Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1Br)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[F:20][CH2:21][C:22](OCC)=[O:23].[Cl-].[NH4+]>O1CCCC1.C(OC(=O)C)C>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:22](=[O:23])[CH2:21][F:20])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CF
Reactant: CC(C)(C)NS(=O)(=O)c1sccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1sccc1C(=O)CF
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
2.98 g (0.0mole) of N-t-butyl-3-bromo-2-thiophenesulfonamide was dissolved in 50mi of dry tetrahydrofuran and the mixture was cooled to -78° C. under nitrogen gas. To the reaction solution was slowly added dropwise 8.4 ml of n-butyl lithium (2.5N) and then the temperature of the mixture was raised slowly to -20° C. and again cooled to -78° C. 1.2 g (0.011 mole) of ethyl fluoroacetate was added slowly to the reaction mixture. The temperature of the mixture was raised again slowly to -20° C. and then the mixture was stirred for 10 minutes. To the reaction mixture was added 100 ml of 5% aqueous ammonium chloride solution, and then added 100 ml of ethylacetate to separate the organic layer. The extracted organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjeced to column chromatography on silica gel to obtain 2.0 g (Yield: 72%) of the pure title compound as a liquid.
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]1=O.[C:15]1([CH2:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+]>C(O)C>[C:24]1([C:23]2[C:22](=[O:30])[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]3[C:3]4=[C:12]5[C:7](=[CH:6][CH:5]=[CH:4]4)[CH:8]=[CH:9][CH:10]=[C:11]5[C:1]=23)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(c2ccccc2)=C2C(=C1c1ccccc1)c1cccc3cccc2c13
Yield: 71.3 %

Procedure:
An amount of 5.9 g (32.4 mmol) of acenaphthenequinone and 7.5 g (35.7 mmol) of 1,3-diphenyl-2-propanone were suspended in 150 ml of ethanol and a solution of 2 g of potassium hydroxide in ethanol was added. After the mixture was heated to the reflux temperature, the same amount of the solution of potassium hydroxide in ethanol was further added and allowed to react for five minutes. The solid substance deposited after cooled on ice was filtered and washed with ethanol to obtain 8.24 g (23.1 mmol) of 7,9-diphenylcyclopenta[a]acenaphthylene-8-one. The yield was 71.3%.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:23](=[O:33])[C:24]([NH:26][C:27]1[CH2:28][O:29][C:30](=[O:32])[CH:31]=1)=[O:25])=[CH:9][N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O.CCCCCC.CCOC(C)=O.CN(C=O)C.CCO.[Pd]>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:10]2[C:11]3[C:7](=[C:6]([CH2:5][OH:4])[CH:14]=[CH:13][CH:12]=3)[C:8]([C:23](=[O:33])[C:24]([NH:26][C:27]3[CH2:28][O:29][C:30](=[O:32])[CH:31]=3)=[O:25])=[CH:9]2)=[CH:21][CH:20]=1
Reactant: C=CCOCc1cccc2c1c(C(=O)C(=O)NC1=CC(=O)OC1)cn2Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3cccc(CO)c23)CO1
Yield: 22.9 %

Procedure:
2-[4-[(allyloxy)methyl]-1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-(5-oxo-2,5-dihydro-3-furanyl)acetamide (239 mg) is dissolved in MeOH/H2O=9/1 (10 ml) then 10% Pd/C (12 mg) and p-toluenesulfonic acid (12 mg) are added. The reaction is refluxed for about 6 h, then it is diluted with DMF and EtOH, the catalyst is filtered on celite and the solvent is removed under reduced pressure. The crude is washed with acetone and filtered. The filtrate is concentrated and the obtained solid is purified by silica gel chromatography (eluent: CH2Cl2/EtOH=95/5) affording 50 mg of pure 2-[1-(4-chlorobenzyl)-4-(hydroxymethyl)-1H-indol-3-yl]-2-oxo-N-(5-oxo-2,5-dihydro-3-furanyl)acetamide. The solid is crystallized from CH3CN affording 63 mg of compound with m.p. 238-240° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC.C(OC(C1C=CC2N(C(CC3C=C4C(=CC=3)N(C)N=C4)=CN=2)N=1)=C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:31]([O:30][C:28]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1)=[CH2:29])[CH3:32]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1ccc2c(cnn2C)c1)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(OCC)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Product: C=C(OCC)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 95.6 %

Procedure:
The title compound (415.0 mg, 86%, 90% purity) was synthesized from 6-chloro-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (390.0 mg, 1.25 mmol), tributyl(1-ethoxyvinyl)stannane (497.0 mg, 1.38 mmol) and Pd(PPh3)4 (145 mg, 0.13 mmol) using the same procedure as described in the synthesis of compound 13.3. LCMS (method A): [MH]+=348, tR=5.86 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.[CH:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35]>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CCCCC=O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCC=Nn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg), triethylamine (130 μl), valeraldehyde (81 μl) and methanol (4.2 ml) was stirred at 70° C. for 3.5 hrs. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (200 mg) as colorless crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[OH:25])=[C:20](Cl)[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])(O)=O.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[OH:25])=[C:20]([C:39]3[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Cl)ncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ncc21
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-((4-chlorophenyl) (hydroxy)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (See Compound 49, step 4, 130 mg, 0.248 mmol), 4-chlorophenylboronic acid (77.37 mg, 0.496 mmol), NaHCO3 (62.5 mg, 0.744 mmol) and aq. 2M K3PO4 (0.62 ml, 1.24 mmol) in dioxane (1 mL) and water (0.2 mL) was added Pd(dppf)Cl2 (7 mg, 0.0096 mmol). The reaction was degassed with nitrogen (3×) and heated at 120° C. (MW) for 1.5 h, cooled to RT then diluted with EA (10 mL) and water (2 mL). The reaction was filtered and the filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-chlorophenyl)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 20% yield) as colorless oil, LCMS: MH+ 600 and TR=2.924 min.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[S:15][C:16]([C:22]2[C:27]([F:28])=[CH:26][C:25]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:24][C:23]=2[F:33])=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20]>>[C:11]([C:8]1([C:6]2[N:7]=[C:2]([NH:13][C:14]3[S:15][C:16]([C:22]4[C:23]([F:33])=[CH:24][C:25]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:26][C:27]=4[F:28])=[CH:17][C:18]=3[C:19]([NH2:21])=[O:20])[CH:3]=[CH:4][CH:5]=2)[CH2:10][CH2:9]1)#[N:12]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: N#CC1(c2cccc(Br)n2)CC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C4(C#N)CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 1-(6-bromopyridin-2-yl)cyclopropanecarbonitrile (107 mg, 0.48 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.C(N(CC)CC)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:26]1(=[O:28])=[O:27]>CN(C)C=O>[O:27]=[S:26]1(=[O:28])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[C:35](=[O:36])[N:25]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1
Reactant: NCC1CCc2ccccc2O1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCNCC1CCc2ccccc2O1
Temperature: 60 °C

Procedure:
The mixture of 5.4 g (0.033 mol) (-)-2-aminomethylchroman (example 92f; αD =-122.8), 6.1 g (0.06 mol) triethylamine, 9.5 g (0.03 mol) N-(4-bromobutyl) saccharin and 80 ml anhydrous dimethyl formamide was heated to 60° C. for 4 h. The solvent was evaporated at 0.01 torr. The residue (13.5 g) was dissolved in toluene/ethyl acetate (5:1) and chromatographed on silica (300 g). The fraction (5.8 g) obtained by elution with toluene/ethyl acetate 1:1 was rechromatographed on 150 g of silica, providing 3.7 g of chemically pure 2-(N-[4-(1,1-Dioxido-3-oxo-2,3-di-hydro-benzisothiazol-2-yl)butyl]aminomethyl}chroman.
Reaction SMILES: O.S(O)(O)(=O)=O.[NH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:14]3[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:13]=3[CH2:12][CH2:11][C:10]=2[N:9]=1.[H][H]>[Pd].Cl.O>[NH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:14]3[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:13]=3[CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: Nc1nc2c(c(=O)[nH]1)-c1ccc([N+](=O)[O-])cc1CC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ccc2c(c1)CCc1nc(N)[nH]c(=O)c1-2

Procedure:
A suspension of 3-amino-5,6-dihydro-8-nitrobenzo[f]quinazolin-1(2H)-one sulfate monohydrate (2.0 g, 5.3 mmoles) and 5% palladium on carbon (10 mg) in 1N HCl (20 ml) was reacted with hydrogen using a Parr hydrogenation apparatus. When uptake of hydrogen ceased, the mixture was filtered and the filtrate was evaporated, leaving a white residue which was resuspended in water (20 ml) with stirring, and filtered. The crude product was recrystallized from 2N H2SO4 to give, after drying, 3,8-diamino-5,6-dihydrobenzo[f]quinazolin-1(2H)-one as a white solid. (1.1 g, 61%) 1H NMR (DMSO-d6, 80 MHz) δ: 2.60-2.65(m, 4H, CH2CH2); 4.99-5.69(br s, 2H, NH2); 6.75-6.79(m, 4H, NH2 +Ar); 8.24-8.35(d, J=9 Hz, 1H, Ar). Anal. Calculated for C12H12N4O.H2SO4.1/2H2O: C, 42.98; H, 4.51; N, 16.71; S, 9.56. Found: C, 42.95; H, 4.54; N, 16.66; S, 9.57.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[C:17]2=[N:16][C:15]=1[CH3:33])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].C(O)C.I[CH2:43][CH2:44][CH2:45][CH3:46].[O-]CC.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)C>[CH2:43]([C:5]([NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[C:17]2=[N:16][C:15]=1[CH3:33])=[O:13])([C:4]([O:3][CH2:1][CH3:2])=[O:34])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:44][CH2:45][CH3:46]
Reactant: CCCCI
Reactant: CCOC(=O)C(NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(=O)OCC
Agent: CC[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCC(NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)(C(=O)OCC)C(=O)OCC
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To 252 mg of diethyl[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]malonate were added 4 ml of ethanol, 0.23 ml of a 20% sodium ethoxide/ethanol solution, and 0.31 ml of 1-iodobutane, followed by stirring at 70° C. for 3 hours. Subsequently, 11 mg of sodium ethoxide was added thereto, followed by stirring at 70° C. for 1 hour. To the reaction mixture were added an aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 69 mg of diethyl butyl[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]malonate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[I:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:24]=1
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)pyrimidine (example A.12) (2.34 g, 8.58 mmol) and commercially available 4-iodo-imidazole (2.50 g, 12.9 mmol) according to the general procedure IVa. Obtained as a light brown solid (2.67 g, 72%). MS (ISP) 431.1 [(M+H)+]; mp 167° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2([CH:14]=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C1C=CC(C2(CO)CCCC2)=CC=1>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC1(c2cccc(C(F)(F)F)c2)CCCC1
Agent: OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: OCC1(c2cccc(C(F)(F)F)c2)CCCC1

Procedure:
(1-(3-(Trifluoromethyl)phenyl)cyclopentyl)methanol (470) was synthesized from 1-(3-(trifluoromethyl)phenyl)cyclopentanecarbaldehyde (469) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentane-methanol (239).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][SH:18])[CH3:14]>>[C:1](=[O:12])([S:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:13][CH3:14])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCN(CC)CCS
Product: CCCCCCC/C=C/C(=O)SCCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(diethylamino)ethanethiol as starting materials to give the aimed compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO.C(Cl)Cl>[O:30]1[CH2:29][CH:28]1[CH2:26][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:15])[F:1])[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrCC1CO1
Reactant: COC(=O)Cc1ccccc1C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(CC1CO1)c1ccccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
Methyl (2-trifluoromethylphenyl)acetate (5.0 g) was dissolved in tetrahydrofuran (10 mL), and the solution was added at −78° C. to a solution containing potassium bistrimethylsilylamide (50 mL) in tetrahydrofuran (190 mL). After stirring for 30 minutes, epibromohydrin (1.96 mL) was added at the same temperature. After further 10 minutes, a boron trifluoride-diethyl ether complex (3.16 mL) was added. After stirring at −78° C. for one hour, the reaction was terminated with a saturated sodium bicarbonate aqueous solution. The organic layer diluted with ethyl acetate was washed with a saturated sodium bicarbonate aqueous solution and brine and dried over magnesium sulfate. Concentration under reduced pressure gave a residue which was dissolved in methanol (50 mL) and methylene chloride (50 mL) and treated with potassium carbonate (15.8 g). After one hour, potassium carbonate was precipitated by adding methylene chloride (200 mL) and removed by filtration through celite. The resulting solution was washed with saturated ammonium chloride aqueous solution and brine and dried over magnesium sulfate. Concentration under reduced pressure gave a crude product. The crude product was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 30%) to obtain a diastereomer mixture (2.61 g).
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)C[CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([OH:39])/[CH:21]=[CH:22]/[C@H:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[N:24]2[CH2:30][C:31]#[C:32][CH2:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[CH:16]=[CH:17][CH:18]=1.IC(C)C>CC(C)=O>[CH:1]([O:37][C:36](=[O:38])[CH2:35][O:34][CH2:33][C:32]#[C:31][CH2:30][N:24]1[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C@@H:23]1/[CH:22]=[CH:21]/[CH:20]([OH:39])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)([CH3:11])[CH3:2]
Reactant: O=C(O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)I
Solvent: CC(C)=O
Product: CC(C)OC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reaction time: 0.08 h
Yield: 58.8 %

Procedure:
DBU (6.6 μL, 0.044 mmol) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-but-2-ynyloxy)-acetic acid (12 mg, 0.030 mmol) in acetone (0.3 mL). After 5 min, 2-iodopropane (15 μL, 0.15 mmol) was added. After 19 h, the reaction mixture was concentrated in vacuo, 0.5 M aqueous HCl (5 mL) was added and the mixture was extracted with EtOAc (3×5 mL). The combine organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 7.9 mg (60%) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3]O.S(Cl)([Cl:14])=O>>[CH3:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: C[C@H](CO)Cc1ccccc1
Product: C[C@H](CCl)Cc1ccccc1

Procedure:
In accordance with the general procedure described in Example 8 (a), 22.5 g (0.15 mol) of (S)-2-methyl-3-phenylpropanol are reacted with 20.2 g (0.17 mol) of thionyl chloride, and the crude product is distilled under a high vacuum (18 torr) to give (b) (b.p. 110°-112° C.) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C:8]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:34][C@H:35]3[CH2:40][CH2:39][C@H:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:37][CH2:36]3)[CH:30]=2)[N:25]=1)([CH3:23])[CH2:9][O:10][P:11]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2[C:67]([F:70])([F:69])[F:68])N=1)(C)CO)(C)(C)C>>[C:1]([O:5][C:6](=[O:45])[NH:7][C:8]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:34][C@H:35]3[CH2:36][CH2:37][C@H:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:39][CH2:40]3)[C:30]=2[C:67]([F:70])([F:69])[F:68])[N:25]=1)([CH3:23])[CH2:9][O:10][P:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reactant: CC(C)(C)OC(=O)NC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Product: CC(C)(C)OC(=O)NC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
[1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-2-(di-tert-butoxy-phosphoryloxy)-1-methyl-ethyl]-carbamic acid tert-butyl ester Enantiomer 1 was synthesized as per [1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-2-(di-tert-butoxy-phosphoryloxy)-1-methyl-ethyl]-carbamic acid tert-butyl ester Enantiomer 1 (Example 29) in 68% yield using {1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-2-hydroxy-1-methyl-ethyl}-carbamic acid tert-butyl ester Enantiomer 1 as starting material.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CCN(CC)CC.[Br:12][C:13]([CH3:18])([CH3:17])[C:14](Br)=[O:15]>C1COCC1.O.C(Cl)Cl>[OH:3][CH2:2][CH2:1][O:4][C:14](=[O:15])[C:13]([Br:12])([CH3:18])[CH3:17]
Reactant: CC(C)(Br)C(=O)Br
Reactant: OCCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(Br)C(=O)OCCO
Reaction time: 8 h
Yield: 82 %

Procedure:
Ethylene glycol (279 g, 4500 mmol) and Et3N (3.34 g, 33.0 mmol) were poured in a 2-necked round bottom flask. To this was added dropwise and a solution of 2-bromoisobutryl bromide (6.90 g, 30.0 mmol) in anhydrous THF (50 mL) at room temperature over ca. 1 h. The colourless solution was stirred overnight, then diluted in 500 mL of water and extracted with 3×200 mL of a mixture of Et2O/CH2Cl2 (4:1). The organic layers, reunited, were washed with 2×200 mL of water and dried over MgSO4. Evaporation of the solvent at reduced pressure (rotavapor, without heating) gave a pale yellow liquid. The latter was dissolved in ca. 30 mL of CH2Cl2 then 10 g of SiO2 were added and the solvent evaporated again until a white powder was obtained. This was poured in a column packed with SiO2, (ca 15 cm depth) previously eluted with petroleum ether/Et2O 5:1 and purified by column chromatography (elute with petroleum ether/Et2O 5:1) to eliminate the impurities. The desired product, using this solvent mixture, has an Rf˜0 (stays on the bottom of the TLC plate). When the impurities have been eliminated, the column was eluted with 100% Et2O, to give a colourless liquid. Yield 82%. IR ν(N—H) 3388 cm− (broad); ν(C═O) 1731 cm−1. 1H NMR (CDCl3) δ=1.97 (s, 6H, CH3); 3.89 (t, J=4.6 Hz; 2H, OCH2CH2OH); 4.33 (t, J=4.6 Hz; 2H, OCH2CH2OH). 13C NMR (CDCl3) δ=30.45 (2C, CH3), 55.55 (1C, C(CH3)2Br); 60.66 (1C, OCH2CH2OH); 65.90 (1C, OCH2CH2OH); 171.69 (1C, C═O).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.O=S(Cl)[Cl:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([Cl:15])=[O:12])=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: O=C(Cl)c1c[nH]c2ccccc12

Procedure:
Indole 3-carboxylic acid, (2.0 g) was dissolved in 5 ml of SOCl2. The mixture was heated to reflux for 30 minutes. Removal of excess of SOCl2 under vacuum provided intermediate 9, indole 3-carbonyl chloride, which was carried to the next step without further purification.