Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17](O)=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)C=O>C(OCC)(=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([C:17]([N:1]3[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]3)=[O:18])[CH2:15][CH2:16]2)=[CH:12][CH:13]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: OC1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(N1CCC(O)C1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyrrolidinol (1.81 g, 0.0208 mol) was added to a mixture of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (3.93 g, 0.0200 mol), benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (8.84 g, 0.0200 mol) and 4-methylmorpholine (9.00 mL, 0.0819 mol) in N,N-dimethylformamide (20.0 mL, 0.258 mol). The mixture was stirred at rt overnight. The mixture was diluted with ethyl acetate (100 mL) and was washed with NaHCO3 (7.5%, 3×30 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NS(=O)(=O)c4ccc(I)cc4)cc3c2C1
Yield: 45.2 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 20.3 mg (0.067 mMol) 4-iodobenzenesulfonyl chloride, 10.3 mg (47%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][CH3:10])=[N:6][CH:7]=1.O.I([O-])(=O)(=O)=[O:13].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9]([CH3:10])=[O:13])=[N:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCc1ccc(Br)cn1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To the stirred solution of 5-Bromo-2-methylsulfanylmethyl-pyridine (1.1 gm, 5.04 mmol) in MeOH: water (10:2 mL) at 0° C. is added sodium periodate (1.08 gm, 5.046 mmol) resulting reaction mixture is stirred RT for 5 h. After completion, solvent is evaporated under reduced pressure then residue is diluted with water and extract with EtOAc (3×50 mL). The combine organic layer is dried over sodium sulphate and evaporated under reduced pressure to get crude which is purified by combi flash using 8% MeOH:DCM as eluent to afford title compound (900 mg) as off white solid. 1NMR (400 MHz, DMSO) δ: 2.56 (s, 3H), 4.11 (d, J=12.6 Hz, 1H), 4.26 (d, J=12.64 Hz, 1H), 7.36 (d, J=8.28 Hz, 1H), 8.05-8.08 (dd, J1=2.44 Hz, J2=8.28 Hz, 1H), 8.71 (d, J=2.32 Hz, 1H). LC-MS (m/z): M+H=235.9.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH:11](Br)([CH3:13])[CH3:12].[OH-].[K+].Cl>C(O)C>[CH:11]([S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccccc1S
Reactant: CC(C)Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Sc1ccccc1C(=O)O
Reaction time: 6 h

Procedure:
To a suspension of thiosalicylic acid (16.7 g; 109 mmol; Fluka) and isopropyl bromide (20.0 g; 163 mmol) in ethanol (125 ml) were added slowly, with vigorous stirring, KOH pellets (17.3 g; 433 mmol). After stirring for 6 h, the reaction mixture was poured into water-ice mixture (1200 ml) and acidified with concentrated hydrochloric acid (approx. 50 ml). The precipitated product was filtered off, washed with 50% aqueous ethanol (2×100 ml) and dried under reduced pressure. Yield 6.4 g (30%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:28]=[C:29]([C:31]([O:33]C)=[O:32])[CH:30]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:11]=1)=[O:9])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:28]=[C:29]([C:31]([OH:33])=[O:32])[CH:30]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:11]=1)=[O:9])([OH:4])=[O:2]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cc(C(=O)OC)cc(C(=O)OC)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cc(C(=O)O)cc(C(=O)O)c2)n1
Yield: 31.9 %

Procedure:
Under the conditions of example 2, 20 mg of 2-[3,5-bis-(methoxycarbonyl)-benzoyl]-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 2 ml of methanol is saponified with 2 ml of 1 n sodium hydroxide solution and worked up. 6 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCNc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCNc2ccccc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
489 mg (2.5 mol) of 5-chloro-1H-indole-7-carboxylic acid, 706 mg (2.5 mmol) of N-(4-tert-butyl-benzyl)-N′-phenyl-ethane-1,2-diamine and 541 mg (2.75 mmol) of EDC.HCl were dissolved in 20 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed with 1N aqueous HCl solution, once with 1N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel; diethyl ether/heptane 1:1) to yield 460 mg (40%) product as a white solid. MS (ISP) 460.3 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18](Br)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>>[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccsc1
Product: c1cn(Cc2ccc(-c3ccsc3)nc2)cn1

Procedure:
Synthesized using 3-thiophenylboronic acid (206 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Brown solid. Yield: 144 mg, 0.61 mmol, 73%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.15 (s, 2H), 6.91 (t, J=1.3 Hz, 1H), 7.12 (s, 1H), 7.40 (dd, J=5.0, 3.2 Hz, 1H), 7.45 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (s, 1H), 7.60 (dd, J=8.2, 0.6 Hz, 1H), 7.64 (dd, J=5.0, 1.3 Hz, 1H), 7.91 (dd, J=3.2, 1.3 Hz, 1H), 8.51 (dd, J=2.2, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 119.0, 120.3, 124.4, 126.1, 126.5, 129.6, 130.3, 135.7, 137.3, 141.4, 148.6, 153.8; MS (ESI): m/z=242.03 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:26]=[CH:25][C:23](=[O:24])[NH:22][C:20]1=[O:21])(=O)C>CO.N>[C@@H:6]1([N:19]2[CH:26]=[CH:25][C:23](=[O:24])[NH:22][C:20]2=[O:21])[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 23 °C
Yield: 88.5 %

Procedure:
1.2 g (purity 80%) of uridine triacetate obtained in EXAMPLE 1 was dissolved in 9.4 ml of a 2 M ammonia methanol solution and stirred at room temperature (23° C.). After the completion of the reaction, the solvent was distilled off to give 0.7 g of crude uridine (purity 87%) as a white solid. Ethanol in an amount 48.5 times by volume as much as the crude uridine was added and uridine was completely dissolved herein by heating to 58° C. Next, the solution was allowed to cool to room temperature (23° C.) and aged for 30 minutes. Then, it was cooled to 5° C. and aged for 30 minutes. The precipitated white crystals were filtered, washed and dried to give 0.3 g of β-uridine (purity 97%). 1H-NMR (400 MHz, in D2O): δ=3.76 (dd, J=12.6, 4.3 Hz, 1H), 3.87 (dd, J=12.6, 2.8 Hz, 1H), 4.09 (m, 1H), 4.18 (m, 1H), 4.31 (m, 1H), 5.86 (m, 1H), 7.83 (d, J=8.1 Hz, 1H)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](=[O:20])(=[O:19])[NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:20])=[O:19])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CS(=O)(=O)Nc2cccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Cc1ccc(CO)cc1)Nc1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
To a solution of 4-(pyridin-3-ylsulfamoylmethyl)benzoic acid methyl ester (1.91 g, 6.23 mmol) in THF (60 mL) at 0° C. was added a 1 M solution of LiAlH4 in THF (13.7 mL, 13.7 mmol), and the mixture was warmed to room temperature. After stirring for 10 minutes, the mixture was heated to reflux temperature for 3 hours. The reaction mixture was cooled to 0° C. and quenched with saturated Na2SO4 aqueous solution (1.9 mL). The mixture was neutralized with 1 N HCl solution (13.7 mL), and then THF was evaporated under reduced pressure. The residue was diluted with water (70 mL) and extracted with CHCl3 (50 mL×3). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC on silica gel (6% MeOH in EtOAc) to afford the titled compound (1.43 g, 83%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.Cl[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:14]=1.C([O-])(=O)C.[K+].B(O)O.[NH4+].[Cl-]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:14]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc(Cl)cnc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: OBO
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 5-chloro-2-fluoropyridin-3-ylboronic acid (1220 mg, 6.96 mmol) (Asymchem Laboratories, Inc.), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2300 mg, 5.98 mmol), and potassium acetate (1200 mg, 12.23 mmol) in dioxane (10 mL)-water (2.0 mL) was placed in a 100 mL flask under argon. A-Phos-PdCl2 (150 mg, 0.212 mmol) was added and the mixture was heated to 95° C. under nitrogen. After 2 h, more boronic acid (600 mg) was added and the mixture was heated for another hour. The mixture was cooled to rt. Saturated NH4Cl was added. The mixture was partitioned between water (5 mL) and EtOAc (30 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified on silica gel using 10-50% EtOAc in hexane to give the desired product as a light yellow solid (2.3 g). LCMS (ES, pos.): calcd for C25H23ClFN5O2: 479.2. found: 480.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=8.02, 2.74 Hz, 1H); 8.25 (d, J=1.37 Hz, 1H); 7.21 (d, J=8.41 Hz, 4H); 6.86 (t, J=8.22 Hz, 4H); 4.81 (d, J=7.24 Hz, 4H); 3.80 (2s, 6H); 2.54 (s, 3H).
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C.O.C(OCC)(=O)C>C1COCC1>[F:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([N:11]3[CH2:12][CH2:13][CH:8]([C:6]([O-:7])=[O:5])[CH2:9][CH2:10]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1.[Na+:2]
Reactant: CCOC(=O)C1CCN(c2cc3cccnc3c(-c3cccc(F)c3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C([O-])C1CCN(c2cc3cccnc3c(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium hydroxide (1 M, 0.25 ml) is added to a solution of 1-[8-(3-fluoro-phenyl)-[1,7]naphthyridin-6-yl]-piperidine-4-carboxylic acid ethyl ester (96 mg, 0.25 mmol) in THF (1 ml). The solution is stirred at room temperature for 24 hours, then heated to 45° C. for 24 hours. Water and ethyl acetate are added and the aqueous phase separated and evaporated to give the title compound. MS: APCI 352.0 MH+.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:18]([O:36][CH3:37])=[C:19]3[C:24]=2[N:23]=[CH:22][C:21]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=2)=[CH:20]3)=[CH:13][C:12]([F:42])=[C:11]([O:43][CH3:44])[N:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CCOC(C)=O>[C:38]([C:17]1[C:18]([O:36][CH3:37])=[C:19]2[C:24](=[C:15]([C:14]3[C:9](=[O:8])[NH:10][C:11]([O:43][CH3:44])=[C:12]([F:42])[CH:13]=3)[CH:16]=1)[N:23]=[CH:22][C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][CH:30]=1)=[CH:20]2)([CH3:41])([CH3:39])[CH3:40]
Reactant: [H][H]
Reactant: COc1nc(OCc2ccccc2)c(-c2cc(C(C)(C)C)c(OC)c3cc(-c4ccc(NS(C)(=O)=O)cc4)cnc23)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1[nH]c(=O)c(-c2cc(C(C)(C)C)c(OC)c3cc(-c4ccc(NS(C)(=O)=O)cc4)cnc23)cc1F

Procedure:
step 5—A mixture of 148 (0.100 g, 0.162 mmol), Pd/C (30 mg) and EtOAc was stirred under one atmosphere hydrogen for 20 h. The catalyst was filtered and washed with EtOAc. The filtrate was concentrated and the crude product purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (30 to 80% EtOAc) to afford 25 mg (29.3%) of I-47.
Reaction SMILES: O[CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([SH:22])[N:17]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([S:22][CH2:2][C:3]3([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]3)[N:17]=2)=[CH:14][CH:15]=1
Reactant: OCC1(CO)CCC1
Reactant: Sc1nccc(-c2ccc(Cl)cc2)n1
Product: OCC1(CSc2nccc(-c3ccc(Cl)cc3)n2)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 19a from [1-(hydroxymethyl)cyclobutyl]methanol and 4-(4-chlorophenyl)-2-pyrimidinethiol. 1H NMR (300 MHz, CDCl3) δ 8.49 (d, J=5 Hz, 1H), 7.95 (d, J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H), 7.32 (d, J=6 Hz, 1H), 4.18 (t, J=7 Hz, 1H), 3.54(d, J=7 Hz, 2H), 3.47 (s, 2H), 2.03-1.69 (m, 6H). GC-MS m/z 320 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH3:20])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([Cu])#N.[C:29]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[C:38]([CH3:46])[CH:39]2[Si:42](Cl)([CH3:44])[CH3:43])=[C:35]([C:47]2[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:50]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:48]=2)[C:34]=1[O:61][CH3:62])([CH3:32])([CH3:31])[CH3:30]>CCOCC.O>[C:29]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[C:38]([CH3:46])[CH:39]2[Si:42]([CH:16]2[C:15]3[C:19](=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=4)[CH:12]=[CH:13][CH:14]=3)[CH:18]=[C:17]2[CH3:20])([CH3:44])[CH3:43])=[C:35]([C:47]2[CH:48]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:50]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:52]=2)[C:34]=1[O:61][CH3:62])([CH3:31])([CH3:30])[CH3:32]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)C=C(C)C2[Si](C)(C)Cl
Reactant: CC1=Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)C=C(C)C2[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 5.54 g (21.1 mmol) of 7-(4-tert-butylphenyl)-2-methyl-1H-indene in 150 ml of ether 8.50 ml (21.3 mmol) of 2.5 M nBuLi in hexanes was added in one portion at −40° C. This mixture was stirred overnight at room temperature, then cooled to −40° C., and 190 mg of CuCN was added. The resulting mixture was stirred for 1 h at −20° C., then cooled to −40° C., and a solution of 10.5 g (21.1 mmol) of [6-tert-butyl-4-(3,5-di-tert-butylphenyl)-5-methoxy-2-methyl-1H-inden-1-yl](chloro)dimethyl-silane in 150 ml of ether was added in one portion. Further on, this mixture was stirred overnight at ambient temperature, then 0.5 ml of water was added. This solution was filtered through a pad of silica gel 60 (40-63 um) which was additionally washed by 2×75 ml of dichloromethane. The combined elute was evaporated to dryness, and the residue was triturated with 70 ml of n-hexane. The obtained suspension was filtered on glass frit, the precipitate was washed with 30 ml of n-hexane and dried in vacuum to give a white powder. Additionally, the mother liquor was evaporated to small volume. The formed suspension was filtered through glass frit (G3), and the precipitate was washed with 2×15 ml of n-hexane and then dried in vacuum. Again, the mother liquor was evaporated to give a yellowish oil which was re-crystallized at −30° C. for two months. Crystals precipitated from this solution were collected and dried in vacuum. Thus, 12.2 g (80%) of the title product was isolated. Assignment in NMR spectra was made using the following abbreviations: L1 for 4-(4-tert-butylphenyl)-2-methyl-1H-inden-1-yl and L2 for 6-tert-butyl-4-(3,5-di-tert-butylphenyl)-5-methoxy-2-methyl-1H-inden-1-yl.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:7][O:6]1)CC=C.[CH3:8][C:9](=[CH:11][CH3:12])[CH3:10]>>[CH3:8][C:9]([CH3:10])=[CH:11][CH2:12][CH2:1][CH:5]1[CH2:7][O:6]1
Reactant: CC=C(C)C
Reactant: C=CCCC1CO1
Product: CC(C)=CCCC1CO1

Procedure:
2-(But-3-enyl)oxirane (1.000 g, 10 mmol) and 2-methylbut-2-ene (10 g, 102 mmol) were stirred at room temperature for 24 hr in a sealed scintillation vial with Zhan catalyst 1 (0.057 g, 0.086 mmol). Solvent was removed under reduced pressure and the residue purified by column chromatography (0-10% EtOAc/n-hexane/silica) to give 2-(4-methylpent-3-enyl)oxirane as a colorless oil. 1H NMR (CDCl3): δ 5.2-5.1 (m, 1H), 2.95-2.88 (m, 1H), 2.75 (dd, 1H J1=5.0, J2=4.1), 2.48 (dd, 1H J1=5.0, J2=2.8), 2.15 (2H, q, J=7.4), 1.70 (s, 3H), 1.63 (s, 3H), 1.60-1.50 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.Cl[C:28]([O:30][CH3:31])=[O:29]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:28](=[O:29])[O:30][CH3:31])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: COC(=O)Cl
Product: COC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 41 %

Procedure:
The title compound was prepared in 41% yield according to the general procedure for the preparation of carbamates (Method D) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and methyl chloroformate.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13]O.S(=O)(=O)(O)O>>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:12])=[C:10]([F:11])[C:2]=1[F:1]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(F)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(F)c1F
Yield: 83.2 %

Procedure:
2,3-Difluoro-4-methyl-benzoic acid (10.0 g, 58.1 mmol) was dissolved in MeOH (200 mL, 6.0 mol) and sulfuric acid (1.00 mL, 19.0 mmol), and was heated at reflux overnight. The mixture was then cooled and concentrated under reduced pressure. The resulting residue was taken up in EtOAc and washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to yield 9.0 g of intermediate (7a) as a white solid. 1H-NMR (CDCl3): 7.61 (1H, t), 7.00 (1H, t), 3.93 (3H, s), 2.35 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([F:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.Br[CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>O>[Cl:21][C:3]1[C:2]([NH:1][CH:23]([C:24]([O:26][CH3:27])=[O:25])[CH3:28])=[CH:7][C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[C:5]([F:20])[CH:4]=1
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: O
Product: COC(=O)C(C)Nc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 140 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
A mixture of 0.12 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-23) and 247 mg of methyl 2-bromopropionate was stirred at 140° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 125 mg (yield, 83%) of 3-{4-chloro-5-[1-(methoxycarbonyl)ethylamino]-2-fluorophenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-89).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[CH2:9][CH:8]=[C:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)=[CH2:3].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[N+](C1C=CC=CC=1C=O)([O-])=O.Cl>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:3][C:2]([CH:4]1[CH2:5][CH:6]=[C:7]([CH:10]=[O:11])[CH2:8][CH2:9]1)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC=C(CO)CC1
Agent: CC(C)[O-]
Agent: Cl
Agent: O=Cc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)C1CC=C(C=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
(S)-(−)-Perillyl alcohol (300 mg, 2.0 mmol) was dissolved in benzene (1 mL), added with aluminum isopropoxide (40 mg, 0.1 eq, 0.20 mmol) and 2-nitrobenzaldehyde (390 mg, 1.3 eq, 2.6 mmol) and stirred at room temperature for 2 hours. The reaction mixture was added with ethyl acetate and made acidic with addition of 2 N hydrochloric acid, and then the organic layer was separated. Subsequently, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain 250 mg (yield: 84%) of the title compound as yellow oil.