Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([OH:22])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C1COCC1.O>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([OH:22])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:40](=[O:41])[CH2:39][Cl:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCC(O)(CCNCc2ccccc2)c2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OCC(O)(CCN(Cc2ccccc2)C(=O)CCl)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2RS)-4-amino-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (6.7 g) in methanol (20 mL) were added magnesium sulfate (3.35 g), triethylamine (1.3 mL) and benzaldehyde (2.1 ml), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added sodium borohydride (3.55 g), and the mixture was stirred at 0° C. for 10 min, and then stirred while warming to room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated. The concentrated residue was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-(benzylamino)-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (8.47 g). To a solution of 4-(benzylamino)-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (8.47 g) in THF (45 mL) were added triethylamine (2.85 mL) and chloroacetyl chloride (1.64 ml), and the mixture was stirred at 0° C. for 10 min, and then stirred while warming to room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (7.41 g).
Reaction SMILES: COC(=O)COC1C=CC(SC#N)=CC=1C.C[O:18][C:19](=[O:43])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:24][C:23]=1[CH3:42]>>[C:33]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]([CH2:29][S:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([OH:43])=[O:18])=[C:23]([CH3:42])[CH:24]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(-c3ccccc3)cc2)cc1C
Agent: COC(=O)COc1ccc(SC#N)cc1C
Product: Cc1cc(SCc2ccc(-c3ccccc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared from (2-methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester in a manner analogous to Example 1D. 400 MHz 1H NMR (DMSO-d6) δ 7.05 (s, 1H), 7.00 (d, 1H, J=10.3 Hz), 6.70 (d, 1H, J=10.3 Hz), 5.00 (s, 1H), 4.73 (s, 1H), 3.63 (s, 3H), 2.09 (s, 3H); MS m/z 213 (M+1). Step 4. Preparation of [4-(Biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester (Compound 2D)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:62][CH2:63][C:64]([N:66]1[CH2:70][CH2:69][CH2:68][C@H:67]1[C:71]#[N:72])=[O:65]>CN(C=O)C>[C:71]([C@@H:67]1[CH2:68][CH2:69][CH2:70][N:66]1[C:64](=[O:65])[CH2:63][NH:62][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)=[O:13])#[N:72]
Reactant: N#C[C@@H]1CCCN1C(=O)CN
Reactant: O=C(O)c1ccnc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1C(=O)CNC(=O)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Commercially available quinoline-4-carboxylic acid (0.078 g, 0.449 mmol) was dissolved in 7 ml of DMF, N-ethyl-N-isopropylpropan-2-amine (0.242 ml, 1.347 mmol), HOBT (0.069 g, 0.449 mmol) and TBTU (0.144 g, 0.449 mmol) were added. After 15 min a solution of (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (0.120 g, 0.449 mmol) (prepared as described under A.1 of the experimental part) in DMF was added. The mixture was stirred overnight at room temperature. The volatiles were evaporated, the residue was dissolved in ethyl acetate and extracted with 1 N citric acid, saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtrated and evaporated. It was purified using column chromatography (1-5 hexane-ethyl acetate).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[CH2:37]2.O>CN(C=O)C>[O:51]=[C:45]1[CH:44]([N:38]2[CH2:37][C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:12](=[O:14])[CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc2ncccc2c1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of quinolin-6-yl-acetic acid (0.19 g, 1.02 mmol) in dry DMF (5 mL) was added CDI (0.16 g, 1.02 mmol). After 1 h of stirring at rt, 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.30 g, 0.81 mmol) was added. After 18 h, water (20 mL) was added. The solids were collected by filtration, washed with water and dried in vacuo for 18 h to give N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(quinolin-6-yl)acetamide as a white solid (355 mg, 99%). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 10/90, CH3CN/0.1% H3PO4, 4.54 min (95.6%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.89-2.10 (m, 1H), 2.37 (qd, J=4.3, 13.2 Hz, 1H), 2.63 (br. s., 1H), 2.80-3.02 (m, 1H), 3.73 (s, 2H), 4.12-4.30 (m, 1H), 4.30-4.48 (m, 3H), 5.10 (dd, J=5.1, 13.2 Hz, 1H), 7.29-7.47 (m, 2H), 7.52 (dd, J=4.2, 8.3 Hz, 1H), 7.60-7.76 (m, 2H), 7.84 (s, 1H), 7.97 (d, J=8.7 Hz, 1H), 8.32 (d, J=7.7 Hz, 1H), 8.75 (t, J=5.9 Hz, 1H), 8.87 (dd, J=1.7, 4.2 Hz, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.48, 31.18, 42.16, 42.31, 47.03, 51.55, 121.53, 122.02, 122.91, 127.07, 127.52, 127.72, 128.72, 130.36, 131.21, 134.66, 135.61, 142.32, 143.73, 146.73, 150.07, 167.87, 169.99, 170.98, 172.86. LCMS: MH=443; Anal Calcd for C25H22N4O4+1.6H2O: C, 63.71%; H, 5.39%; N, 11.89%. Found: C, 63.71%; H, 5.25%; N, 11.99%.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:9](=[O:10])[CH2:8][C:7]2([CH2:14][C:13](=[O:15])[NH:12][CH2:11]2)[C:6]1=[O:16])[CH3:4].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:3]([N:5]1[C:9](=[O:10])[CH2:8][C:7]2([CH2:14][C:13](=[O:15])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)[C:6]1=[O:16])[CH3:4]
Reactant: CCN1C(=O)CC2(CNC(=O)C2)C1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CC2(CC(=O)N(Cc3ccccc3)C2)C1=O
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A suspension of sodium hydride (2.20 g of 60% oil suspension (0.055 mole) washed with toluene) in 50 ml N,N-dimethylformamide was treated gradually with a solution of 10.0 g (0.051 mole) 2-ethyl-2,7diazaspiro[4.4]nonane-1,3,8-trione in 100 ml N,N-dimethylformamide. After stirring 15 minutes, there was added dropwise 6.4 ml (0.055 mole) benzyl chloride and the mixture was stirred overnight, concentrated in vacuo and shaken with water-methylene chloride. The organic layers were dried, evaporated, and the product crystallized from toluene-hexane to afford 11.1 g of the title compound, mp 125°-126.5° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[O:22])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:13]>ClCCl>[CH2:15]([O:14][C:12]([NH:13][C@:3]([OH:9])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([F:10])([F:11])[F:1])=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@](O)(NC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 48 h

Procedure:
To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (1500 g, 8.82 mol) in dichloromethane (5000 mL) was added benzyl carbamate (1330 g, 8.82 mol). After 2 days, the reaction mixture was filtered to afford ethyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoro-2-hydroxyalaninate. The material was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25]>O1CCCC1.O>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1cc(C=O)oc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1ccc(C(O)c2cc(C)c(C)o2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
2-Bromo-5-picoline (1.5 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6 M hexane solution (5.6 ml) of n-butyllithium was added dropwise to the solution at −78° C. The reaction solution was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raise to room temperature with stirring. Water was added to the reaction solution to stop the reaction. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(5-methyl-pyridin-2-yl)-methanol (855 mg, yield 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][NH:6][C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C(NCc1cccc(Br)c1)c1ccccc1
Product: O=Cc1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Yield: 64.3 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 2 g (6.9 mmol) of N-(3-bromo benzyl)-benzamide with 1.6 g (10.3 mmol) of 4-formylbenzene-boronic acid, 1.4 g (65%) of expected product are obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH-:6].C(=O)(O)[O-].[Na+].[C:18](Cl)(Cl)=[S:19]>ClCCl.O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:6]=[C:18]=[S:19]
Reactant: S=C(Cl)Cl
Reactant: [NH-]Cc1ccccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN=C=S
Reaction time: 0.5 h

Procedure:
A solution containing 2-trifluoromethylbenzylamide (3.50 g, 0.02 mol) in 50 ml of dichloromethane and a solution containing sodium bicarbonate (3.4 g, 0.04 mol) in 55 ml of water are added simultaneously over one hour at a temperature close to 20° C. to a solution of thiophosgene (2.28 g, 0.02 mol) in 15 ml of dichloromethane. Agitation is carried out for 30 minutes. The reaction mixture is decanted and the organic phase washed with 100 ml of water then with 100 ml of a solution of salt water. The organic phase is dried over magnesium sulphate and the solvent is evaporated off with a rotary evaporator. The expected compound is obtained in the form of an oil (3.50 g, 81%). Considering its reactivity, it is used immediately for the following reaction.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:19]>>[Br:19][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(N)cc(C(=O)O)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 0 °C
Yield: 68 %

Procedure:
3-Amino-5-(methoxycarbonyl)benzoic acid (1.0 g, 5.12 mmol, 1 eq.) was dissolved in 15% HBr (22.5 mL) at RT, then cooled to 0° C. with stirring. A 2.5 M aqueous solution of NaNO2 (2.3 mL, 5.64 mmol, 1.1 eq.) was added slowly via an addition funnel to generate the diazonium salt. In a separate flask, CuBr was partially dissolved in 15% HBr (9 mL) and cooled to 0° C. with stirring, to which the diazonium salt solution was subsequently added. A slight exotherm was observed. The reaction was stirred at RT for 30 minutes then carefully heated at 70° C. for 1 hour. The reaction was worked up by filtering off insoluble material as crude product. The solids were dissolved in water/EtOAc and the layers separated. The aqueous layer was extracted again with EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated to give an off-white solid. The product was purified over silica gel in 1:1 hexanes/EtOAc to 100% EtOAc to 4:1 methylene chloride/MeOH to yield 3-bromo-5-(methoxycarbonyl)benzoic acid (0.90 g, 3.47 mmol, 68% yield) as a white solid. MS found: (M−H)+=257/259.
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
Methyl vinyl sulfone (1.8 mL, 20.1 mmol) was added to a solution of 1-(tert-butyloxycarbonyl)piperazine (1.50 g, 8 mmol) in methanol (84 mL). The reaction mixture was stirred at room temperature for 4 h and concentrated to a white solid. Purification of the solid by flash column chromatography (silica gel, eluting with 1-5% methanol in methylene chloride) gave 1-tert-butyloxycarbonyl-4-(2-methanesulfonylethyl)piperazine as a white solid (2.29 g, 95%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)[CH:24]=4)=[N:21][CH:22]=3)[CH:14]=[N:13]2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CC(O)C>[CH3:34][N:32]1[CH:33]=[C:29]([C:25]2[CH:24]=[C:23]([C:20]3[N:21]=[CH:22][C:17]([C:15]4[CH:14]=[N:13][N:12]([CH:9]5[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]5)[CH:16]=4)=[CH:18][N:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:30]=[N:31]1
Reactant: CCOC(=O)C1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCC(C(=O)O)CC5)c4)cn3)c2)cn1
Yield: 63.6 %

Procedure:
A solution of 4-(4-{2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid ethyl ester (50 mg; 0.11 mmol; 1.0 eq.) and NaOH (5.00 mL of a 1N solution; 5.0 mmol; 46 eq.) in iPrOH (20 mL) was stirred at RT for 16 h. It was then poured into a 1 N solution of HCl and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a cis-trans mixture of the title compound as a yellow solid (30 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.57-8.47 (m, 2H), 8.27 (s, 1H), 8.24-8.17 (m, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.78-7.66 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.31-4.15 (m, 1H), 3.89 (s, 3H), 2.66-1.45 (m, 9H). HPLC (Condition A): Rt 3.23 min (purity 93.0%). HPLC (Chiralpak IA, EtOH:TFA:THF 90:0.1:10): Rt 7.23; 10.97 min (purity 30.2: 66.6%); MS (ESI+): 429.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C(N(CC)CC)C.[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)#[CH:19]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]#[C:18][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: C#Cc1cncc(OC)c1
Reactant: COc1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
Dissolve 1-fluoro-4-iodo-2-methoxybenzene, (prepared as described in PREPARATION 47), (1.0 g, 4.0 mmol) in triethylamine (15 mL, 108 mmol) and add 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (500 mg, 3.8 mmol) followed by bis(triphenylphosphine)palladium (II) dichloride (100 mg, 0.14 mmol) and copper (I) iodide (60 mg, 0.32 mmol). Stir for 18 h at room temperature, concentrate and purify by silica gel chromatography, eluting with 3:1 hexanes:ethyl acetate. Further purify on silica gel, eluting with 9:1 dichloromethane:ethyl acetate, to give the title compound as a white solid (650 mg, 65%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].[Br:31][C:32]1[CH:40]=[CH:39][C:35](C(Cl)=O)=[C:34]([F:41])[CH:33]=1>C(Cl)(Cl)Cl>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=3)[CH2:12][CH2:13]2)=[O:7])=[C:34]([F:41])[CH:33]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
4-(3-Chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.4 g), which is the intermediate described in Preparation Example 48, was dissolved in chloroform (2.5 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was alkalified with 1N aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. By reaction and treatment in the same manner as in Preparation Example 8 and using the obtained residue and 4-bromo-2-fluorobenzoyl chloride (1.1 g), the title compound (1.9 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([F:23])[CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+]>>[F:23][C:4]1[CH:3]=[C:2]([NH:1][CH3:24])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: C[C@H]1CN(Cc2ccc(N)cc2F)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(F)c1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(4-amino-2-fluorophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D66) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. overnight prior to addition of sodium borohydride and for 24 h after addition. δH (CDCl3, 400 MHz) 7.11 (1H, t), 6.35 (1H, dd), 6.27 (1H, dd), 4.17 (1H, br.s), 3.78 (2H, m), 3.44 (2H, m), 3.07 (1H, td), 2.82 (3H, s), 2.75 (1H, m), 2.59 (1H, m), 2.14 (1H, dd), 1.99 (1H, m), 1.44 (9H, s), 1.21 (3H, d).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(O)C.[C].[Pd]>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(C(C)(C)C)ccc2c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2cc(C(C)(C)C)ccc2c1
Yield: 92.5 %

Procedure:
A solution of ethyl 7-tert-butyl-4-chloroquinoline-3-carboxylate (2.06 g, 7.06 mmol) and triethylamine (1.97 ml, 21.2 mmol) in ethanol (70 ml) was hydrogenated over 5% palladium-carbon (300 mg) at balloon pressure for 1.5 hours. After the catalyst was filtered through a pad of celite, the filter cake was washed with CH2Cl2. The filtrate and washings were evaporated in vacuo to give crude product, which was purified by column chromatography on silica gel with hexane-ethyl acetate (8:1) to give the title compound (1.68 g, 92.5%) as yellow colored oil. 1H NMR (270 MHz, CDCl3) δ ppm 1.43-1.51 (3H, m), 1.45 (9H, s), 4.48 (2H, q, J=7.0 Hz), 6.69-7.75 (1H, m), 7.85-7.91 (1H, m), 8.13 (1H, s), 6.79-8.82 (1H, m), 9.41-9.44 (1H, m).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Cl[C:27]1[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[CH:29][N:28]=1>>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[CH:29][N:28]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ncc([N+](=O)[O-])cc2C)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) and 2-chloro-3-methyl-5-nitropyridine as described in Example 111, Step A to provide a light-yellow solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[NH:14][CH:13]=[C:12]2[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22]CCCl.O=P(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:22])=[N:14][CH:13]=[C:12]2[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: N#Cc1c[nH]c(=O)c2ccc(SCc3ccccc3)cc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A vial was charged with 6-(benzylthio)-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile (0.492 g, 1.683 mmol) and DCE (8.41 ml). POCl3 (0.314 ml, 3.37 mmol) was added and the reaction was stirred overnight at 90° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (40 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford 6-(benzylthio)-1-chloroisoquinoline-4-carbonitrile as a brown solid. m/z (ESI) 311.1 (M+H)+.