.69 (td, J=9.1, 2.4 Hz, 1H), 6.56 (dd, J=8.5, 4.7 Hz, 1H), 2.38 (s, 3H), 1.98 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 161.0, 157.9, 154.2, 143.3, 139.9, 137.4, 129.8, 128.8, 107.8 (d, J=10.2 Hz), 106.9 (d, J=25.3 Hz), 103.1 (d, J=25.2 Hz)21.1, 17.5; Mass spec.: 270.17 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[C-:17]#[N:18].[Na+]>CCO.O>[F:14][C:13]([F:16])([F:15])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]=1[CH2:2][C:17]#[N:18]
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(C(F)(F)F)cccc1C(F)(F)F

Procedure:
A solution of 0.73 g (2.4 mmol) 2-bromomethyl-1,3-bis-trifluoromethyl-benzene and 0.183 g (3.7 mmol) sodium cyanide in 10 ml EtOH/H2O 6:1 (v/v) was hated to reflux for 3h. Then the reaction mixture was evaporated, the residue taken up in water and extracted with tert-butyl methyl ether. The combined extracts were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and evaporated. Purification by flash chromatography on silica gel with a gradient of 95:5 to 70:30% heptane/ethyl acetate provided (2,6-bis-trifluoromethyl-phenyl)-acetonitrile as colourless crystalline product of m.p. 84.5-86° C.: MS (EI): 253.0 (M.+ ), 234.1 ((M-F) .+), 233.1 ((M-HF)+.), 184.0 (((M-CF3)+.), 100%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Br:16])[CH:15]=1)[CH:11]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH2:1])[CH:13]=[C:14]([Br:16])[CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A solution of methyltriphenylphosphonium bromide (20.30 g, 56.8 mmol) in dry THF (50 mL) is cooled to 0° C. under N2 and then treated with solid potassium tert-butoxide (6.38 g, 56.8 mmol) in portions. The resultant yellow slurry is warmed to rt and stirred for 30 minutes. The mixture is cooled to −78° C., and a solution of 3,5-dibromobenzaldehyde (10.0 g, 37.9 mmol) in THF (50 mL) is added dropwise. The reaction is warmed to rt and stirred for 1 hour. The mixture is poured into ice water containing 1 N HCl (56 mL) and then extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 10/1 hexanes/ethyl acetate to afford 4.56 g (46%) of the title compound. Rf=0.64 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5]([CH3:8])([CH3:7])[CH2:4][O:3]1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>ClCCl>[CH3:1][C:2]1([CH3:9])[N:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:8])([CH3:7])[CH2:4][O:3]1
Reactant: CC1(C)COC(C)(C)N1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1C(C)(C)COC1(C)C
Reaction time: 16 h
Yield: 80 %

Procedure:
12.11 g (100.0 mmol) of 2,2,4,4-tetramethyl-1,3-oxazolidine (can also be employed in the form of the mixed fraction) were added gradually at room temperature to a solution of 5.43 g (50.0 mmol) of ethyl chloroformate in 50 ml of dry dichloromethane. After stirring for 16 hours, the reaction mixture was poured into 40 ml of 2N HCl. The phases were separated, the aqueous phase was extracted three times with 20 ml of ether each time and the combined organic phases were deacidified and dried over solid sodium hydrogen sulphate and sodium sulphate in the amount ratio 1:2. After the removal of the solvent in vacuo at a maximum of 100 mbar/40° C. bath temperature, the crude product was distilled under reduced pressure. 8.05 g (80%) of the title compound were obtained as a colorless liquid of b.p.: 87° C./10 mbar and RF =0.61 (silica gel, ether/pentane 1:1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1
Reactant: N#CCc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCc1cccc(Br)c1
Temperature: -5 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A suspension of LiAlH4 (3.04 g, 80 mmole) in dry THF (100 mL) was cooled to −5° C. Concentrated H2SO4 (3.9 g, 40 mmole) was added dropwise, and the resulting mixture was stirred at −5° C. for 1 hour. A solution of 3-bromo-benzenacetonitrile (9.80 g, 50 mmole) in THF (5 mL) was added dropwise, and the reaction was allowed to warm to room temperature when the addition was complete. The reaction was stirred at room temperature for 1 hour, and then cooled back to 0° C. and quenched by the addition of a 1:1 THF: H2O mixture (12.4 mL). Et2O was added (50 mL), followed by a 3.6 M solution of NaOH (24.4 mL). The mixture was filtered through Celite, and the solids were washed well with additional Et2O. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound (9.7 g, 97%). The crude compound was used in subsequent steps. 1H NMR (400 MHz, CDCl3) δ 7.38-7.30 (m, 2H), 7.20-7.10 (m, 2H), 2.96 (t, 2H), 2.72 (t, 2H), 1.35 (br s, 2H). MS (ESI) m/z: Calculated: 199; Observed: 200/202 (M++1).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1.[OH-].[Na+].Cl>CCO>[CH:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:18])=[O:2])=[CH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(C=Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(C=Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
74A (357 mg, 1.5 mmol) was suspended in EtOH (2 mL) and aqueous NaOH (1 M, 6 mL) and was heated to 80° C. for thirty minutes. Upon cooling to room temperature, the solution was acidified with HCl (concentrated), was cooled to 0° C., and was filtered. The white crystalline precipitate was dried under vacuum (303 mg, 90%). NMR 1H (ppm, CDCl3): 8.26 (s, 1H), 7.99 (d, J3=7.7 Hz, 1H), 7.73 (d, J3=8.2 Hz, 1H), 7.53 (d, J3=7.3 Hz, 2H), 7.46 (td, J3=7.7 Hz, J4=2.2 Hz, 1H), 7.37 (t, J3=7.4 Hz, 2H), 7.30-7.24 (m, 1H), 7.21 (d, J3=17 Hz, 1H), 7.13 (d, J3=16 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C([O-])(=O)C.[Na+].[Cl-].[NH4+]>CCOCC.CN(C)C(=O)C>[C:8]([O:12][CH3:13])(=[O:11])/[CH:9]=[CH:10]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CC(=O)OC
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: COC(=O)/C=C/c1ccccc1
Temperature: 100 °C
Yield: 98.7 %

Procedure:
Compound 5 (30 mg, 2 μmol Pd), iodobenzene (0.20 g, 1 mmol), methyl acrylate (0.13 g, 1.5 mmol), sodium acetate (0.12 g, 1.5 mmol), and N,N-dimethylacetamide (3 mL) were sequentially added to a 15 mL septum-sealed test tube under protection of nitrogen. The reaction mixture was heated at 100° C. for 8 h. After it was cooled to the room temperature, 8 mL of anhydrous ether was added to precipitate compound 5. The mixture was centrifuged and the upper liquid layer was transferred via a syringe into a 20 mL round-bottom flask. Repeated the above precipitation procedure once. The combined liquid layer was concentrated under reduced pressure to give an oily residue. A saturated ammonium chloride solution (5 mL) was then added. The resulting mixture was extracted by ethyl acetate (10 mL×3), dried over anhydrous magnesium sulfate, filtrated, and concentrated to give a crude product. The crude product was further purified by column chromatography (silica gel, hexane/ethyl acetate=4/1) to give 0.16 g (99% yield) of trans-methyl cinnamate. Rf=0.53 (9:1 hexane:ethyl acetate), 1H NMR (300 MHz, CDCl3) δ 3.81 (s, 3H), 6.45 (d, J=15.6 Hz, 1H), 7.29–7.64 (m, 5H), 7.69 (d, J=15.6 Hz, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15])=[CH:4][C:3]=1[N:22]1[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]2=[N:23]1.[OH:31][C:32]1[CH:45]=[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:43]=[CH:42][C:33]=1[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>>[N:23]1[N:22]([C:3]2[CH:4]=[C:5]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH3:16])[CH:6]=[C:7]([CH2:8][C:45]3[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:43][CH:42]=[C:33]([C:34](=[O:35])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:32]=3[OH:31])[C:2]=2[OH:1])[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=12
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCN(CC)Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Product: CCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Following the general procedure of Example 5 using the Mannich intermediate of Example 2 and 2-hydroxy-4-dodecyloxybenzophenone, the title compound is obtained as a yellow crystalline solid melting at 78°-82° C.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:25]=[CH:24][NH:23][C:17]=4[N:18]=[C:19]([O:21][CH3:22])[N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:26]N1C(=O)CCC1=O>O1CCCC1>[CH:1]1([C@H:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[C:25]([I:26])=[CH:24][NH:23][C:17]=4[N:18]=[C:19]([O:21][CH3:22])[N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nc(-c2cnn(C(CC#N)C3CCCC3)c2)c2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: COc1nc(-c2cnn([C@H](CC#N)C3CCCC3)c2)c2c(I)c[nH]c2n1
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a solution of 3-cyclopentyl-3-[4-(2-methoxy-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.532 g, 1.58 mmol) in tetrahydrofuran (20 mL) was added N-iodosuccinimide (0.36 g, 1.6 mmol). The reaction was stirred for 30 min and the solvent was removed in vacuo. The residue was purified by flash column chromatography, eluting with a gradient from 0-65% ethyl acetate in hexanes to afford a yellow solid (250 mg, 34%). 1H NMR (300 MHz, CDCl3): δ 10.31 (br s, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 7.29 (s, 1H), 4.34-4.21 (m, 1H), 4.06 (s, 3H), 3.14 (dd, 1H), 3.03-2.90 (m, 1H), 2.66-2.49 (m, 1H), 2.02-1.17 (m, 8H); LCMS (M+H)+: 463.0.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:22]C(=O)OCC2C=CC=CC=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO.C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH2:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1Cc2cc(C(F)(F)F)ccc2N(Cc2ccccc2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC1Cc2cc(C(F)(F)F)ccc2N(Cc2ccccc2)C1
Yield: 90.2 %

Procedure:
A suspension of 149E (740 mg, 1.682 mmol) and 5% Pd/C (Degussa type, 300 mg) in a mixed solvent of MeOH-THF (20 mL, 1:1 ratio) was hydrogenated ar RT under hydrogen balloon for 1 h. After filtration to remove the catalyst, the filtrate was concentrated and the residue dried in vacuo to afford compound 149F as a clear oil (465 mg, 90%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:23])[N:15]=2)=[O:13])[CH2:3]1.[CH3:24][C:25]1[S:26][C:27]([C:33]2[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=2)=[C:28]([C:30](O)=[O:31])[N:29]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:30]([C:28]3[N:29]=[C:25]([CH3:24])[S:26][C:27]=3[C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)=[O:31])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:23])[N:15]=2)=[O:13])[CH2:3]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3nn(C)c4ccccc34)[C@H]2C1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2nn(C)c3ccccc23)c1

Procedure:
prepared by reaction of 1-methyl-1H-indazole-3-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12](Br)[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:23][C:24](I)([F:26])[F:25]>[Cu].CN(C)C=O>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([C:24]([F:26])([F:25])[F:23])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(Br)c1
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a solution of 0.01 moles of ethyl α- hydroxy-γ-(3-bromo-4-cyclohexylphenyl)butyrate in 50 ml. of dimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder. The reaction is shaken in a sealed tube for 5 hours at 140°C, cooled and then filtered and evaporated in vacuo. 200 ml. of water is added to the residue and extracted with ether. The ether extract is dried, evaporated to dryness and distilled to obtain ethyl α-hydroxy-γ-(3-trifluoromethyl-4-cyclohexylphenyl)butyrate.
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:38]=[C:39]([C:44]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[C:54]([F:59])[CH:53]=2)([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[OH:45])[CH:40]=[CH:41][C:42]=1[F:43].Cl[CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([C:71](=[O:73])[CH3:72])=[CH:67][C:66]=1[O:74][CH3:75].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[F:59][C:54]1[CH:53]=[C:52]([C:44]([C:39]2[CH:40]=[CH:41][C:42]([F:43])=[C:37]([F:36])[CH:38]=2)([OH:45])[CH:46]2[CH2:51][CH2:50][N:49]([CH2:61][CH2:62][CH2:63][O:64][C:65]3[CH:70]=[CH:69][C:68]([C:71](=[O:73])[CH3:72])=[CH:67][C:66]=3[O:74][CH3:75])[CH2:48][CH2:47]2)[CH:57]=[CH:56][C:55]=1[F:58]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: OC(c1ccc(F)c(F)c1)(c1ccc(F)c(F)c1)C1CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Solvent: CC(C)O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(O)(c2ccc(F)c(F)c2)c2ccc(F)c(F)c2)CC1
Yield: 50.4 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 1.4 g (0.004 mole) of α,α-bis(3,4-difluorophenyl)-4-piperidinemethanol, 1.0 g (0.004 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 1.6 g (0.015 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 1.1 g (48%) of the title compound as an off-white solid, mp 143°-146° C. (2-propanol).
Reaction SMILES: [NH2:1][C:2]1([CH:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>C(Cl)Cl>[Cl:17][C:12]1[CH:11]=[C:10]([CH:8]([OH:9])[C:2]2([NH:1][S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:15]=[C:14]([Cl:16])[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(C(O)c2cc(Cl)cc(Cl)c2)CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC2(C(O)c3cc(Cl)cc(Cl)c3)CCCCC2)cc1
Temperature: 35 °C

Procedure:
To a stirred solution of (1-amino-cyclohexyl)-(3,5-dichloro-phenyl)-methanol and pyridine (100 μL, 1.24 mmol) in CH2Cl2 (4 mL) was added p-toluenesulfonyl chloride. The mixture was heated at ca. 35° C. for 8 hours. The mixture was applied to a 10 mL Chem Elut cartridge pre-wetted with 5% aqueous HCl (5 mL) and eluted with CH2Cl2 (25 mL). The eluate was applied to a second Chem Elut cartridge pre-wetted with saturated aqueous NaHCO3. The eluate from the second cartridge was evaporated to leave N-{1-[(3,5-dichloro-phenyl)-hydroxy-methyl]-cyclohexyl}-4-methyl-benzenesulfonamide (139 mg) as an oil. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.7 (d, 2H), 7.2 (s, 2H), 7.15 (d, 2H), 7.1 (s, 1H), 4.82 (s, 1H), 4.16 (s, 1H), 2.33 (s, 3H), 0.9-1.9 (m, 10H).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:35][CH3:36])[C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Li+].[OH-].Cl>C1COCC1>[CH2:28]([NH:27][C:25](=[O:26])[N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:37])=[O:2])[CH:6]=1)[CH2:35][CH3:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)NCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccccc1

Procedure:
[2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.1 g) in THF (2 mL) was treated with 1N aqueous LiOH (2 mL) for 2 hours at room temperature. The mixture was acidified with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by preparative HPLC to give [2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid. M+H is 501.