Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[C:5](NN)=[N:4][N:3]=1>C1C=CC=CC=1.C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=[N:4][N:3]=1
Reactant: NNc1nnc(Cl)c2c(-c3ccccc3)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Product: Clc1nncc2onc(-c3ccccc3)c12
Temperature: 0 °C
Yield: 65 %

Procedure:
The compound prepared in Example 81 (4.40 g) was dissolved in benzene (500 mL)-ethanol (50 mL) and 1 mol/L aqueous sodium hydroxide (67.0 mL) was added. This mixture was cooled to 0° C. Oxygen was bubbled through the vigorously stirred mixture for 30 minutes. The mixture was separated and the aqueous portion was extracted with dichloromethane. The combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (2.53 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[Cl:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[Cl:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 70 °C

Procedure:
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2-chloro-5-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg, 0.24 mmol), NaOH (70 mg, 1.75 mmol), H2O (2 mL) and THF (6 mL) was heated at 70° C. for 1 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to “pH” 2-3 by addition of concentrated aqueous HCl. The white solid was collected by filtration to give the title compound which was used for next step reaction without further purification.
Reaction SMILES: C(OC([N:8]1[C:21]2[C:12](=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][C@H:15]([C:22]([CH3:30])([CH3:29])[O:23][SiH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[O:14]3)[CH2:11][CH2:10][CH:9]1O)=O)(C)(C)C>ClC1C=CC=CC=1Cl>[C:25]([SiH2:24][O:23][C:22]([CH3:30])([CH3:29])[C@H:15]1[CH2:16][CH2:17][C:18]2[C:13](=[C:12]3[C:21](=[CH:20][CH:19]=2)[N:8]=[CH:9][CH:10]=[CH:11]3)[O:14]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1c2ccc3c(c2CCC1O)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC3
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CCc2ccc3ncccc3c2O1
Yield: 69.8 %

Procedure:
A solution of (6R)-6-(tert-butyl-dimethyl-silanyloxymethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H,6H-5-oxa-1-aza-phenanthrene-1-carboxylic acid tert-butyl ester (0.45 g, 1.0 mmole) in o-dichlorobenzene (150 mL) was stirred at 180° C. for 4 hours. The solvent was removed in vacuum. The residue was purified by column chromatography on silica gel (10% methylene chloride/hexane) to afford 0.23 g (70%) of the title compound as an oil, [α]25D=−61.94° (c=10.7, THF).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[C@@H:23]([CH3:24])[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[CH2:20][C@@H:19]1[CH3:33])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH:19]([CH3:33])[CH:20]=[C:21]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:22][CH:23]1[CH3:24])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C[C@H]1C=C(OS(=O)(=O)C(F)(F)F)C[C@H](C)N1C(=O)OC(C)(C)C
Reactant: Nc1ccc(B(O)O)cc1
Product: CC1C=C(c2ccc(N)cc2)CC(C)N1C(=O)OC(C)(C)C
Yield: 56.9 %

Procedure:
The title compound was then prepared according to the Suzuki coupling procedure of Example 35, step (b) using 4-aminophenylboronic acid (219 mg, 1.00 mmol) and cis/trans-2,6-dimethyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared above, 321 mg, 1.00 mmol). Silica gel chromatography (10-20% EtOAc/hexanes) afforded 4-(4-amino-phenyl)-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (172 mg, 57%): Mass spectrum (ESI, m/z): Calcd. for C18H26N2O2, 303.2 (M+H) found 303.1. A solution of 4-(4-amino-phenyl)-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared above, 380 mg, 1.25 mmol) in MeOH (10 mL) was hydrogenated over 10% Pd/C (190 mg) at 20 psi for 1 h. The solution was filtered through a pad of Celite and concentrated to give the title compound (360 mg, 94%). Mass spectrum (ESI, m/z): Calcd. for C18H28N2O2, 305.2 (M+H). found 305.6.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=1[NH2:14].C(O)(=O)C>O>[F:11][C:12]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc(F)cc1F
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(F)cc1F
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of (7.9 g., 0.05 mole) 2-chloro-3-nitropyridine and 12.9 g. (0.10 mole) of 2,4-difluoroaniline was purged with nitrogen and heated in an oil bath to 110° C. when the temperature rose spontaneously to 135° C. Heating was continued to 145° C. when a second spontaneous temperature rise occurred requiring temperature control with ice. The maximum internal temperature was 185° C. After slight cooling, 40 ml. of acetic acid and 60 ml. of water was added. After stirring one hour the crystalline precipitate was collected (11.1 g., m.p. 110° C.) and recrystallized from hexane to give 2-(2,4-difluoroanilino)-3-nitropyridine, m.p. 112°-114° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][O:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][O:11][CH3:12]
Reactant: Oc1ccccc1Br
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccccc1Br
Temperature: 80 °C
Yield: 67 %

Procedure:
To a solution of 2-bromophenol (5.0 g, 28.90 mmol) and chloro(methoxy)methane (3.4 g, 43.35 mmol) in DMF (50 mL) was added sodium carbonate (18.7 g, 57.8 mmol). The reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×100 mL), dried over sodium sulfate and concentrated under reduced pressure to yield desired 1-bromo-2-(methoxymethoxy)benzene (4.2 g, 67.7%) as a clear liquid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH:36]1([C:39]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:40])[CH2:38][CH2:37]1>ClCCl.O.C(N(CC)CC)C>[CH:36]1([C:39]([N:41]2[CH2:46][CH2:45][N:44]([C:8]([C:7]3[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=3)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:43][CH2:42]2)=[O:40])[CH2:37][CH2:38]1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: O=C(C1CC1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of 3-(methoxycarbonyl)benzoic acid (0.9 g, 5 mmol) in dichloromethane (20 mL), 1-hydroxybenzotriazole (0.75 g, 5.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.06 g, 5.5 mmol) and triethyl amine (2 mL) were added. The mixture was stirred at room temperature for 30 min, and then cyclopropyl(piperazin-1-yl)methanone (1.0 g, 5 mmol) was added and the mixture was stirred at room temperature for 16 h. The resulting mixture was added water (50 mL) and extracted with dichloromethane (100 mL×3), the organic phase was washed with sodium bicarbonate, brine and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 2:1), 0.95 g of methyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate as an oil was obtained, Yield 60%. 1H-NMR (400 MHz, CDCl3) 0.80-0.82 (m, 2H), 1.00-1.04 (m, 2H), 1.24-1.27 (m, 1H), 3.25-3.78 (m, 8H), 3.94 (s, 3H), 7.52-7.55 (t, J=7.6 Hz, 1H), 7.63-7.65 (d, J=7.6 Hz, 1H), 8.09-8.14 (m, 2H); LC-MS (ESI) m/z: 317 (M+1)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:21][CH2:20][C:15]3(OCC[O:16]3)[CH2:14][CH2:13]2)=[C:8]([F:22])[C:7]=1[F:23])[CH2:2][CH2:3][CH3:4].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]2)=[C:8]([F:22])[C:7]=1[F:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C2CCC3(CC2)OCCO3)c(F)c1F
Solvent: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Temperature: 30 °C
Yield: 97.7 %

Procedure:
The compound (10) (47.8 g), formic acid (87%; 67.0 ml) and toluene (200 ml) were mixed, and the mixture was heated to reflux for 2 hours. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (1,000 ml) were added to the mixture and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the resulting residue was purified with a fractional operation by means of column chromatography using silica gel as a stationary phase powder and toluene as an eluent. The product was further purified by recrystallization from heptane to give 1-(4-butoxy-2,3-difluorophenyl)-cyclohexan-4-one (11) (40.4 g). The yield based on the compound (10) was 97.8%.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@@H:59]1[CH:64]2[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]2)[CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@@H:59]5[CH:64]6[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]6)[CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-(+)-3-aminoquinuclidine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.43 (m, 3H) 1.57-1.92 (m, 12H) 2.69 (d, J=6.57 Hz, 2H) 2.71 (m, 3H) 2.89 (m, 1H) 3.13 (m, 1H) 3.31 (s, 3H) 3.95 (s, 3H) 3.97-4.16 (m, 2H) 4.45 (m, 1H) 7.47 (d, J=8.0 Hz, 1H) 7.49 (s, 1H) 7.93 (s, 1H) 8.14 (d, 1H) 8.21 (s, 1H) 8.26 (d, J=8.0 Hz, 1H). [M+H] calculated for C29H37F2N7O3, 570. found 570.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10])#[N:2].[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])#[N:2]
Reactant: CNC
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccccc1C#N
Yield: 85 %

Procedure:
A solution of 2-cyanobenzensulfonylchloride (2.0 g, 10 mmol), dimethyl amine (1.18 g, 10 mmol, 40 wt % in water) and triethylamine (1.5 mL, 10 mmol) were stirred together at room temperature for 30 min. The resulting slurry was diluted with ethyl acetate and filtered. The filter cake was washed with ethyl acetate and the combined filterate was washed with water, dried (Na2SO4) and concentrated to give the title product as orange plates (1.78 g, 85% yield). 1HNMR (300 MHz, CDCl3) δ: 8.02 (1H, dd, J=8.05, 1.46 Hz), 7.87 (1H, dd, J=7.32, 1.47 Hz), 7.79–7.76 (2H, m), 2.86 (6H, s). LCMS calcd for C9H11N2O2S (M+H): 211.05; found: 211.09.
Reaction SMILES: [N+:1]([CH2:3][CH2:4]C(S(C1C=C(C=CC=1)N)(=O)=O)C)#[C-:2].[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24])([O-:19])=[O:18].CCOC(C)=O>CO>[CH3:4][C:3]1[N:1]=[CH:2][O:24][C:23]=1[C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1
Reactant: [C-]#[N+]CCC(C)S(=O)(=O)c1cccc(N)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ncoc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 3-{[1-(isocyanoethyl)ethyl]sulfonyl}aniline (60 g, 0.287 mol) in dry MeOH (800 mL), was added dry powdered K2CO3 and stirred at rt for 1 h. The reaction mixture was re-cooled to 0° C. and 3-nitro benzaldehyde (43 g, 0.287 mol) added. The reaction mixture was warmed to rt, followed by heating at 55° C. overnight with stirring. The excess solvent was removed under reduced pressure, the residue was dissolved in water (100 mL) and extracted with EtOAc (3×350 mL). The combined organic layers were washed with brine, water, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica get (60-120 mesh) column chromatograph using 15% EtOAc in petroleum-ether to yield product as yellow solid. Yield 50 g (86%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])C.CN.CNC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:41]([S:38]([N:35]1[CH2:36][CH2:37][CH:32]([C:23]2[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=[C:20]([C:14]4[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([CH2:11][NH:9][CH3:8])[CH:13]=4)[CH:21]=3)[NH:25][CH:24]=2)[CH2:33][CH2:34]1)(=[O:40])=[O:39])[CH3:42]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CN(C)C)c4)cc23)CC1
Agent: CN
Agent: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CNC)c4)cc23)CC1
Yield: 16 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methylamine (50 μL, 0.214 mmol) for the dimethylamine to afford 10 mg of the title compound (16%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[Br:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[Br:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]([CH3:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=3)[N:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3-methyl-4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example A.40) (0.401 g, 1.4 mmol) and commercially available 3-bromo-benzene-boronic acid (0.366 g, 1.82 mmol) according to the general procedure IVb. Obtained as a light yellow oil (0.13 g, 23%). MS (ISP) 409.2 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26].CCN(CC)CC>C1COCC1>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 3 h
Yield: 113.5 %

Procedure:
to a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (780 mg, 3.30 mmol), 2-bromo phenyl isocyanate (0.41 ml, 3.30 mmol) in THF (7 ml) was added Et3N (0.092 ml, 0.66 mmol) at room temperature. After 3 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2bromophenyl)ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 138-145° C. (dec.); 1H-NMR (CDCl3) δ1.44 (s, 9H), 2.33 (s, 3H), 3.51 (s, 2H), 6.90 (dt, J=9.0, 1.4 Hz, 1H), 7.18-7.31 (m, 4H), 7.39 (dd, J=8.1, 2.9 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H); Anal. Calcd. for C20H22BrN2O3.0.2H2O: C, 56.80; H, 5.58; N, 6.62. Found: C, 56.85; H, 5.42; N, 6.62.
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.[CH3:19][C:20](OC(C)=O)=[O:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:2]1[C:6]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:5][CH2:4][N:3]1[C:20](=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate hydrochloride (400 mg, 1.445 mmol) in DCM (5 mL) was treated with TEA (0.604 mL, 4.34 mmol), followed by Ac2O (0.164 mL, 1.734 mmol), stirred at room temperature for 2 h. To this reaction mixture was added TFA (2.115 mL, 27.5 mmol) and stirred at room temperature for h. Concentrated under reduced pressure to obtain crude material which purified by SCX cartridge, loading with MeOH, washed with additional MeOH. Product was recovered eluting with 2M NH3 in MeOH. Solvent evaporation gave 1-(2,8-diazaspiro[4.5]decan-2-yl)ethanone (165 mg)
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH:7](O)[CH2:6][C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH:7]=[CH:6][C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CC(O)C2(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc2c(cc1Br)C(C)(C)C=CC2(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a solution of 15.3 g (51.5 mmol) of 2-bromo-3-methyl-6-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 120 ml of pyridine was added 17.9 ml (192 mmol) of phosphorus oxychloride. The reaction mixture was heated to 100°. After 6 h, cooled to room temperature and carefully poured onto ice with stirring. After 1 h, extracted with ethyl acetate, washed with 2 N HCl and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by gravity chromatography (gradient elution: hexane-10% ethyl acetate/hexane) to afford 12.5 g (87%) of 2-bromo-3,5,5,8,8-pentamethyl-5,8-dihydronaphthalene.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[CH:4]=[N:3]1.CC(C)=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:11])=[O:8])[CH:4]=[N:3]1
Reactant: Cn1cc(C=O)cn1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: Cn1cc(C(=O)O)cn1
Yield: 52 %

Procedure:
3.9 g of 1-methylpyrazole-4-aldehyde (described in J. Chem. Soc., page 3314, 1957) was dissolved in 20 ml of acetone, and while heating the solution, the Jones reagent was added. After the reaction, the excess of the Jones reagent was treated with a dilute aqueous alkaline solution, and the precipitate was collected by filtration. The filtrate was made weakly acidic and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.3 g (yield 52%) of 1-methylpyrazole-4-carboxylic acid. m.p. 205°-206° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:5])[C:3]=1[C:15]([OH:17])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:50]([NH2:56])=[N:51][CH:52]=[C:53]([Br:55])[CH:54]=2)=[CH:45][CH:44]=1>C(Cl)Cl.CN(C=O)C.O>[NH2:56][C:50]1[C:49]([C:46]2[CH:45]=[CH:44][C:43]([NH:42][C:15]([C:3]3[C:4](=[O:5])[N:6]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:7]([CH3:8])[C:2]=3[CH3:1])=[O:17])=[CH:48][CH:47]=2)=[CH:54][C:53]([Br:55])=[CH:52][N:51]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(-c3cc(Br)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To the antipyric acid (0.163 g) in 5 mL of DCM, 0.5 mL of DMF and TEA (1.4 mmol) was added the HATU (0.266 g) and stirred for 30 minutes. To the activated ester was added the compound prepared in Example 43 (0.185 g) and stirred for 1 hour. The reaction mixture was diluted with water, extracted with additional DCM, and the organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The DCM layer was filtered and concentrated, and the crude was chromatographed on silica gel using 10:1 DCM:MeOH to give the title compound (0.3 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.30 g of methyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate, 0.19 g of bromobenzene, 57mg of 1,1-bis(diphenylphosphino)ferrocene dichloropalladium and 0.55 g of potassium carbonate were dissolved in 15 ml dimethoxyethane, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate and water were added thereto. The mixture was filtered through Celite, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), methyl 2-chloro-4-phenylbenzoate was obtained. Then, the resulting methyl 2-chloro-4-phenylbenzoate was dissolved in 4 ml methanol, and 2 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 0.12 g of 2-chloro-4-phenylbenzoic acid.