Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40](O)=[O:41].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:40](=[O:41])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccn1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 98 mg (0.561 mmol) of 2-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 209 μl (1.50 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.60, FD-MS: M+ =546.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:10]1([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: Nc1ccc(Br)cc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(C2CC2)cc1F
Temperature: 100 °C
Yield: 45 %

Procedure:
(According to the procedure of D. Wallace and C. Chen, Tetrahedron Lett., 43, 6987 (2002)) 4-Bromo-2-fluoroaniline (19.0 g, 100 mmol) was reacted with cyclopropyl boronic acid (11.3 g, 131 mmol), palladium(II) acetate (1.12 g, 4.79 mmol), tricyclohexyl phosphine (2.80 g, 13.2 mmol), and potassium phosphate (74.2 g, 265 mmol) in toluene (400 mL) and water (30 mL). The mixture was heated in an oil bath at 100° C. for 2 days, cooled, and the liquid was filtered through a pad of celite. The residual solid in the reaction vessel was triturated with water (200 mL), and the suspension was filtered through celite. The aqueous filtrate was extracted once with hexanes (100 mL), the combined organic layers were dried over anhydrous magnesium sulfate. The dried organic layers were filtered through a silica gel pad, and the pad was washed with 80% v/v dichloromethane in hexanes (250 mL). The filtrates were concentrated in vacuo to give a red oil that was fractionally distilled (Vigreux column, 6 plates). The fraction distilling between 65-73° C. at 6-7 mbar was collected to give 6.8 g (45 mmol, 45%) of 4-cyclopropyl-2-fluoroaniline as a pale yellow liquid.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26]5[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]5)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=O)=O.[C-:33]#[N:34].[Na+]>CS(C)=O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:32]=[C:28]1[NH:29][CH2:30][CH2:31][N:26]([CH:23]2[CH2:24][CH2:25][CH:20]([O:19][C:10]3[C:9]4[C:8]5[C@@H:7]([CH2:6][C:33]#[N:34])[CH2:18][CH2:17][C:16]=5[S:15][C:14]=4[N:13]=[CH:12][N:11]=3)[CH2:21][CH2:22]2)[CH2:27]1
Reactant: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Reactant: [C-]#N
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of [(3S)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate (450 mg, 0.94 mmol, 1.00 equiv) in DMSO (10 mL) was added NaCN (276 mg, 5.63 mmol, 6.00 equiv) and DMAP (11 mg, 0.094 mmol, 0.10 equiv) at room temperature. The resulting solution was stirred for 2 h at 80° C. After cooling to r.t, the resulting solution was diluted with DCM (100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with DCM/MeOH (10:1) to afford 330 mg (86%) of 2-[(3R)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetonitrile as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].Br[CH2:22][C:23]#[C:24][CH3:25]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([S:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCCCCC(Sc1ccc(O)cc1)C(=O)OCC
Reactant: CC#CCBr
Product: CC#CCOc1ccc(SC(CCCCCC)C(=O)OCC)cc1

Procedure:
2-(4-But-2-ynyloxy-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 2). Starting from 2-(4-hydroxy-phenylsulfanyl)-octanoic acid ethyl ester 13.6 g, 46 mmol) and 1-bromo-2-butyne(6.23 g, 47mmol). Yield 13.78 g (86%); amber oil; MS: 349.0 (M+H)+
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]([CH3:16])([CH3:15])[CH2:9]OS(C)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[C-:19]#[N:20].[K+].O>CS(C)=O>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]([CH3:16])([CH3:15])[CH2:9][C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(CC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 120 °C
Yield: 57.6 %

Procedure:
To the solution of methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl ester (5 g, 16.8 mmol) in anhydrous dimethyl sulfoxide (50 mL) was added KCN (2.85 g, 44 mmol). The reaction mixture was heated at 120° C. for 16 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4) to give 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyronitrile as a yellow oil (2.2 g, 57%).
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH3:10])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O>[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(C)(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 99.3 %

Procedure:
Methanol (4 ml) and 2 ml of water were added to 663 mg of methyl α-methylthio-α-(m-phenoxyphenyl)propionate, and then 300 mg of sodium hydroxide was added. The mixture was heated under reflux for 2 hours, diluted with 30 ml of water, and extracted with 10 ml of diethyl ether. The aqueous layer was acidified with about 1 ml of conc. hydrochloric acid, and extracted three times with 20 ml of diethyl ether. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 628 mg of α-methylthio-α-(m-phenoxyphenyl)propionic acid as an oil in a yield of 99%. This product crystallized on standing at room temperature. Recrystallization from hexane and carbon tetrachloride affored colorless crystals having a melting point of 87° to 88° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([S:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[Br:17]Br>C(Cl)Cl>[Br:17][C:5]1[C:4](=[O:16])[N:3]([CH2:1][CH3:2])[C:8]2[N:9]=[C:10]([S:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=1
Reactant: BrBr
Reactant: CCn1c(=O)ccc2c(C)nc(SC)nc21
Solvent: ClCCl
Product: CCn1c(=O)c(Br)cc2c(C)nc(SC)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.31 g, 26.84 mmol) in DCM was added Br2 (4.79 g, 29.52 mmol) dropwise at room temperature. Then the reaction mixture was stirred at room temperature overnight. After filtration the solid was suspended in DCM (100 mL), and triethylamine (20 mL) was added. The mixture was washed with water and dried with Na2SO4, and the product 6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.96 g, 83% yield) was obtained after evaporation of DCM. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 4.56 (q, J=7.2 Hz, 2H), 2.68 (s, 3H), 2.62 (s, 3H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](C2C(=O)CC(C(F)(F)F)CC=2O)[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[F:36][C:37]([F:53])([F:52])[C:38]1[CH:43]=[CH:42][C:41]([CH:44]2[CH2:49][C:48](=[O:50])[CH2:47][C:46](=[O:51])[CH2:45]2)=[CH:40][CH:39]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:47]2[C:46](=[O:51])[CH2:45][CH:44]([C:41]3[CH:40]=[CH:39][C:38]([C:37]([F:52])([F:53])[F:36])=[CH:43][CH:42]=3)[CH2:49][C:48]=2[OH:50])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(C(F)(F)F)CC2=O)cc1
Reactant: O=C1CC(=O)CC(c2ccc(C(F)(F)F)cc2)C1
Product: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(c3ccc(C(F)(F)F)cc3)CC2=O)cc1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 12), using 5-(4-(trifluoromethyl)phenyl)cyclohexane-1,3-dione (500 mg, 1.95 mmol) as starting material. Yield: 930 mg; ESI mass spectrum [M+H]+=574, Retention time HPLC: 0.85 min (V011_S01).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.C[O:33][C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:33][C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: COc1cc(C)ccc1B(O)O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1O
Yield: 65 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.10 g; 0.314 mmol), tetrakis(triphenylphosphine) palladium(0) (0.036 mg; 0.031 mmol), N,N-diisopropylethylamine (0.216 mL; 1.25 mmol) and 2-methoxy-4-methylphenylboronic acid (0.078 g; 0.47 mmol in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.082 g (65%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([N:8]=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[NH2:25].[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[Na+]>C(O)(=O)C.O>[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[NH2:24][C:21]1/[C:22](=[N:8]/[C:5]2[C:4](=[O:10])[N:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])/[CH:23]=[C:18]([CH3:17])[C:19](=[NH2+:25])[CH:20]=1
Reactant: Cc1ccc(N)cc1N
Reactant: Cc1c(N=O)c(=O)n(-c2ccccc2)n1C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC1=C/C(=N\c2c(C)n(C)n(-c3ccccc3)c2=O)C(N)=CC1=[NH2+]
Reaction time: 0.5 h

Procedure:
50 mmol of 1,5-dimethyl-4-nitroso-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in a solution of 850 ml of acetic acid and 1250 ml of water. This solution was admixed with 50 mmol of 4-methylbenzene-1,3-diamine and stirring was continued for 2 h 30 min. Sodium perchlorate was added to saturation, and the mixture was left to stand for 30 minutes at zero degrees.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cl[Mg]Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1

Procedure:
To a solution of p-chlorobenzylmagnesium chloride in ethyl ether (prepared from 16 parts of p-chlorobenzyl chloride and 3 parts of magnesium turnings in 100 parts of ethyl ether) is added dropwise a solution of 19 parts of N-benzyl-4-piperidone in 50 parts of ethyl ether, the reaction vessel being cooled in an ice bath during the addition. When the addition is complete, mixture is refluxed for 2 hours, cooled, and the Grignard decomposed with saturated ammonium chloride solution. Evaporation of the ethyl ether gives N-benzyl-4-p-chlorobenzyl-4-hydroxypiperidine. ##STR13##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH:6][NH2:7].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([CH3:1])[CH:3]=2)[C:15](=[O:14])[CH:16]=1
Reactant: Cc1cc(CNN)ccc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cc(Cn2[nH]c(N)cc2=O)ccc1Cl
Reaction time: 8 h

Procedure:
20.5 g of 3-methyl-4-chlorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 19.1 g of β-amino-βethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 200 ml of ethanol. The reaction solution was sitirred overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 131°, 10 g (35%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[Cu](C#N)[C:13]#[N:14].CCOCC>CN(C=O)C>[C:2]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:11])[C:13]#[N:14])(=[O:3])[CH3:1]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)c1cc(C#N)ccc1O
Temperature: 160 °C
Yield: 70.1 %

Procedure:
A solution of 5-bromo-2-hydroxyacetophenone (11, 10.00 g, 46.5 mmoles) in anhydrous DMF (25 mL) was mixed with copper cyanide (6.25 g, 69.75 mmoles) and the resulting reaction mixture was heated for about 8 to 16 hours at a temperature of about 160° C. The reaction mixture was cooled to room temperature and mixed with ether, the ether mixture was filtered through celite and the filtrate concentrated to afford a solid which was purified by flash column chromatography through silica using Hexane/EtOAc (4:1) as eluant to yield compound 12 as a clear colorless oil (5.25 g, 70%).
Reaction SMILES: [CH:1]1([C:6]([OH:23])([C:17]#[C:18][Si](C)(C)C)[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F-]>CO>[CH:1]1([C:6]([OH:23])([C:17]#[CH:18])[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#C[Si](C)(C)C)C2CCCC2)O1
Agent: [F-]
Solvent: CO
Product: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Yield: 54.5 %

Procedure:
A solution of crude 6-[2-cyclopentyl-2-hydroxy-4-(trimethylsilyl)but-3-yn-1-yl]-2,2-dimethyl-4H-1,3-dioxin-4-one (25 mmol), ceasium fluoride (7.6 g, 50 mmol) dissolved in MeOH (75 mL) was stirred over night. The solvent was removed and the residue was diluted with EtOAc, washed with 0.5 N citric acid, 1 N NaHCO3, brine, dried over MgSO4 and concentrated. Purification by flash column chromatography (20% to 30% EtOAc in hexanes) gave the product (3.6 g, 54%). 1H NMR (300 MHz, CDCl3) □: 1.45–1.80 (m, 8 H), 1.72 (s, 3 H), 1.74 (s, 3 H), 2.13–2.18 (m, 1 H), 2.49 (s, 1 H), 2.56 (s, 1 H), 2.58 (s, 2 H), 5.43 (s, 1 H).
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH:3]=[CH:2]1.[Cl:14]N1C(=O)CCC1=O.BrC1C2C=CSC=2NC=1C(OCC)=O>>[Cl:14][C:8]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[NH:6][C:7]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Agent: CCOC(=O)c1[nH]c2sccc2c1Br
Product: CCOC(=O)c1[nH]c2sccc2c1Cl
Yield: 18.8 %

Procedure:
The title compound was synthesized from ethyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (0.20 g, 1.02 mmol) and N-chlorosuccinimide (NCS) (0.17 g, 1.2 mmol) using the halogenation conditions to synthesize ethyl 4-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate. Separation of the desired product by RP-HPLC (10-100% gradient 0.1% formic acid in H2O to CH3CN over 10 min) afforded ethyl 4-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.044 g, 19% yield). 1H NMR (400 MHz, CD3OD) δ (ppm): 9.96 (br s, 1H), 6.98 (d, J=5.4 Hz, 1H), 6.92 (d, J=5.4 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ (ppm): 161.1, 136.8, 131.3, 124.4, 123.5, 121.5, 116.5, 61.3, 14.6. LCMS m/e 230 (M+H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][S:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][NH:18][O:19][CH3:20].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>O1CCCC1.C(Cl)CCl>[CH3:20][O:19][N:18]([CH3:17])[C:13](=[O:15])[C@H:9]([CH2:10][S:11][CH3:12])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CNOC
Reactant: CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: CON(C)C(=O)[C@H](CSC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of Boc-S-methylcysteine (5 g), N,O-dimethylhydroxylamine hydrochloride (2.28 g) and N-hydroxybenzotriazole monohydrate (3.16 g) in tetrahydrofuran (60 ml) was treated with N-methylmorpholine at 0° C. under nitrogen. EDC (4.89 g) was added and the reaction was warmed to RT and stirred for 48 hours. The reaction mixture was concentrated in vacuo, to give a colourless residue which was partitioned between ethyl acetate (100 ml) and 10% citric acid (100 ml). The organic phase was washed with saturated sodium bicarbonate (70 ml) and brine (70 ml), dried (MgSO4), and evaporated to dryness in vacuo to give the title compound as a pale waxy solid (1.16 g, 29%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][O:6][C@@H:5](/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C@@H:4]1[OH:19].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([O:19][C@@H:4]1[C@@H:3]([O:2][CH3:1])[C@@H:8]([CH3:9])[CH2:7][O:6][C@H:5]1/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCCCCC/C=C\[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCC/C=C\[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1OC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A mixture of (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(Z)-1-nonenyl]tetrahydro-2H-pyran-3-ol (9.0 mg), N-(tert-butoxycarbonyl)glycine (17.5 mg), 4-dimethylamino pyridine (12.0 mg), and dicyclohexylcarbodiimide (21.0 mg) in dry dichloro- methane (0.5 ml) was stirred for 3 hours at room temperature. To the reaction mixture water was added, and the mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography gave (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(Z)-1-nonenyl]tetrahydro-2H-pyran -3-yl N-(tert-butoxycarbonyl)glycinate (12.8 mg, y. 91%), EI-MS: m/z 427 (M+)
Reaction SMILES: C[Si](C)(C)C#C[CH:5]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:17][OH:18])[CH:11]=2)[S:6]1.[CH2:21]1COC[CH2:22]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:21]([CH:17]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[S:6][CH2:5][CH2:14][C:13]2([CH3:15])[CH3:16])[OH:18])#[CH:22]
Reactant: C1CCOC1
Reactant: CC1(C)CC(C#C[Si](C)(C)C)Sc2ccc(CO)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C#CC(O)c1ccc2c(c1)C(C)(C)CCS2
Reaction time: 1 h

Procedure:
5.9 g (19.4 mmol) of α-trimethylsilylethynyl-4,4-dimethyl-6-thiochromanmethanol and 50 ml of THF were introduced into a round-bottomed flask and 21.3 ml (23.3 mmol) of a tetrabutylammonium fluoride solution (1.1M in THF) were added dropwise. Stirring was carried out at room temperature for 1 hour and the reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and hexane (1/4). After evaporating the solvents, 3.9 g (87%) of α-ethynyl-4,4-dimethyl-6-thiochromanmethanol were recovered in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)=[N:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.Br[CH2:34][CH2:35][O:36][CH2:37][CH2:38]Br.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)=[N:4][N:5]([C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=1
Reactant: Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2Br)cc1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(N2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of 2.4 g 4-(4-bromo-1-trityl-1H-pyrazol-3-yl)phenylamine (compound in Production Example 152), 0.7 mL 2-bromoethyl ether, 80 mg sodium iodide, 1.52 g potassium carbonate and 50 mL N,N-dimethylformamide was stirred at 80° C. for 3 days. Ethyl acetate and water were added to the reaction solution, then water was added thereto, and the organic layer was separated, washed with an aqueous saturated solution of sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1.21 g of the title compound as a pale yellow amorphous.