Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:15][CH2:14][CH2:13][CH2:12][C:6]21[O:10][CH:9]([CH3:11])[CH2:8][O:7]2)([CH3:4])([CH3:3])[CH3:2].C(C1CCCCC1=O)(C)(C)C.C(O)C(O)C>[Pd].[Ru].C(O)(C)C>[C:1]([CH:5]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:6]1[O:7][CH2:8][CH:9]([OH:10])[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1COC2(CCCCC2C(C)(C)C)O1
Agent: [Pd]
Agent: [Ru]
Agent: CC(C)(C)C1CCCCC1=O
Solvent: CC(O)CO
Solvent: CC(C)O
Product: CC(O)COC1CCCCC1C(C)(C)C
Yield: 81.6 %

Procedure:
A 500 ml capacity autoclave was charged with 30 g (0.14 mol) of 6-t-butyl-2-methyl-1,4-dioxaspiro[4.5]decane which has been prepared from 2-t-butylcyclohexanone and 1,2-propanediol, 150 ml of isopropyl alcohol, 0.29 g of a catalyst of 5% palladium supported on active carbon and 0.01 gof a catalyst of 5% ruthenium supported on active carbon. The reaction was carried out under a hydrogen pressure of 70 kg/cm2 and at a temperature of 190° C. for 10 hours until completion of the absorption of hydrogen. After the reaction, the catalysts were removed by filtration and the resulting filtrate was subjected to distillation to obtain 24.5 g of 1-(2-t-butylcyclohexyloxy)-2-propanol (b.p.=112° to 113° C./5 mmHg; yield=81%; cis:trans=66:34).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([O:33][CH3:34])=[C:28]([CH3:35])[CH:27]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]2=[O:25])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.C(OCC)(=O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]([S:46]([CH3:45])(=[O:48])=[O:47])[S:46]([CH3:45])(=[O:48])=[O:47])=[CH:3][CH:4]=2)([C:26]2[CH:27]=[C:28]([CH3:35])[C:29]([O:33][CH3:34])=[C:30]([CH3:32])[CH:31]=2)[C:9]1=[O:25]
Reactant: COc1c(C)cc(C2(c3ccc(N)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(C)cc(C2(c3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Reaction time: 2 h
Yield: 182.1 %

Procedure:
Combine 3-(4-amino-phenyl)-1-(2-chloro-benzyl)-3-(4-methoxy-3,5-dimethyl-phenyl)-1,3-dihydro-indol-2-one (73 mg, 0.15 mmol), N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) and methanesulfonyl chloride (0.013 mL, 0.165 mmol) in CH2Cl2 (1 mL). After 5 h. stirring at room temperature TIC (50% EtOAc/hexanes) shows reaction not complete. Add more N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) and methanesulfonyl chloride (0.013 mL, 0.165 mmol) and stir 2 h. more at which time reaction complete. Dilute with ethyl acetate and wash with water amd brine. Dry (MgSO4), filter and concentrate in vacuo to give 96 mg of a residue. Purify by radial chromatography (step gradient of 10% EtOAc/hexanes, 20% EtOAc/hexanes, 25% EtOAc/hexanes and 33% EtOAc/hexanes to obtain 56 mg (58%) of the title compound. MS (ES): m/z=639 (M+1); 1H NMR(DMSO-d6); δ7.54-7.45 (m, 4H), 7.37-7.22 (m, 5H), 7.15 (t, J=7.5, 1H), 7.00 (m, 2H), 6.87 (s, 2H), 5.09 (s, 2H), 3.64 (s, 3H), 3.53 (s, 6H), 2.17 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9]2)[C:3]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.C(N=[C:32]=[O:33])C>N1C=CC=CC=1>[CH3:7][N:6]1[C:2]2[NH:1][C:32](=[O:33])[C:24]3[CH2:25][CH2:26][CH2:27][CH2:28][C:23]=3[C:3]=2[C:4]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9]2)=[N:5]1
Reactant: CCN=C=O
Reactant: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)c(C2=CCCCC2)c1N
Solvent: c1ccncc1
Product: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)c2c3c(c(=O)[nH]c21)CCCC3
Yield: 76.9 %

Procedure:
To a stirring solution of EXAMPLE 24D (0.967 g, 2.54 mmol) in pyridine (10 mL) was added ethyl isocyanate (0.6 mL, 7.62 mmol) and the solution heated at reflux for 24 hours. After cooling, the mixture was concentrated and the residue recrystallized from methanol. The white solid was collected by filtration, washed with methanol and dried to give the title compound (794 mg, 77%). 1H NMR (DMSO-d6): 1.66-1.77 (m, 4H), 2.01-2.17 (m, 1H), 2.18-2.27 (m, 1H), 2.37-2.43 (m, 2H), 2.86-2.92 (m, 2H), 3.33-3.46 (m, 1H), 3.49-3.64 (m, 2H), 3.68-3.76 (m, 1H), 3.76 (s, 3H), 3.77-3.85 (m, 1H), 5.08 (s, 2H), 7.29-7.35 (m, 1H), 7.34-7.39 (m, 5H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13](=[O:14])[N:46]1[CH2:45][CH2:44][N:43]([C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[CH2:48][CH2:47]1)[CH3:2]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(c3ccncc3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg (1.04 mmol) 1-pyridin-4-yl-piperazine.
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.I[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23]>CCOCC>[F:26][C:21]([F:27])([C:22]([F:25])([F:24])[F:23])[C:20]([F:29])([F:28])[S:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[CH:6][CH:7]=1
Reactant: Nc1ccc(S)cc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOCC
Product: Nc1ccc(SC(F)(F)C(F)(F)C(F)(F)F)cc1
Yield: 63.2 %

Procedure:
To an acetonitrile solution (20 ml) of 4-aminothiophenol (1.25 g, 9.98 mmol) and triethylamine (1.11 g, 11.0 mmol) was added 1-iodoheptafluoro-n-propane (5.91 g, 19.9 mmol), and the resultant mixture was stirred at room temperature for 3 hours. The mixture was diluted with ether, and washed with a 1N sodium hydroxide aqueous solution. Then, the product was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.85 g (yield 63%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1>>[C:41]([C:40]1[CH:43]=[C:36]([C:2]2[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:37]=[N:38][CH:39]=1)#[N:42]
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 195.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow resin. UPLC-MS (Condition 3) tR=1.13 min, m/z=488.3 [M+H]+, m/z=486.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=6.97 Hz, 3H) 3.15 (q, J=6.93 Hz, 2H) 3.36-3.40 (m, 2H) 3.44-3.56 (m, 2H) 4.55 (br. s, 1H) 7.70 (d, J=8.56 Hz, 2H) 7.85-7.99 (m, 2H) 8.10 (d, J=2.45 Hz, 1H) 8.53 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 9.04 (dd, J=4.03, 2.08 Hz, 2H) 10.36 (s, 1H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.O>ClCCl>[F:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(F)cnc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: COc1ncc(F)nc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
After dissolving 447 mg of methyl 6-fluoro-3-methoxypyrazine-2-carboxylate in 8 ml of dichloromethane, the solution was cooled to −78° C. Next, 1.76 ml of diisobutylaluminium hydride (1.5 M, toluene solution) was added dropwise and the mixture was stirred for 30 minutes. After adding 10 ml of 1N hydrochloric acid dropwise to the reaction solution, water was added and extraction was performed with dichloromethane. After then drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (245 mg, 65% yield).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:8])=[O:4].[C:18]([O-:21])(=[S:20])[CH3:19].[Na+].C(O)(=S)C.[Na]>CO>[C:18]([S:20][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:8])=[O:4])(=[O:21])[CH3:19]
Reactant: CC([O-])=S
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=O)CCl
Agent: CC(O)=S
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(=O)SCC(=O)NCC(=O)NCC(=O)NCC(=O)O
Yield: 88.5 %

Procedure:
The crude chloroacetylglycylglycylglycine product (1.0 g, 0.0037 mol) was suspended in 50 ml of anhydrous methanol under nitrogen. Sodium thioacetate (prepared from 0.58 g (0.0076 mol) of thioacetic acid and dry methanol to which 175 mg (0.0076 mol) of sodium had been added) in methanol was added. The reaction mixture was refluxed for 1.5 hr. After removal of solvent under reduced pressure, 2N HCl was added with stirring. The solid was isolated by filtration and washed with CHCl3. Crystallization from methanol/water gave 1.00 g (90%) of product.
Reaction SMILES: C1(C#CC2CC3(CCNCC3)ON=2)C=CC=CC=1.[C:19]([C:21]1[CH:22]=[C:23]([C:27]#[C:28][C:29]2[CH2:43][C:32]3([CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)[O:31][N:30]=2)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[CH2:35]1[C:32]2([CH2:43][C:29]([C:28]#[C:27][C:23]3[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=3)[C:19]#[N:20])=[N:30][O:31]2)[CH2:33][NH:34]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(C#Cc3cccc(C#N)c3)=NO2)C1
Agent: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Product: N#Cc1cccc(C#CC2=NOC3(CNC3)C2)c1
Yield: 90.4 %

Procedure:
The title compound was synthesized following the method reported for the Compound 1c, substituting Compound 1b with Compound 81a. The crude residue was used without further purification in the next reaction. Yield: 90.4%.
Reaction SMILES: C[Li].[CH3:3]COCC.[C:8]([O:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[C:18](=[O:27])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCCCCC.CCOC(C)=O>C1COCC1.CCOC(C)=O>[C:8]([O:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[C:18]([OH:27])([CH3:3])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2=O
Reactant: CCOCC
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)O
Temperature: 140 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a flame dried 250 mL 3-necked rb flask equivuipped with a magnetic stir bar was added Ce(III)Cl-7 H2O (2.74 g, 7.35 mmol, 2 equiv). The flask was heated in a 140° C. oil bath under reduced pressure (~1 torr) for 2.5 h. The flask was cooled to rt and slowly filled with N2G. The white powder was suspended in dry THF (30 mL), stirred at rt for 1 h and then cooled to -78° C. To the white suspension was added a 1.4M solution of methyl lithium (MeLi) in Et2O (5.25 mL, 7.35 mmol, 2 equiv) by syringe. The dark yellow/brown solution stirred at -78° C. for 1 h and then 1-t-butoxycarbonyl-1,2,3,4-tetrahydro-7-methoxy-4-quinolone dissolved in 3 mL THF was added. The solution stirred at -78° C. for 3 h and was warmed to 0° C. for 2 h. The reaction did not go to completion and starting material was observed by TLC (silica gel, hexane/EtOAc, 3:1). The reaction was quenched with H2O (1 mL) and allowed to warm to rt. The solution was neutralized with sat NH4Cl solution (5 mL), extracted with EtOAc (3×100 mL), washed with brine (1×100 mL), dried over Na2SO4 and concentrated in vacuo to give a mix of the desired alcohol and starting material. The mixture was taken up in EtOAc and concentrated on Celite™ to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 3:1) to give 796 mg (74%) of the desired product as a vicious clear colorless oil. Data for 1-t-butoxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methyl-7-methoxy-quinoline: Rf =0.20 (hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 7.42 (d, J=8.7, 1H), 7.33 (d, J=2.5, 1H), 6.66 (dd, J=2.5, 8.6, 1H), 3.98 (m, 1H), 3.79 (s, 3H, OCH3), 3.61 (m, 1H), 1.98 (m, 2H), 1.58 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[C:17]([NH:26][C:27]4[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=4[CH3:35])[CH:18]=[C:19](Br)[CH:20]=3)[C:15](=[O:36])[C:14]=2[CH:13]=[C:12](Br)[CH:11]=1.[C:39]1([S-:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Na+].CO>CN(C=O)C>[C:1]1([CH3:38])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[C:17]([NH:26][C:27]4[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=4[CH3:35])[CH:18]=[C:19]([S:45][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:20]=3)[C:15](=[O:36])[C:14]=2[CH:13]=[C:12]([S:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:11]=1
Reactant: [S-]c1ccccc1
Reactant: Cc1cc(C)c(Nc2cc(Br)cc3c2C(=O)c2cc(Br)cc(Nc4c(C)cc(C)cc4C)c2C3=O)c(C)c1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C)c(Nc2cc(Sc3ccccc3)cc3c2C(=O)c2cc(Sc4ccccc4)cc(Nc4c(C)cc(C)cc4C)c2C3=O)c(C)c1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
16.5 g of 1,5-bis(mesitylamino)-3,7-dibromoanthraquinone are suspended at RT in 50 ml of DMF and heated to 120° C. After cooling to 50° C., a suspension of 8.5 g of sodium thiophenolate in 25 ml of DMF is added thereto. The mixture is then heated to 120° C. again and stirred at that temperature for 1.5 hours. After cooling the mixture to 60° C., 100 ml of methanol are added and the mixture is stirred overnight at RT. The precipitate is filtered off, washed with a methanol/water mixture (1:1) and dried in vacuo.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[OH:24])=[CH:12][CH:11]=[CH:10][N:9]=1.CI.[C:30](OCC)(=O)C>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[O:24][CH3:30])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1cccc(Br)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cnccc1CCCOc1cccnc1Oc1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.26 g, 6.5 mmol) is suspended in DMF (30 ml), and thereto is added 2-(3-bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (2.0 g, 5.0 mmol) obtained in Example 32 at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added methyl iodide (0.78 g, 0.34 mmol) under ice-cooling, and the mixture is further stirred for 30 minutes. To the reaction solution is added ethyl acetate (250 ml), and the organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent: chloroform/ethyl acetate), and recrystallized from diethyl ether to give the title compound (0.75 g) as colorless crystals, m.p. 134-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]([N:8]([CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[CH2:27]([NH:34][CH:35]=[CH:36][C:37](=[O:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:37]([C:36]1[CH:18]([CH2:17][CH2:16][CH2:15][N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:19]=[CH:20][N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=1)(=[O:39])[CH3:38]
Reactant: COc1ccc(C(=O)N(CCC/C=C/C=O)c2ccccc2)cc1OC
Reactant: CC(=O)C=CNCc1ccccc1
Product: COc1ccc(C(=O)N(CCCC2C=CN(Cc3ccccc3)C=C2C(C)=O)c2ccccc2)cc1OC

Procedure:
The title compound 36 is prepared according to the procedure reported in step D of Example 8 with aldehyde 38 (706 mg, 2 mmol) and enamine 30 (350 mg, 2 mmol) as reactants. (Yield 360 mg, 35%).
Reaction SMILES: NC1C=C(C2SC3C=CC=CC=3N=2)C([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=CC=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1)=[N+]=[N-]>>[NH2:25][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][C:29]=1[O:11][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8]
Reactant: Nc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2nc3ccccc3s2)c1
Reactant: Cc1ccc2nc(-c3ccc(N=[N+]=[N-])cc3)sc2c1
Product: Cc1ccc2nc(-c3ccc(N)c(OS(=O)(=O)C(F)(F)F)c3)sc2c1

Procedure:
This compound was prepared in a similar way to the compound of Example XIV from 2-(4-azidophenyl)-6-methyl-benzothiazole. (Found: M+ 388. C15H11F3N2O3S2 requires MW 386).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:30]3[C:31]4[C:27](=[CH:26][C:25]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:24][C:23]=4[F:22])[CH:28]=[CH:29]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)c1cc(F)c2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)cc(F)c43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and 7-Fluoro-5-(methylsulfonyl)-1H-indole (intermediate-22) (0.060 g, 23%).
Reaction SMILES: CO[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:7]2[CH2:6]1.[NH2:17][CH2:18]CC#N>>[N+:14]([C:12]1[CH:13]=[C:7]2[CH2:6][N:5]([CH2:4][CH2:3][C:18]#[N:17])[CH2:10][CH2:9][N:8]2[N:11]=1)([O-:16])=[O:15]
Reactant: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Reactant: N#CCCN
Product: N#CCCN1CCn2nc([N+](=O)[O-])cc2C1
Yield: 81.4 %

Procedure:
Following the procedure of Example 296d, and starting with 1-(2-bromoethyl)-5-(chloromethyl)-3-nitro-1H-pyrazole 296d (268 mg, 1.00 mmol) and 3-aminopropanenitrile (210 mg, 3.00 mmol) afforded 338a as a white solid (180 mg, 81%). MS-ESI: [M+H]+ 222.1
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: Cc1cccc(OCCCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: Cc1cccc(OCCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3O)cc2)c1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.742 g of 1-(3-bromopropoxy)-3-methylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.46.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21].[H-].[Na+].[CH2:24](I)[CH3:25]>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH2:24][CH3:25])[C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21]
Reactant: CCI
Reactant: Cc1c(N2CCNC(=O)C2)nc2cc(F)cc(F)c2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc3cc(F)cc(F)c3c(Br)c2C)CC1=O
Reaction time: 8 h

Procedure:
The 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one (70 mg, 0.20 mmol) was dissolved in THF (2.0 mL). To the solution was added sodium hydride (24.0 mg, 1.00 mmol) (60% dispersion) followed by addition of ethyl iodide (0.16 mL, 2.00 mmol). The reaction was stirred overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 100% EtOAc:hexanes) to give 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)-1-ethylpiperazin-2-one. Mass Spectrum (ESI) m/e=384.1 (M+1).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N+:22]([O-])=O)[CH3:2].P(OCC)(OCC)OCC>>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:11]=[C:12]2[C:13]([CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17]2)=[N:22]1)[CH3:2]
Reactant: CCSc1ccccc1N=Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Product: CCSc1ccccc1-n1cc2ccc(C(F)(F)F)cc2n1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
A mixture of 777 mg of (2-ethylsulfanylphenyl) (2-nitro-4-trifluoromethylbenzylidene)amine and 3 ml of triethyl phosphite was stirred at 100° C. for 15 minutes and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 558 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-2H-indazole (hereinafter, referred to as Compound of Present Invention 1).
Reaction SMILES: [H-].[K+].CCCCCC.[C:9](#[N:13])[CH2:10][C:11]#[N:12].[CH2:14]([C:21]1[C:22](=[O:32])[C:23]2[C:28]([C:29](=[O:31])[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.CCCCCC.C(OCC)(=O)C>[NH2:12][C:11]1[O:31][C:29]2[C:28]3[C:23]([C:22]([OH:32])=[C:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:30]=2[C:10]=1[C:9]#[N:13])=[CH:24][CH:25]=[CH:26][CH:27]=3
Reactant: N#CCC#N
Reactant: O=C1C=C(Cc2ccccc2)C(=O)c2ccccc21
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(N)oc2c1c(Cc1ccccc1)c(O)c1ccccc12
Temperature: 25 °C
Yield: 36.5 %

Procedure:
A mixture of potassium hydride (7.56 g, 63 mmol, 35% oil dispersion) and hexane (250ml) was stirred at room temperature under nitrogen. Solvent was decanted off and substituted with dry tetrahydrofuran (250ml). Malononitrile (4.16 g, 63 mmol), dissolved in tetrahydrofuran (50 ml), was then added to the slurry dropwise. A mixture of 2-benzyl-1,4-naphthoquinone (15.62 g, 63 mmol) and tetrahydrofuran (50 ml) was then added dropwise. The reaction mixture was set at reflux for 2h, allowed to cool to room temperature and quenched with methanol (50 ml). The mixture was poured into water (100 ml) and extracted into ethyl acetate (3 x 250 ml). The organic layer was dried (magnesium sulfate) and evaporated to an oil. Chromatography (silica gel: hexane/ethyl acetate (2 : 1) as eluant) of the oily residue afforded 7.48 g (23 mmol, 38%) of product as green crystals, m.p. 224°-225 ° C.; 1H NMR (d6DMSO): 4.5(s,2H), 7.1-7.6 (m, 7H), 7.9(d, 1H), 9.25(s, 1H); IR (nujol): 3460, 3310, 3240, 3190, 2220; High resolution mass spectrum: calculated 314.1055, measured 314.1061.