Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]([C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]([C:29]34[CH2:30][CH:31]5[CH2:32][CH:33]([CH2:34][CH:35]([CH2:37]5)[CH2:36]3)[CH2:38]4)=[O:28])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=C(OCCCBr)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)C12CC3CC(CC(C3)C1)C2

Procedure:
To a stirred solution of 3-bromopropanol (5.5 g, 0.04 mol) in 50 mL of methylene chloride, adamantane-1-carboxylic acid chloride (5.6 g, 0.02 mol) and triethylamine (4 g, 0.04 mol) were added. The reaction mixture was stirred at room temperature overnight, the methylene chloride was washed with water, dried over anhydrous Na2SO4 and removed under reduced pressure to afford 12 g of the intermediate adamantane-1-carboxylic acid bromopropyl ester. The title compound was prepared by stirring 4-[bis(4-fluorophenyl)-methylene]piperidine (2 g, 0.07 mol), adamantane-1-carboxylic acid bromo-propyl ester (2.1 g, 0.007 mol) and triethylamine (1 g, 0.01 mol) in 50 mL of CH2Cl2 for 24 hours. The methylene chloride was washed with water, dried (anhydrous Na2SO4) and removed under reduced pressure. The remaining residue was subjected to preparative HPLC over silica gel using ethylacetate as the eluent and the desired product (TLC Rf =0.7 in 30% ethanol/ethylacetate system) was separated and converted to the hydrochloride salt (0.6 g, 16% yield), mp. 267°-269° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].ClCCl>C(#N)C.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([NH:20][CH3:19])=[O:22])=[CH:24][CH:25]=3)[CH:3]=2)[NH:8][N:9]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccccc1-c1n[nH]c2ncc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Product: CNC(=O)c1ccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)cc1
Temperature: 130 °C
Yield: 19.4 %

Procedure:
To a solution of 5-bromo-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine (26 mg, 0.085 mmol) in acetonitrile (1 mL) and saturated aqueous NaHCO3 (1 mL) in a microwave vial was added 4-(N-methylaminocarbonyl)phenylboronic acid (17 mg, 0.094 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (3.5 mg, 0.004 mmol). The vial was capped, flushed with N2, evacuated under vacuum, and heated in a microwave at 130° C. for 1800 seconds. The material was extracted into EtOAc and the organic layer was dried over Na2SO4. The material was adsorbed onto SiO2 and purified by flash chromatography in a EtOAc (containing 10% MeOH) and hexane gradient. The clean fractions were concentrated via rotary evaporation to afford the title compound as a white powder (5.9 mg, 20% yield). 1H NMR (500 MHz, CD3OD) δ 8.85 (s, 1H), 8.41 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.67 (d, J=7.5 Hz, 1H), 7.48 (t, 7.0 Hz, 1H), 7.21 (d, J =8.5 Hz, 1H), 7.11 (t, J=7.0 Hz, 1H), 3.89 (s, 3H), 2.95 (s, 3H). MS: m/z 359.1 [M+H+].
Reaction SMILES: Cl.[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][NH:4][CH2:3]1.C(Cl)Cl.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH2:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:2][CH2:3][N:4]([C:16](=[O:18])[CH3:17])[CH2:5]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2ccccc2CC1
Yield: 95 %

Procedure:
To a solution of 2,3,4,5-Tetrahydro-1H-benzo[d]azepine hydrochloride (7.0 g) in DCM (200 ml) Et3N (12.1 ml, 2.5 eq) was added followed by a dropwise addition of acetic anhydride (4 ml). After 2 h the mixture was washed in sequence with 1N HCl, 5% aqueous NaHCO3 and brine, then dried over Na2SO4 and concentrated to afford a white solid (6.9 g, 95% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[O:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:25]([CH3:29])[N:26]=[C:27]([CH3:28])[C:3]=12.C1C[O:33]CC1>C(N(CC)C(C)C)(C)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][C:8]([C:7]2[C:2]([OH:33])=[C:3]3[C:27]([CH3:28])=[N:26][N:25]([CH3:29])[C:4]3=[N:5][CH:6]=2)=[O:9])=[O:12])=[CH:15][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: C1CCOC1
Reactant: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3ccc(F)c(C(F)(F)F)c3)c(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3ccc(F)c(C(F)(F)F)c3)c(O)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of (4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide (0.050 g) in THF (5 mL) was dissolved in a 1:3 mixture of N,N-diisopropylethylamine (DIPEA) and water (4 mL). The solution was stirred at room temperature for 24 h, concentrated, and the residue purified by column chromatography on silica-gel eluting with 3:1 EtOAc-MeOH to give the title compound as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([NH:11]C(=O)C)=[CH:9][CH:8]=1.[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([NH2:11])=[CH:9][CH:8]=1
Reactant: COc1ccc(COc2ccc(NC(C)=O)cc2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(COc2ccc(N)cc2)c(OC)c1

Procedure:
p-(2,4-Dimethoxybenzyloxy)acetanilide (3 g, 0.01 M) in ethanol (30 ml) is treated with potassium hydroxide (3 g), then the mixture is heated under reflux for 12 hours. The solvent is removed by evaporation, the residue treated with water and extracted with ether. The ether solution is treated with charcoal, dried and concentrated to afford p-(2,4-dimethoxybenzyloxy)aniline.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(OC(C)C)(C)C.C(N(CC)CC)C.Cl[C:21]([C:23]([F:34])([F:33])[CH:24]([O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:25][CH3:26])=[O:22]>>[CH2:1]([O:5][C:21]([C:23]([F:33])([F:34])[CH:24]([O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:25][CH3:26])=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)Cl
Reactant: CCCCO
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCCCC
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Into a 1 L glass flask with a dropping funnel, 62.8 g (0.847 mol, 1.2 eq) of n-butanol, 510 g of diisopropyl ether, 100 g (0.988 mol, 1.4 eq) of triethylamine and 1 g of antioxidant “Nonflex MBP” (manufactured by Seiko Chemical Co., Ltd.) were added. The resulting solution was cooled to 0° C. and stirred, followed by dropping thereto 170 g (purity: 99%, 0.706 mol) of methacrylic acid 1-chlorocarbonyl-1,1-difluoro-2-butyl ester. The thus-obtained reaction solution was stirred for 1 hour at room temperature. The completion of the reaction was confirmed by 19F NMR. The reaction-completed solution was separated into an organic layer and an aqueous layer by the addition of 500 mL of water. The organic layer was dehydrated with magnesium sulfate, filtrated, and then, concentrated under a reduced pressure. The concentration residue was subjected to distillation under a reduced pressure. With this, 179 g of methacrylic acid 1-(n-butoxycarbonyl)-1,1-difluoro-2-butyl ester was obtained as a colorless transparent liquid (yield: 91%, purity: 99%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:32]=1[C:33]([NH:35][CH3:36])=[O:34]>>[Br:41][C:38]1[CH:39]=[CH:40][C:31]([NH:30][C:2]2[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)=[C:32]([C:33](=[O:34])[NH:35][CH3:36])[CH:37]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1cc(Br)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and Compound 106A. MS (ES+): tn/z 646.31 (100) [MH+]; HPLC: tR=1.14 min (UPLC, purity).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])/[C:25](/[C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:26]\[O:27][CH3:28])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19])(=[O:9])[NH2:8].[C:36]([O:39][CH:40](Br)[CH3:41])(=[O:38])[CH3:37].Cl>CN(C)C=O.C(OCC)(=O)C>[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])/[C:25](/[C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:26]\[O:27][CH3:28])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([O:20][CH:40]([O:39][C:36](=[O:38])[CH3:37])[CH3:41])=[O:19])(=[O:9])[NH2:8]
Reactant: CC(=O)OC(C)Br
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.42 h

Procedure:
Potassium carbonate (760 mg, 5.5 mmole) was added to a solution of (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (4.57 g, 11 mmole) in N,N-dimethylformamide (25 ml) and the mixture was stirred at ca 20° for 25 minutes. 1-Bromoethyl acetate (1.8 g, 11 mmole) in N,N-dimethylformamide (5 ml) was added to the above solution and the reaction mixture was stirred for 40 minutes at ca 20°. The reaction mixture was worked up by pouring it into excess 2 N hydrochloric acid, followed by extraction with ethyl acetate (3 times). The combined organic extracts were washed with 2 N hydrochloric acid and saturated sodium bicarbonate solution, dried (magnesium sulphate) and evaporated in vacuo to yield a foam which was dissolved in ethyl acetate and precipitated from ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12](OCC)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: C1COCCN1
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N2CCOCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (200 mg) and morpholine (2 ml) was heated at 120° C. for 15 h to obtain 27 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-morpholinoethanone after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([CH2:12][N:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:23][CH2:22]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1>CO.[C].[Pd]>[O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([CH2:12][N:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([F:30])([F:31])[F:29])[CH2:23][CH2:22]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2ccc(=O)[nH]c2n1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(n1)NC(=O)CC2)C1CCN(C(=O)C(F)(F)F)CC1
Temperature: 47.5 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of 0.30 g of tert-butyl ((7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl)methyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate in 40 mL of methanol, 0.10 g of 10% palladium-carbon was added, and the mixture was stirred at 45 to 50° C. for 9 hours 30 minutes under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble substance was filtered off, and the filtration residue was washed with methanol. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:3 to obtain 0.18 g of tert-butyl ((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.O1CCCCC1[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1>>[F:21][C:20]([F:23])([F:22])[CH2:19][N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:24]=[CH:25][C:2]([C:38]5[CH:37]=[N:36][N:35]([CH2:34][CH2:33][OH:32])[CH:39]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1
Reactant: FC(F)(F)Cn1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Product: OCCn1cc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Yield: 48 %

Procedure:
Following the procedure for 182, 9-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 206 (0.056 g, 48%). 1H NMR (400 MHz, DMSO) δ 8.33 (d, J=8.4, 1H), 8.24 (s, 1H), 8.07 (d, J=11.7, 2H), 7.95 (d, J=8.9, 1H), 7.41 (dd, J=8.4, 1.7, 1H), 7.28 (d, J=1.7, 1H), 5.91 (q, J=8.8, 2H), 4.91 (t, J=5.3, 1H), 4.54 (dd, J=10.8, 5.6, 4H), 4.16 (t, J=5.6, 2H), 3.87-3.69 (m, 2H). MS (ESI(+)): m/z 446.1 (M+H)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:31][OH:32])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25](I)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:31][OH:32])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:40][C:37]4[CH:36]=[CH:35][C:34]([Cl:33])=[CH:39][N:38]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(I)n4)c3CO)ncc2c1
Reactant: Nc1ccc(Cl)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(Cl)cn5)n4)c3CO)ncc2c1
Temperature: 95 °C
Yield: 52.3 %

Procedure:
A small round bottom flask was charged with 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-iodo-1H-pyrazole-4-carbonitrile (212 mg, 0.39 mmol), 5-chloropyridin-2-amine (65 mg, 0.51 mmol), XANTPHOS (56 mg, 0.098 mmol), and cesium carbonate (381 mg, 1.17 mmol). Dry dioxane (5.7 ml) was added and the mixture was thoroughly degassed with argon. Pd2(dba)3 (46 mg, 0.051 mmol) was added and the material was again degassed with argon. The flask was placed in an oil bath heated to 95° C. for 2.5 hours. The flask was cooled to ambient and ethyl acetate (30 ml) and water (30 ml) were added. The contents were shaken in a separatory funnel and the organic phase was collected. The aqueous phase was back extracted with ethyl acetate (2×30 ml), and the organic phase was combined, dried with magnesium sulfate, filtered and stripped. The crude material was purified by preparative thin layer chromatography (2 plates, eluting with 4% methanol in methylene chloride). The product band was collected, providing the desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-chloro-pyridin-2-ylamino)-1H-pyrazole-4-carbonitrile as a light yellow powder (111 mg). LC/MS calc'd for C28H23ClFN7O2 (m/e) 543.98, obs'd 544 (M+H, ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15]3)[N:11]([CH2:26][C:27]3[CH:40]=[CH:39][C:30]([C:31](NC4NN=NN=4)=[O:32])=[CH:29][CH:28]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(C)(C)[CH:43]=[O:44].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH2:18][CH2:19]3)[N:11]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([O:44][CH3:43])=[O:32])=[CH:39][CH:40]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)C(=O)N1CCC(c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C2CCN(CC(C)(C)C)CC2)cc1

Procedure:
To a solution of the intermediate from Example 142 step F (100 mg, 0.225 mmol) in 1,2-dichloroethane (3 mL) was added trimethyl acetaldehyde (29 mg, 0.337 mmol) and sodium triacetoxy borohydride (71 mg, 0.337 mmol). After 16 hours the reaction was diluted with DCM (10 mL) and washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. This material was used in the next step without any further purification. LC-MS: 3.44 min; (M+H)=514.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:12](=O)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH:12](/[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:13]\[CH2:14][CH2:15][CH3:16]
Reactant: C1CCNC1
Reactant: CCCCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC/C=C/N1CCCC1
Reaction time: 6 h
Yield: 85.7 %

Procedure:
To 200 mL (170.4 g, 2.40 mol) of rapidly stirred pyrrolidine at 3° C., under argon, was added 100 g (0.72 mmol) of potassium carbonate followed by 127 mL (102.9 g, 1.19 mol) of valeraldehyde dropwise over 75 min. After stirring at 3°-5° C. for 6 hr, the suspension was stored at ca. 0° C. for 64 hr, filtered and the collected solids were washed with 2×50 mL of anhydrous ether. The combined filtrates were concentrated in vacuo and the residue was distilled to give 142.32 g (85.7%) of N-[1-(E)-penten-1-yl]pyrrolidine, bp 54°-56° C. (0.6-0.7 mm Hg).
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13].[CH:18]1[CH:19]=[CH:20][C:21]2[S:26][CH:25]=[CH:24][C:22]=2[CH:23]=1>>[S:26]1[C:25]([CH2:4][C:5]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=2[C:12]([F:15])([F:14])[F:13])=[CH:24][C:22]2[CH:23]=[CH:18][CH:19]=[CH:20][C:21]1=2
Reactant: CON(C)C(=O)c1cc(Br)ccc1C(F)(F)F
Reactant: c1ccc2sccc2c1
Product: FC(F)(F)c1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
To a solution of the above N-methoxy-N-methyl-5-bromo-2-iodobenzamide (2.67 g) in N-methyl-2-pyrrolidinone (12 ml) were added copper (I) bromide (124 mg) and methyl fluorosulfonyl(difluoro)acetate (1.34 ml), and the mixture was stirred under heating for 1.5 hours. The reaction mixture was cooled to room temperature, and then, a diluted aqueous ammonia was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-85:15) to give N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide (1.59 g) as colorless oil. APCI-Mass m/Z 312/314 (M+H). (3) The above N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide and thianaphthene were treated in a manner similar to Reference Example 45 to give 1-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-trifluoromethylbenzene as a colorless solid. ESI-Mass m/Z 369/371 (M−H).
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=[O:15])[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:19])(=O)=O>C(O)(=O)C>[CH2:1]([O:5][N:6]=[C:7]([C:13](=[O:15])[CH2:14][Cl:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCC(C)C)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCC(C)C)C(=O)CCl
Yield: 65.5 %

Procedure:
Ethyl 2-iso-butoxyimino-3-oxobutyrate (syn isomer, 42 g.), acetic acid (42 ml.) and sulfuryl chloride (27.1 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 31.9 g.).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([F:18])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][C@@H:10]([CH3:12])[C:9]=2[C:13]=1[F:18]
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNCCc2ccc(Cl)c(F)c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 197.8 %

Procedure:
A solution of (S)—N-trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 25° C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 93 mg of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=8, 8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 3.58 (m, 1H), 3.25-3.15 (m, 3H), 2.93 (d, J=13 Hz, 1H) 2.75-2.60 (m, 3H), 1.96 (bs, 1H), 1.33 (d, J=8 Hz, 3H). MS calculated for C11H13ClFN+H: 214, observed: 214.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:25])=O>>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([Cl:25])=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
p-n-Dodecyloxybenzoic acid (8 g) together with thionyl chloride (20 ml) were heated under reflux for 2 hours, followed by distilling off excess thionyl chloride to obtain p-n-dodecyloxybenzoic acid chloride, which was made up into a toluene solution thereof without any particular purification. On the other hand, optically active hydroquinonemono (2-methylbutyl) ether (4.7 g) obtained above in the item (I) was dissolved in pyridine (30 ml). To this solution kept at 0° C. was dropwise added the toluene solution of p-n-dodecyloxybenzoic acid chloride obtained above, followed by heating the mixture at 90° C. for 2 hours for reaction, separating the resulting esterified substance in a conventional manner, and twice repeating recrystallization to obtain colorless crystals of p-n-dodecyloxybenzoic acid p'-(2-methylbutyloxy)phenyl ester (C-SC* point, 50.5° C.; SC*-SA point, 51.2° C.; SA-I point, 65° C.; and [α]D25° =+5.2° (as measured in chloroform solution)) (6.5 g). Further its elemental analysis values accorded well with its theoretical values as follows: