Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][CH:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Si:41]([O:40][CH:37]1[CH2:36][CH2:35][CH:34]([CH2:33][CH:16]([N:11]2[CH:12]=[C:13]([O:14][CH3:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:25]#[N:26])=[CH:9][C:10]2=[O:24])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:39][CH2:38]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(COS(=O)(=O)C(F)(F)F)CC1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(CC2CCC(O[Si](C)(C)C(C)(C)C)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
500 mg (1.26 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 712 mg (1.89 mmol) of (4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methyl trifluoromethanesulphonate (trans/cis mixture) and 1.39 ml (1.39 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF were reacted according to General Method 7B. Purification by column chromatography (120 g silica cartridge, flow rate: 85 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 479 mg (63% of theory)
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])=[CH:29][CH:28]=1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Reactant: NNc1ccc(Cl)cc1
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNc1ccc(Cl)cc1)C(=O)N2
Yield: 70 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and 4-chlorophenyl hydrazine and following the method described in Example 21,the desired compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]#[N:13])[CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:15][OH:16].C(N(CC)CC)C>CO>[NH2:13][C:12](=[N:15][OH:16])[C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH:11]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: NO
Reactant: CCOC(=O)c1cncc(C#N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1cncc(C(N)=NO)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Ethyl-(5-cyano-3-pyridyl)carboxylate) (WO 96/30372) (1.8 g, 10.2 mmol) was dissolved in methanol (50 mL), the solution was cooled to 0° C. then hydroxylamine hydrochloride (0.71 g, 10.2 mmol) and triethylamine (1.4 mL, 10.2 mmol) were added and the mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (graded elution of dichloromethane/methanol 95:5 to 93:7) to give the title compound as a white solid which contained 0.3 equivalents of triethylamine hydrochloride (2.5 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])=[O:4].CCN(C(C)C)C(C)C.[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>C1COCC1>[O:4]=[C:3]1[N:5]([CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])[C:21](=[S:22])[NH:1][CH2:2]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCC(NC(=O)CN)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C(=O)O)N1C(=O)CNC1=S
Yield: 38 %

Procedure:
To a mixture of 2-(2-aminoacetamido)butanoic acid (0.5 g, 3.12 mmol) and DIPEA (1.812 g, 14.05 mmol) in anhydrous THF 10 mL is added 1,1′-thiocarbonyldiimidazole (0.834 g, 4.68 mmol) and heated to reflux overnight. The resulting reaction mixture is concentrated to dry and the pure product 2-(5-oxo-2-thioxoimidazolidin-1-yl)butanoic acid (0.24 g, 1.187 mmol, yellow solid) is obtained by column chromatography using acetic acid/DCM, 0-5% ration solvent system. 1H-NMR (CD3OD/300 MHz): 5.21 (dd, J=10.5, 5.1 Hz, 1H), 4.09 (d, J=5.4 Hz, 2H), 2.25 (m, 2H), 0.90 (t, J=7.2 Hz, 3H). MS (ES+, m/z): 200.9 (M−, 100.0).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=O)[NH:7][C:6]([CH3:10])=[N:5][S:4]1(=[O:12])=[O:11])[CH3:2].P(Cl)(Cl)([Cl:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:15][C:8]1[N:3]([CH2:1][CH3:2])[S:4](=[O:12])(=[O:11])[N:5]=[C:6]([CH3:10])[N:7]=1
Reactant: CCN1C(=O)NC(C)=NS1(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN1C(Cl)=NC(C)=NS1(=O)=O
Yield: 93 %

Procedure:
225 parts of 2-ethyl-5-methyl-2H-1,2,4,6-thiatriazin-3-one-1,1-dioxide were introduced into a mixture of 1,300 parts of phosphorus oxychloride and 292 parts of phosphorus pentachloride in the course of 2 minutes, while stirring. The reaction mixture was stirred under reflux for 7 hours and then concentrated under reduced pressure. The oil which remained was taken up in 350 parts of 1,2-dichloroethane and chromatographed over neutral alumina (activity I). The solution was then evaporated down, giving 230 parts (93% of theory) of 3-chloro-2-ethyl-5-methyl-2H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 57°-59° C. (NMR (60 MHz, CDCl3): CH3 -C 2.3δ, N-CH2 3.68-4.03δ (q), CH3 -C 1.2-1.43δ (t)).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])=O.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1COCC1.[Cl-].[Na+].O.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:11][C:5]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=1/[C:2](=[N:18]\[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH3:1]
Reactant: CC(=O)c1cccc(F)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C/C(=N/[S@](=O)C(C)(C)C)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of 2,3-difluoroacetophenone (25.0 g, 160 mmol) in THF (500 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (38.8 g, 320 mmol) followed by tetraisopropoxytitanium (142 mL, 480 mmol). The reaction was heated to reflux for 3 days. The mixture was allowed to cool to room temperature and then treated with brine (550 ml). The resulted suspension was stirred for 15 min and filtered through celite. The filter cake was washed with EtOAc. The filtrate was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (10-35% EtOAc/hexane) to afford (R,Z)-N-(1-(2,3-difluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (35.6 g, 137 mmol, 86% yield) as yellow oil. MS m/z=260.1 [M+H]+ calculated for C12H15F2NOS: 259.3
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[Cl:30])[N:19]2[N:31]=[CH:32][C:33]([C:34]#[N:35])=[C:18]12)=[O:16]>>[Cl:30][C:24]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:20]1[N:19]2[N:31]=[CH:32][C:33]([C:34]#[N:35])=[C:18]2[N:17]([C:15](=[O:16])[CH2:14][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)[CH2:22][CH:21]=1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cc(Cl)ccc1Cl
Reactant: c1ccc(C2CCNCC2)cc1
Product: N#Cc1cnn2c1N(C(=O)CN1CCC(c3ccccc3)CC1)CC=C2c1cc(Cl)ccc1Cl

Procedure:
The above compound was prepared by the reaction of 4-phenylpiperidine with the compound of Example 9 by the method of Example 16, mp 199°-200° C.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N+:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])#[C-:34]>CN(C)C=O>[CH:1]1([C:7]2[O:9][CH:34]=[N:33][C:35]=2[C:36]([O:38][CH3:39])=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CCCCC1
Reactant: [C-]#[N+]CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
To an ice-cold mixture of cyclohexanecarboxylic acid (5.40 g, 42.1 mmol) and K2CO3 (23.3 g, 168.4 mmol) in N,N-dimethylformamide (60 mL) were added diphenylphosphoryl azide (16.1 g, 58.5 mmol) and methyl isocyanoacetate (5.0 g, 50.5 mmol). After being stirred at room temperature for 16 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated NaHCO3 solution, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting light yellow solid was recrystallized from hexane-ethyl acetate to give the title compound (4.47 g, 51%) as an off-white solid. The mother liquid was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 30:70) to give a light yellow solid. This solid was triturated with hexane-diisopropyl ether to give the title compound (2.05 g, 23%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8]([F:14])=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)=[C:4]([C:17](=[O:23])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:3]=1.P(Cl)(Cl)([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8]([F:14])=[N:9][C:10]([Cl:26])=[CH:11][CH:12]=2)=[C:4]([CH:3]=1)[C:17]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc[n+]([O-])c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide (420 mg, 1.096 mmol) in 15 mL of DCM was added dropwise phosphorus oxychloride (301 μL, 3.29 mmol) followed by 2 drops of DMF. After stirring at rt for 1 h, the reaction was quenched with sat. NaHCO3, extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA=10:1 to 5:1 to 3:1) gave 5-bromo-2-(6-chloro-2-fluoropyridin-3-yloxy)-N,N-diethylbenzamide as a colorless gum.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:23])([F:22])[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[O:9]>O>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]([F:22])([F:23])[F:6])=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)c1ccc(CCNC(=O)C(F)(F)F)cc1
Solvent: O
Product: CC(C)c1ccc(CCNC(=O)C(F)(F)F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chlorosulfonic acid (2.05 mL) was added to 1.6 g of 2,2,2-trifluoro-N-[2-(4-isopropylphenyl)ethyl]acetamide, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-water, and water was added to the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.463 g of 5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11].[OH-].[K+]>CCO.O.C(OCC)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)(C)c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(C)(C(=O)O)c1cccc(Cl)c1Cl
Temperature: 95 °C
Yield: 79.5 %

Procedure:
A mixture of methyl 2-(2,3-dichlorophenyl)-2-methylpropanoate (5.50 g, 22.3 mmol) and KOH (6.24 g, 111 mmol) in EtOH/water (5:1, 150 mL) in a 500 mL round bottom flask, was heated at 95° C. for 18 hours. The solution was diluted with diethyl ether (200 mL), and washed with 1N NaOH(aq) (3×75 mL). The aqueous solution was made acidic (pH=2) with concentrated HCl. The mixture was then extracted with EtOAc (3×100 mL), and the combined organic layers were washed with deionized water (100 mL) and with brine (75 mL). The organic layer was then dried over MgSO4, concentrated, and dried in vacuo. The crude product was purified by flash column chromatography (silica, 0-100% DCM in hexane) to give the title compound (4.1338 g). MS m/e=233 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25](=[O:40])[CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][N:10]=2)[CH2:7][CH2:6][CH:5]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([C:25](=[O:40])[CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=3)[CH2:21]2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Reactant: CNC(=O)c1ccc(C2(O)CCC(=O)CC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1ccc(C2(O)CCC(N[C@H]3CCN(C(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.9 %

Procedure:
6-(1-Hydroxy-4-oxocyclohexyl)-N-methylnicotinamide (100 mg, 0.4 mmol) and 126 mg (0.4 mmol) of N-{2-[(3S)-3-aminopyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide were dissolved in 10.0 mL of methylene chloride. To the solution was added 170 mg (0.8 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 2 h. Direct chromatography on silica gel gave 48 mg (23%) of the final desired product (top spot on TLC and first peak on HPLC). MS: (M+H)+ 547.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:11]=[N:12][NH:13][N:10]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(Cc2nn[nH]n2)cc1
Yield: 46.7 %

Procedure:
4-Bromophenylacetonitrile (30.0 g, 0.15 mol), sodium azide (10.9 g, 0.17 mol) and ammonium chloride (8.9 g, 0.17 mol) were heated in DMF (300 mL) at 90° C. for 2 days. After concentration, water (200 mL) was added to the residue, the mixture was basified with 1M NaOH (170 mL) and washed with ether (2×100 mL). Acidification of the aqueous layer with 1N HCl and collection of the precipitate by suction filtration produced the crude product. This was purified by recrystallization from ethanol to provide 5-[(4-bromophenyl)methyl]-2H-tetrazole (17.2 g, 0.07 mol) in 44% yield, mp. 173°-175° C.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[C:40]([N:44]([CH3:49])[C:45](=O)[CH2:46]Cl)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([N:44]([CH3:49])[CH2:45][CH2:46][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CN(C(=O)CCl)C(C)(C)C
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCCN(C)C(C)(C)C)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 104.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and N-tert-butyl-2-chloro-N-methylacetamide (8.9 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.6 mg) was obtained.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:21])[C:17](Br)([F:19])[F:18])[CH3:14]>[Cu].CS(C)=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:17]([F:19])([F:18])[C:16]([O:15][CH2:13][CH3:14])=[O:21])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C(F)(F)C(=O)OCC)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, ethyl 4-iodobenzoate (Compound 1d; 1.38 g, 5.0 mmol), bromodifluoroacetic acid ethyl ester (1.015 g, 5.0 mmol), copper powder (635.5 mg, 10.0 mmol) and DMSO (10 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 24 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 4-(2-ethoxy-1,1-difluoro-2-oxethyl)benzoic acid ethyl ester (Compound 2d) was obtained with a yield of 80%.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:26]([F:29])([F:28])[F:27])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[NH:24][N:23]=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][C:12](=[O:25])[NH:11]2)=[O:7])=[CH:4][CH:3]=1.CCCCCC>CC(O)C>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH2:9][C@:10]2([C:26]([F:28])([F:27])[F:29])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[NH:24][N:23]=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][C:12](=[O:25])[NH:11]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(-c3ccn[nH]3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C1Nc2ccc(-c3ccn[nH]3)cc2[C@](CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1

Procedure:
4-Fluoro-N-{[2-oxo-6-(1H-pyrazol-5-yl)-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}benzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [K].C[Si]([N-][Si](C)(C)C)(C)C.[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:34][C:35]1[N:39](CC#CC)[C:38]([C:44]([O:46][CH3:47])=[O:45])=[C:37]([CH:48]=O)[N:36]=1.O>C1(C)C=CC=CC=1.O1CCCC1>[Br:34][C:35]1[NH:39][C:38]([C:44]([O:46][CH3:47])=[O:45])=[C:37](/[CH:48]=[CH:12]/[O:13][CH3:14])[N:36]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC#CCn1c(Br)nc(C=O)c1C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CO/C=C/c1nc(Br)[nH]c1C(=O)OC
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
Under an argon atmosphere 38 ml of a 0.5 M solution of potassium-bis(trimethylsilyl)amide in toluene are added dropwise to an ice-cooled solution of 6.64 g methoxymethyltriphenyl phosphonium chloride in 140 ml of tetrahydrofuran over 10 min. The reaction mixture is stirred for a further 15 min in the ice bath and then cooled to −70° C. Then a solution of 4.41 g methyl 2-bromo-3-(2-butyn-1-yl)-5-formyl-3H-imidazole-4-carboxylate in 40 ml of tetrahydrofuran is added dropwise over 30 min. After a further 45 min stirring at −70° C. the solution is heated to ambient temperature and stirred for another 1 h at this temperature. Then water is added to the reaction solution and this is extracted with ethyl acetate. The organic extracts are dried over sodium sulphate, the solvent is removed and the residue is chromatographed through silica gel (cyclohexane/ethyl acetate 9:1->7:3).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4]Br.[C-:12]#[N:13].[Na+]>C(O)C.O>[F:10][C:8]1[CH:9]=[C:2]([CH3:1])[C:3]([CH2:4][C:12]#[N:13])=[C:6]([CH3:11])[CH:7]=1
Reactant: [C-]#N
Reactant: Cc1cc(F)cc(C)c1CBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(F)cc(C)c1CC#N

Procedure:
A solution of 1.86 g (9 mmol) 2,6-dimethyl-4-fluoro-benzyl bromide and 0.420 g (9 mmol) sodium cyanide in 21 ml ethanol/water 6:1 was heated to reflux for 4h. The cooled reaction mixture was concentrated and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. Filtration of the residue through a silica gel pad with heptane/ethyl acetate 1:1 provided (4-fluoro-2,6-dimethyl-phenyl)-acetonitrile as colourless solid: MS (EI): 163.1 (M+.), 148.1 ((M-CH3)+.), 136.1 ((M-HCN)+., 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>ClCCl>[CH3:1][O:2][C:3]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])=[CH:8][CH:7]=1)=[O:20]
Reactant: C=C(C)C(=O)Cl
Reactant: COC(=O)C=Cc1ccc(OCCCCCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)OC)cc1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
To an ice-cooled solution of 20 g (72 mmol) 3-[4-(6-hydroxy-hexyloxy)-phenyl]-acrylic acid methyl ester, 11.7 g (116 mmol) triethylamine and 4 crystals of BHT in 150 ml of dichloromethane was added dropwise 11.3 g (108 mmol) of methacryloyl chloride in 5 ml dichloromethane. The mixture was allowed to react for 2 hours, at which time the dichloromethane was removed under reduced pressure. The mixture was partitioned between water (100 ml) and ethyl acetate (100 ml) and the aqueous layer subsequently extracted twice more with 100 ml portions of ethyl acetate. The combined organic layers were washed with 100 ml portions of 1M HCl, water, 5% sodium hydrogen carbonate and brine and then dried with magnesium sulfate and concentrated. Recrystallization from ethanol gave 18 g (72% yield) of a white solid. H1 NMR (CDCl3): 7.65 (d, 1H, J=16 Hz), 7.47 (dd, 2H, J=2.1, 6.4 Hz), 6.89 (dd, 2H, J=1.9, 6.6 Hz), 6.30 (d, 1H, J=15.7 Hz), 6.1 (m, 1H), 5.56 (m, 1H), 4.17 (m, 2H), 4.00 (m, 2H), 3.80 (s, 3H), 1.95 (m, 3H), 1.8-1.4 (m, 8H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]C(C)(C)C.[CH3:21][O:22][C:23]1[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=1/[N:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1COCC1.CCCCC>[CH3:21][O:22][C:23]1[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=1[NH:25][CH:26]([C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: COc1ccccc1/N=C/c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NC(c1ccccc1)c1cc2ccccc2c2ccccc12
Temperature: -80 °C

Procedure:
To a solution of 5.14 g (20.0 mmol) of 9-bromophenanthrene in 80 mL of THF, 26.7 mL (40.1 mmol) of 1.5 M tBuLi in pentane was added with vigorous stirring at −80° C. This mixture was additionally stirred for 1 hr at this temperature and then slowly warmed to room temperature. The resulting mixture was stirred for 30 min at ambient temperature and then cooled to −80° C. A solution of 4.22 g (20.0 mol) of 9 in 50 mL of THF was added. To the resulting mixture, 5 mL of water was added, and then this mixture was evaporated to dryness. The title product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether=40:1, vol.). Yield 7.32 g (94%).