Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:23]([C:26]2[N:30](COCC[Si](C)(C)C)[C:29]3[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:28]=3[N:27]=2)([OH:25])[CH3:24])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2].C(C1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)(O)C)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2)C.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[CH2:1]([C:3]1[C:4]([C:23]([C:26]2[NH:30][C:29]3[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:28]=3[N:27]=2)([OH:25])[CH3:24])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of a mixture of (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.5 g, 2.38 mmol) and ethylenediamine (1.61 mL, 23.85 mmol) was added TBAF in THF (1M, 23.85 mL, 23.85 mmol), and then the mixture was stirred at 60° C. for 3 h. The reaction was quenched by H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The organic phase was successively washed with H2O and brine, dried over Na2SO4, and filtered. After concentration of the filtrate the resulting residue was purified by silica gel flash chromatography (heptanes/EtOAc=66/34, isocratic) to give the title compound. MS (ESI+) m/z 499.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14](O)=[O:15].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:32][NH2:33]>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]([NH:32][NH2:33])=[O:15]
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)O)c1Cl
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)NN)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
To a solution of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.050 g, 0.175 mmol) in anhydrous THF (2 mL), under N2, was added CDI (0.030 g, 0.184 mmol). The mixture was stirred at rt for 4 h and additional CDI (0.030 g, 0.184 mmol) was added. After 45 min, additional CDI (0.079 g, 0.49 mmol) was added. After 5 min, hydrazine (0.112 g, 3.5 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was partitioned between EtOAc and 0.2N NaOH. The organic phase was washed with 0.2N NaOH and sat'd brine. The combined aqueous phases were extracted with EtOAc (×2). The second EtOAc phases were washed with sat'd NaHCO3 solution and brine. The organic phases were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-10% MeOH—CH2Cl2 gradient) to afford the title compound (0.027 g, 52% yield): MS (ES) m/z 299 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[S:17][CH:18]=[C:19]([C:21]([NH:23][C:24]2[C:25]([N:33]3[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39]C(=O)OC(C)(C)C)[CH2:34]3)=[C:26]3[S:32][CH:31]=[CH:30][C:27]3=[N:28][CH:29]=2)=[O:22])[N:20]=1>C(Cl)Cl>[NH2:39][C@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([C:25]2[C:24]([NH:23][C:21]([C:19]3[N:20]=[C:16]([C:10]4[C:9]([F:8])=[CH:14][CH:13]=[CH:12][C:11]=4[F:15])[S:17][CH:18]=3)=[O:22])=[CH:29][N:28]=[C:27]3[CH:30]=[CH:31][S:32][C:26]=23)[CH2:34]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3ccsc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3ccsc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
TFA (2.0 mL) was added to a solution of tert-butyl {(3S)-1-[6-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[3,2-b]pyridin-7-yl]piperidin-3-yl}carbamate (92.2 mg, 0.161 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (43.9 mg, 58%). LCMS calc. for C22H20F2N5OS2 (M+H)+: m/z=472.1. found 472.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cccc(Br)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
A mixture of 3-bromophenol (1.00 g, 5.78 mmol), and imidazole (984 mg, 14.45 mmol) in 6 mL of DMF was cooled to 0° C. and triisopropylsilyl chloride (922 μL, 6.94 mmol) was added and the solution was stirred for 24 hours. The reaction mixture was quenched with 10 mL H2O and 5 mL saturated aqueous NaHCO3. The aqueous layer was extracted with ether (3×10 mL), the pooled organic extracts were washed with brine, dried (MgSO4), and concentrated. The resulting oil was flash chromatographed on silica gel with hexanes to yield 209 (1.50 g, 79%). 1H NMR (CDCl3) δ 1.09 (d, J=7.2 Hz, 18H), 1.17-1.30 (m, 3H), 6.75-6.81 (m, 1H), 7.00-7.10 (m, 3H); 13C NMR (CDCl3) 156.89, 130.26, 124.14, 123.29, 122.5, 118.47.
Reaction SMILES: [CH:1]1([CH:7]=[N:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClN1C(=O)CCC1=O.[NH4+].[Cl-].[CH3:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:20][C:21]1[N:25]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][OH:9])[N:24]=[N:23][N:22]=1
Reactant: Cc1nnn[nH]1
Reactant: ON=CC1CCCCC1
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nnnn1C(=NO)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a solution of cyclohexane carboxaldehyde oxime (35.6 g, 280 mmol) in DMF (300 ml) is added N-chlorosuccinimide (39.2 g, 294 mmol) portionwise, while maintaining the reaction temperature below 45° C. On complete addition, the mixture is stirred overnight at room temperature before adding a saturated aqueous NH4Cl solution (900 ml). The mixture is extracted with ethyl acetate. The organic layer is washed successively with water (500 ml) and brine (500 ml), dried (MgSO4), filtered and concentrated. The residue and 5-methyltetrazole (24.7 g, 294 mmol) are diluted in dichloromethane (400 ml) and triethyamine (50.8 ml, 364 mmol) is added dropwise at room temperature. After stirring overnight, the mixture in concentrated and the residue is taken up in ethyl acetate. The solution is washed successively with a saturated aqueous NH4Cl solution, water and brine, then dried (MgSO4), filtered and concentrated. Silica-gel chromatography of the residue affords 16.6 g of 5-methyl-1-(cyclohexylcarbohydroximoyl)-tetrazole [yield 28.3%; 1H-NMR (CDCl3) δppm: 1.1-1.5 (m, 4H), 1.62-1.98 (m, 6H), 2.55 (s, 3H), 2.8 (m, 1H), 9.3 (broad, 1H); HPLC/MS: m/z=210 (M+H)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[O:8]C.[NH:14]1[CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C.C(Cl)CCl>CN(C=O)C>[N:14]1([C:11](=[O:13])[CH2:10][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: C1CNC1
Reactant: COc1ccc(CC(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(O)c(F)c1)N1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3-fluoro-4-methoxyphenyl)acetic acid (0.94 g, 5.52 mmol) in 8 ml anhydrous DMF at RT was added azetidine (0.379 g, 6.63 mmol) and N,N-diisopropylethylamine (2.89 ml, 16.6 mmol), and EDC (1.59 g, 8.29 mmol) was added into the solution and stirred at RT for 4 hrs. The residue was purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 10-100% acetonitrile in 0.1% formic acid in water gradient), to give the title compound. LC/MS (m/z) 210.2 (M+15)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([Cl:18])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[Cl:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-benzyloxy-3-chloro-benzoic acid methyl ester (CAB02121, 4.15 g, 15.0 mmol) in THF (30 mL) was added slowly with a syringe to a suspension of lithium aluminium hydride (1.0 g, 26.3 mmol) in THF (30 mL). The reaction mixture was stirred for 30 minutes at room temperature and then carefully quenched by addition of 2N sodium hydroxide solution in water. After 20 minutes stirring the colour of the mixture turned from grey to white. The white precipitate was filtered off, the filtrate was dried over sodium sulphate and concentrated under reduced pressure to give an colourless oil, which was used without further purification. Yield: 3.61 g (97%). 1H-NMR (400 MHz, CDCl3) δ=2.12 (s, 1H, —OH), 4.56 (s, 2H), 5.16 (s, 2H), 6.93 (d, J=8.6 Hz, 1H), 7.14 (dd, J=8.6, 2.3 Hz, 1H), 7.31-7.48 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15](OCC)(=O)[CH2:16][CH2:17][CH2:18][C:19](OCC)=[O:20]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:9]3[CH2:10][CH2:11][N:12]4[C:15]([C:8]=3[NH:7][C:6]2=[CH:5][CH:4]=1)=[CH:16][CH2:17][CH2:18][C:19]4=[O:20]
Reactant: CCOC(=O)CCCC(=O)OCC
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c3c(c2c1)CCN1C(=O)CCC=C31

Procedure:
A mixture of 5-methoxytryptamine (420 mg) and diethyl glutarate (460 mg) is heated at 175° C. for 18 h. eparation on a column (eluent: EtOAc) gives the amide ster 2. This product is treated with a trace of ara-toluenesulphonic acid in xylene and the water formed is removed using Dean-Stark apparatus. After refluxing for 9 h and separation on a silica plate, N-[2-(5-methoxy)indol-3-ylethyl)]glutarimide is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: C#CCCc1ccc2ccccc2n1
Reactant: Brc1ccccn1
Product: C(#Cc1ccccn1)CCc1ccc2ccccc2n1
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (87 mg, 0.55 mmol) and 2-but-3-ynyl-quinoline (100 mg, 0.55 mmol). Reaction time: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 74 mg (0.29 mmol, 52%) of 2-(4-(pyridin-2-yl)but-3-ynyl)quinoline as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[CH:23]/[C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:18][CH2:17]1)=[O:15].C(=O)([O-])O.[Na+]>C(#N)C>[CH3:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1/[CH:23]=[CH:22]/[CH:19]1[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:17][CH2:18]1
Reactant: Cc1cccc(C)c1/C=C/C1CCN(C(=O)CCl)CC1
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(C)c1/C=C/C1CCN(C(=O)Cn2ccnc2)CC1
Yield: 94.4 %

Procedure:
84 mg of 1H-imidazole and 142 mg of potassium carbonate were added to a solution of 300 mg of 1-(chloroacetyl)-4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidine in 5 ml of acetonitrile, followed by heating under reflux for 3 hours. After cooling, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform-methanol-ammonia water) to give 314 mg of 4-[(E)-2-(2,6-dimethylphenyl)vinyl]-1-(1H-imidazol-1-ylacetyl)piperidine as yellow crystals. A portion of 288 mg from the crystals was dissolved in 2 ml of ethanol and 334 μl of 4N hydrochloric acid-ethyl acetate was added to the solution, followed by concentrating under reduced pressure. The residue was crystallized from ethanol-diethyl ether and the crystals were collected by filtration. The crystals were then washed with diethyl ether. The crystals were recrystallized from ethanol-diethyl ether to give 188 mg of 4-[(E)-2-(2,6-dimethylphenyl)vinyl]-1-(1H-imidazol-1-ylacetyl)piperidine monohydrochloride.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[C:10](O)(=[O:13])[CH2:11][OH:12].C(N(CC)CC)C>O1CCCC1>[C:1]([S:4][CH2:5][CH2:6][C:7]([O:9][C:11](=[O:12])[CH2:10][OH:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)O
Reactant: O=C(O)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCCC(=O)OC(=O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Acetylthio)propanoic acid (2.96 g) and 1,1'-carboxyldiimidazole (3.24 g) are dissolved in 20 ml of dry tetrahydrofuran with stirring at room temperature. After twenty minutes, a solution of glycolic acid (1.52 g) and 2.80 ml of triethylamine in 15 ml of dry tetrahydrofuran are added. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the crude residue taken up into ethyl acetate, washed with 1N hydrochloric acid and three times with water, dried over magnesium sulfate and the O-(3-acetylthiopropanoyl)glycolic acid is concentrated to dryness in vacuo, yield 3.9 g. This is dissolved in ether and dicyclohexylamine is added. The dicyclohexylamine salt precipitates, yield 2.85 g.; m.p. 150-157° . The salt is converted to the free acid by adding to ethyl acetate and adding 10% potassium bisulfate solution, yield 1.5 g.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH:13]1[CH:18]2[CH:14]1[CH2:15][N:16]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=1)[CH2:17]2.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH:13]1[CH:14]2[CH:18]1[CH2:17][N:16]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[CH2:15]2
Reactant: CCOC(=O)c1ccc(N2CC3C(C2)C3NCc2ccc3ccccc3c2)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CC3C(C2)C3NCc2ccc3ccccc3c2)cc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
Ethyl 4-{6-[(naphthalen-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}-benzoate (500 mg, 1.29 mmol) was stirred in THF (30 ml) with potassium trimethylsilanolate (332 mg, 2.58 mmol) at r.t. under N2 for 6 h. More potassium trimethylsilanolate (332 mg, 2.58 mmol) was added and the reaction stirred at 50° C. for 4 days. The reaction was allowed to cool to r.t. and a precipitate formed. This was isolated by filtration, dried and used in the next step without further purification. LCMS purity 60%, m/z 359 [M+H]+.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=3)[C:6]=2[N:7]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Clc1ncc2scc(Br)c2n1
Product: O=[N+]([O-])c1cccc(-c2csc3cnc(Cl)nc23)c1
Yield: 73 %

Procedure:
2-Chloro-7-(3-nitrophenyl)thieno[3,2-d]pyrimidine (430 mg, 73% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromo-2-chlorothieno[3,2-d]pyrimidine (500 mg, 2.02 mmol) and 3-nitrophenylboronic acid (337 mg, 2.02 mmol).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.C([Li])CCC.CCCCCC.[Cl:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH3:33])=[CH:26][CH:25]=1>O1CCCC1.O>[Cl:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=2)=[C:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][CH3:33])=[CH:26][CH:25]=1
Reactant: Ic1cccc(I)c1
Reactant: CCC(=Cc1ccc(OCCCl)cc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(OCCCl)cc1)c1cccc(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 1,3-diiodobenzene (5.45 g, 16.5 mmol) in dry tetrahydrofuran (25 ml) at -78° C. under nitrogen was treated with a solution of n-butyl lithium in hexane (1.6M; 10.3 ml, 16.5 mmol). After 5 min, a solution of 1-[4-(2-chloroethoxy)-phenyl]-2-phenyl-1-butene (5.0 g, 16.5 mmol) in dry tetra-hydrofuran (15 ml) was added and the mixture allowed to warm to room temperature. After 20 h, the mixture was poured into water (100 ml) and the products extracted with ether (2×50 ml). The extracts were concentrated under vacuum and the residue dissolved in ethanol (80 ml). Concentrated hydrochloric acid (30 ml) was added and the mixture heated under reflux. After 4 h, the mixture was cooled and partitioned between water (100 ml) and ether (2×60 ml). The ether layers were dried with sodium sulphate, concentrated, and the residue chromatographed on silica gel (Merck 15111, 60 g). Elution with 1:20 l dichloromethane-light petroleum (b.p. 60°-80° C.) gave 1-[4-(chloroethoxy) phenyl]-1-(3-iodophenyl)-2-phenyl-1-butene as a ca. 1.5:1 mixture of E (trans) and Z (cis) isomers (determined by n.m.r. spectroscopy) and as an oil (6.46 g, 80% yield). This mixture (3.63 g) was dissolved in a solution of methylamine (30% w/v) in ethanol, and the resulting solution heated in a sealed vessel at 100° C. for 4 h, then cooled and concentrated to dryness. The residue was partitioned between aqueous sodium hydroxide (100 ml) and ether (100 ml). The ether solution was washed with water (50 ml), dried with sodium sulphate and the residual oil dissolved in cyclohexane (10 ml). Eventually 3-iodotamoxifen crystallised (1.51 g, 41%), m.p. 55°-57° C. NMR: δH (CDCl3, 250 MHz) 0.91 (3H, t, J 7.4 Hz, CH3CH2), 2.29 (3H, s, NMe2), 2.43 (2H, q, J 7.4 Hz, CH3CH2), 2.65 (2H, t, J 5.8 Hz, OCH2CH2N), 3.93 (2H, t, J 5.8. Hz, OCH2CH2N), 6.57 (2H, d, J 8.8 Hz, ArH ortho to side chain), 6.74 (2H, d, J 8.8 Hz, ArH meta to side chain), 7.05-7.26 (7H, m, ArH), 7.58- 7.63 (2H, m, ArH ortho to I).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]([F:15])[C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]#[N:23]>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[N:7]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]([F:15])[C:9]=1[F:16])[CH2:21][C:22]#[N:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)cc(F)c1F
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC#N)c1cc(Br)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution (3 mL) of tert-butyl(5-bromo-2,3-difluorophenyl)carbamate (182 mg, 0.591 mmol) in DMF was added to a suspension of 60% sodium hydride-oil dispersion (31.2 mg) in DMF, and stirred at room temperature for 15 minutes. To the reaction solution, bromoacetonitrile (0.041 mL, 0.591 mmol) was added, and stirred at room temperature for 4 hours. After quenched with a saturated aqueous ammonium chloride solution under ice-cooling, extraction was performed with ethyl acetate. The resulting organic phase was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.Cl.Cl[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C(Cl)Cl>O.C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([S:11][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: ClCc1cccnc1
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Clc1cc(Cl)cc(SCc2cccnc2)c1
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
Sodium hydroxide (0.154 g. 3.85 mmol) in 2 mL water was added to 3,5-dichloro-benzenethiol (0.328 g, 1.83 mmol) in 5 mL of ethanol. After 10 min stirring, 3-chloromethyl-pyridine hydrochloride (0.301 g, 1.83 mmol) in 2 mL water was added slowly. The resulting reaction mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction mixture. The organic phase was washed with saturated aqueous sodium bicarbonate solution and brine. After removal of the solvent, the crude product was purified with flash chromatography to give 0.470 g (95% yield) of 3-(3,5-dichloro-phenylsulfanylmethyl)-pyridine. This compound was converted to N-[3-(1H-indol-4-yl)-5-(pyridin-3-ylmethylsulfanyl)-phenyl]-acetamide as described in Example 35. 1H NMR (400 MHz, CD3OD): δ 8.42 (s, 1H), 8.35 (d, J=4.7 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.66 (s, 2H), 7.38-7.31 (m, 2H), 7.27-7.23 (m, 2H), 7.13 (t, J=7.7 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.44 (d, J=3.1 Hz, 1H), 4.20 (s, 2H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([Mg]Cl)([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].[Mg].ClC(C)(C)CCCC.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].Cl>CCOCC>[Cl:19][CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:2]([CH3:7])([CH3:1])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)CCCCl
Reactant: CCCCC(C)(C)[Mg]Cl
Agent: CCCCC(C)(C)Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(C)(C)C(=O)CCCCl
Reaction time: 12 h

Procedure:
Four hundred ml. of a solution in ether of 1,1-dimethylpentylmagnesium chloride prepared from magnesium (24.3 g., 1.0 mole) and 1-chloro-1,1-dimethylpentane (134.5 g., 1.0 mole) according to the procedure of Whitmore and Badertscher [J. Am. Chem. Soc., 55, 1559 (1933)] is added dropwise with stirring to 4-chlorobutyryl chloride (197 g., 1.4 moles) in ether (400 ml.) during 6 hours. The reaction mixture is stirred for an additional 12 hours. It is then poured into a mixture of ice and dilute hydrochloric acid. The ether layer is separated, washed with water, and dried over sodium sulfate. The ether is evaporated and the residue distilled at aspirator vacuum through a Vigreaux column to yield the product as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[OH-].[Na+]>CO>[Cl:19][C:16]1[S:15][C:14]([C:12]([NH:11][C@@H:7]2[C@@H:8]([OH:10])[CH2:9][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[O:13])=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@H]1C[C@@H](C(=O)O)C[C@@H]1O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a stirred suspension of (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (611 mg; example 1B) in MeOH (4 ml) was added 1N NaOH (4 ml). The reaction mixture which slowly turned into a clear solution was stirred at r.t. for 2 hrs, then concentrated. The residue was dissolved in H2O and washed with Et2O. The aqueous phase was acidified with 3N HCl, then extracted with CH2Cl2/MeOH 9:1. The combined organic layers were washed with H2O and brine, dried over MgSO4 and concentrated to give (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid (442 mg) as off-white solid. MS: 288.0 ([M−H]−).