Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]([O:20][Si](C)(C)C)[C:18]#N)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH-:26].[K+].[OH2:28]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:17]([OH:20])[C:18]([OH:28])=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: [OH-]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2C(C#N)O[Si](C)(C)C)cc1
Agent: Cl
Agent: [K+]
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2C(O)C(=O)O)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
To a round bottom flask containing (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-trimethylsilanyloxy-acetonitrile was added 100 mL concentrated HCl and heated to 80° C. After overnight heating, the reaction was diluted with 150 mL water and extracted with DCM (3×100 mL). The organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was then re-dissolved in about 75 mL methanol, followed by the addition of KOH (0.45 g, 8 mmol) and the solution was refluxed for 2 h. The reaction mixture was then cooled to room temperature, concentrated under vacuum. Several pieces of crushed ice were added to the flask with the reaction residue and acidified with 1N HCl. The mixture was then diluted with 100 mL water and extracted with DCM (3×100 mL). The organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum to yield 0.35 g (60%) of the desired product. No further purification was attempted. Expected mass=288. Observed mass=289.
Reaction SMILES: [C:1](/[C:3](=[C:9]1/[CH2:10][CH2:11][C:12]2[C:17]/1=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)/C(OCC)=O)#[N:2].[C-:19]#[N:20].[K+]>C(O)C.O>[C:1]([CH2:3][C:9]1([C:19]#[N:20])[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)#[N:2]
Reactant: CCOC(=O)/C(C#N)=C1\CCc2cc(F)ccc21
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1(C#N)CCc2cc(F)ccc21
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a solution of (E)-ethyl 2-cyano-2-(5-fluoro-2,3-dihydro-1H-inden-1-ylidene)acetate (Prep11, 100 g, 0.408 mol) in ethanol (800 ml) a solution of KCN (67 g, 1.02 mol) in water (240 ml) was added, and warmed to 65° C. The mixture was stirred for 24 h.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]([CH3:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:29](OCC)=[O:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])C>C(OCC)C>[OH:9][CH2:10][C:11]([CH3:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:22])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:29][OH:30]
Reactant: CCOC(=O)C(C)(CCCCSCCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(CO)(CCCCSCCCCC(C)(CO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Under nitrogen atmosphere, to a solution of lithium aluminum hydride (1.0 M solution in diethyl ether, 60 mL, 60 mmol) in diethyl ether (150 mL) was added a solution of 6-(5-ethoxycarbonyl-5-phenylhexylsulfanyl)-2-methyl-2-phenyl-hexanoic acid ethyl ester (9.45 g, 18 mmol) in anhydrous diethyl ether (50 mL). The reaction mixture was heated to reflux for 3 h and was stirred at rt overnight. The excess of lithium aluminum hydride was carefully quenched by addition of ethyl acetate (20 mL) and the precipitate was completely dissolved with 6 N HCl (10 mL) and water (100 mL). The mixture was extracted with diethyl ether (4′ 60 mL). The combined organic layers were washed with saturated NH4Cl solution (20 mL), dried over MgSO4, and concentrated in vacuo to give a crude product (6.9 g). Purification by column chromatography on silica gel (hexanes/ethyl acetate=10/1) yielded 6-(6-hydroxy-5-methyl-5-phenylhexylsulfanyl)-2-methyl-2-phenylhexan-1-ol (5.36 g, 69%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 7.40-7.13 (m, 10H), 3.69 (d, J=11.0 Hz, 2H), 3.53 (d, J=11.0 Hz, 2H), 2.38 (t, J=7.3 Hz, 4H), 1.85-1.63 (m, 2H), 1.60 (br., 2H), 1.58-1.40 (m, 6H), 1.40-1.20 (m, 2H), 1.34 (s, 6H), 1.15-0.93 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): d (ppm): 144.63, 128.43, 126.62, 126.14, 72.42, 43.34, 37.91, 31.85, 30.31, 23.16, 21.53. HRMS (HR, LSIMS, gly): Calcd. for C26H39O2S, (MH+): 415.2671, found: 415.2670. HPLC: 97.3% purity.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4cccc(OC(F)(F)F)c4)noc3N)CC2)c1
Yield: 66.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (562 mg, 1.22 mmol, 66%) was obtained.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]1[O:21][C:20]2[CH:19]=[CH:18][C:8]([O:9][CH:10](Cl)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][C:6]=2[O:5]1>CN(C=O)C>[CH2:4]1[O:21][C:20]2[CH:19]=[CH:18][C:8]([O:9][C:14]3[CH:15]=[CH:16][CH:11]=[C:10]([O:9][C:8]4[CH:18]=[CH:19][C:20]5[O:21][CH2:4][O:5][C:6]=5[CH:7]=4)[C:13]=3[CH2:12][C:1]#[N:2])=[CH:7][C:6]=2[O:5]1
Reactant: ClC(Oc1ccc2c(c1)OCO2)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1c(Oc2ccc3c(c2)OCO3)cccc1Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.3 %

Procedure:
Sodium cyanide (85 mg, 1.6 mmol) was added to a solution of 2,6-bis-[(3,4-(methylenedioxy)phenoxy]-benzyl chloride (435 mg, 1.1 mmol) in DMF (3 ml) at room temperature. The resulting dark brown solution was stirred at room temperature for 18 hours. The DMF was removed under high vacuum and the remaining brown residue was extracted into ethyl acetate and washed with brine (1×5 ml). After drying over MgSO4, the solvent was removed by evaporation and the remaining solid was purified by column chromatography using 10% ethyl acetate-hexanes which yielded 217 mg (51% yield) of the pure benzyl cyanide as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([OH:12])=[CH:7]2
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2Cl)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by reacting 1-chloro-6-methoxy-2-(4-methoxyphenyl)naphthalene (0.65 g, 2.18 mmol) with boron tribromide (6.5 mL of 1N solution) according to method D to yield 0.44 g (75%) of a white solid: mp>220° C.;
Reaction SMILES: Br.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[C:8]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3Br)[CH:9]=[CH:10][C:3]1=2.C([Mg]Cl)C.[CH3:24][S:25]SC>O1CCCC1>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[C:8]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3[S:25][CH3:24])[CH:9]=[CH:10][C:3]1=2
Reactant: CSSC
Reactant: BrC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Agent: Br
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CSC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
3-(Benzo[b]thiophen-5-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (0.4 g; prepared as described in Example 28) was added in portions under nitrogen at 0-5° C. over 8 minutes to a stirred solution of ethylmagnesium chloride (2M solution in ether; 1.4 ml) in tetrahydrofuran (10 ml), then the mixture was stirred at 0° C. for 20 minutes and at ambient temperature for 1.25 hours. Dimethyl disulphide (0.14 ml) was added at 0-5° C., the mixture was stirred at this temperature for 10 minutes and at ambient temperature for 4.5 hours, then it was quenched by the addition of saturated aqueous ammonium chloride solution (10 ml) and water (20 ml). The product was extracted into ethyl acetate (30 ml+2×25 ml), the combined extracts were washed with water (2×25 ml) and saturated aqueous sodium chloride solution (25 ml), then they were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 9:1 mixture of ethyl acetate and methanol as eluant. Appropriate fractions were combined and the solvents were removed in vacuo to give 3-(benzo[b]thiophen-5-yl)-2-(methylthio)-5,6-dihydroimidazo[2,1-b]thiazole (2 mg) as a yellow solid, 1H-nmr (DMSO-d6): δH 2.25 (3H, s, —SCH3), 3.68-4.19 (4H, m, —CH2CH2—), 7.36 (1H, d, J 1.7 Hz, ArH), 7.39-7.41 (1H, m, ArH), 7.54 (1H, d, J 5.45 Hz, ArH), 7.87 (1H, d, J 1.4 Hz, ArH), 7.96 (1H, d, J 8.3 Hz, ArH).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH3:10])=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1ccc(C(C)=O)cc1

Procedure:
0.15 ml of guaiacol 67, 167 mg of 4-fluoroacetophenone 68 and 335 mg of potassium carbonate are heated in 5 ml of dimethyl sulfoxide at 170° C. in a microwave for 10 min. The reaction solution is poured into water, and the emulsion is extracted three times with an ethyl tert-butyl ether. The combined organic phase is extracted twice with 1 N NaOH and once with saturated NaCl solution, dried and concentrated in vacuo. 240 mg of the desired product are obtained. C15H14O3 (242.28) MS (ESI): 215.10 (M+H+).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:17][C:18](=[O:39])[C:19](=[CH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)=[C:27]([O:37][CH3:38])[CH:26]=2)[CH2:20][CH2:21][CH2:22]Cl)[CH3:16])[CH:12]=[CH:13][CH:14]=1.O>C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([C@H:15]([N:17]2[CH2:22][CH2:21][CH2:20]/[C:19](=[CH:24]\[C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)=[C:27]([O:37][CH3:38])[CH:26]=3)/[C:18]2=[O:39])[CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cc(C=C(CCCCl)C(=O)N[C@@H](C)c2cccc(F)c2)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(/C=C2\CCCN([C@H](C)c3cccc(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a DMF (3 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (100 mg) obtained according to the method described in Example 418 and (S)-1-(3-fluorophenyl)ethylamine hydrochloric acid salt (31 mg), IPEA (0.2 mL) and HOBT (36 mg) and EDC (51 mg) were added, and the reaction solution was agitated at room temperature for 3 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over magnesium sulfate and concentrated under reduced pressure. By purifying the residue with silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate 1:1->ethyl acetate), 79 mg of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid ((1S)-1-(3-fluorophenyl)ethyl)amide was obtained. Sodium hydride (40% mineral oil content, 8 mg) was added to the DMF (3 mL) solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid ((1S)-1-(3-fluorophenyl)ethyl)amide obtained, and the reaction solution was agitated at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate system 1:1->ethyl acetate) to obtain 48 mg of the racemic title compound. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24]2)[C:8]2[C:9](=[N:11][N:12]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC1C=CC=CC=1[C@H](O)C>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:28])([F:29])[CH2:24]2)[C:8]2[C:9](=[N:11][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH3:15])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1Cl)n1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: C[C@@H](O)c1ccccc1Cl
Product: C[C@@H](c1ccccc1Cl)n1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-2-[(R)-1-(2-chloro-phenyl)-ethyl]-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 28), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-1-(2-chlorophenyl)ethanol and isolated as white solid (3.7 mg, 21%). MS (m/e): 421.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24]([O:26]C)=[O:25])[S:22][CH:23]=2)=[N:10]1.C1COCC1.[OH-].[Na+]>CO.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24]([OH:26])=[O:25])[S:22][CH:23]=2)=[N:10]1
Reactant: COC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Temperature: 90 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To a mixture of methyl 4-(1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (32.0 mg) obtained in Example 36 in methanol (2 mL)/THF (2 mL)/water (2 mL) was added 8 M aqueous sodium hydroxide solution (0.026 mL) at 0° C. The reaction mixture was stirred at 90° C. for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1 N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (31.1 mg).
Reaction SMILES: [N:1]#[C:2][NH2:3].[C:4]([O:8][C:9](=[O:26])[N:10]([CH2:24][CH3:25])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1)([CH3:7])([CH3:6])[CH3:5].CC(C)([O-])C.[K+].Br[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=1)=[O:36]>C(#N)C.C(O)(C)(C)C.O>[C:4]([O:8][C:9](=[O:26])[N:10]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[S:23][C:34]([C:35](=[O:36])[C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=3)=[C:2]([NH2:3])[N:1]=2)=[CH:19][CH:20]=1)[CH2:24][CH3:25])([CH3:6])([CH3:7])[CH3:5]
Reactant: CCN(CCCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)CBr)cc1F
Reactant: N#CN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: CCN(CCCOc1ccc(Nc2nc(N)c(C(=O)c3ccc(OC)c(F)c3)s2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of cyanamide (21.2 mg, 0.499 mmol) (Aldrich) in acetonitrile (2.5 mL) and tert-butanol (2.5 mL) was added ethyl-[3-(4-isothiocyanato-phenoxy)propyl]carbamic acid tert-butyl ester (153.8 mg, 0.4571 mmol from Example 66, step C) followed by a solution of potassium tert-butoxide (0.50 mL, 1 M in tert-butanol) (Aldrich). After 30 minutes at room temperature, 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethan-1-one (112.5 mg, 0.4553 mmol) (Maybridge Chemical) was added. The reaction mixture was stirred at room temperature for 1 hour and then heated at 75° C. for 2 hours. The resulting mixture was poured into water (10 mL). The product was collected by filtration, washed with diethyl ether and dried in vacuo to provide (3-[4-[4-Amino-5-(3-fluoro-4-methoxy-benzoyl)-thiazol-2-ylamino]-phenoxy]-propyl)-ethyl-carbamic acid tert-butyl ester (245.1.6 mg, 99% yield). HRMS, observed: 545.2230; Calcd for M+H: 545.2229.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:33]1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C1CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])[C:11]([CH2:30][CH3:31])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:33][CH2:16]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.96-1.00, 1.26-1.32, 2.04, 2.35-2.40, 2.61-2.66, 3.0-3.04, 3.22-3.27, 4.09-4.14, 4.68-4.70, 5.08, 5.45-5.48, 7.23-7.31; MS (ESI+) for C24H23Cl2N3O m/z 440 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][NH:39][CH3:40])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[Na+]>CN1CCCC1=O>[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:40])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[CH:8]=[C:7]([OH:27])[CH:6]=[CH:5][C:4]=2[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C@@H:16]([OH:20])[CH2:15][CH2:14]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CNCCCOCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCOCc1ccccc1
Yield: 44.1 %

Procedure:
A solution of 486 mg of 11β-fluor-7α-(5-iodopentyl)-estra-1,3,5(10)-triene-3,17β-diol in 10 ml of 1-methyl-2-pyrrolidinone is stirred with 540 mg of (3-benzyloxy-propyl)-methyl-amine for 3 hours at a bath temperature of 80° C. Then, the batch is added to saturated sodium chloride solution, extracted with ether, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with methylene chloride/methanol/ammonia. 237 mg of 7α-{5-[(3-benzyloxy-propyl)-methyl-amino]-pentyl}-11β-fluor-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam [α]D=+48° (c=0.5 in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([C:30]3([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:37].CO>C(OCC)C>[ClH:1].[ClH:37].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([C:30]3([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(-c3ccc(Cl)c(Cl)c3)c2)C2(O)CCCCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OC1(C(CN2CCNCC2)c2cccc(-c3ccc(Cl)c(Cl)c3)c2)CCCCC1
Reaction time: 18 h
Yield: 81 %

Procedure:
tert-butyl 4-[2-(3′,4′-dichloro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (0.39 g 0.73 mmol) was dissolved in diethyl ether (15 mL) then a 2N ethereal solution of hydrochloric acid (10 mL) was added. Methanol (approximately 1 mL) was then added until the resulting precipitate dissolved, and the homogeneous solution was stirred for 18 h. The precipitated product was collected by filtration, washed with diethyl ether and dried in a vacuum oven at 50° C. to yield 0.28 g (81%) of 1-[1-(3′,4′-dichloro-1,1′-biphenyl-3-yl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride as a white solid. MS (ESI) m/z 433/435/437 ([M+H]+); HRMS: calcd for C24H30N2OCl2.2.00 HCl, 433.1813; found (ESI), 433.1813.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:11])=[O:10])=[CH:4][N:3]=1.[N-:12]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:11])(=[NH:12])=[O:10])=[CH:4][N:3]=1
Reactant: CS(=O)Cc1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=N)(=O)Cc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 34 %

Procedure:
To a stirred mixture of 2-chloro-5-[(methylsulfinyl)methyl]pyridine (B) (7.34 g, 39 mmol) and sodium azide (4.04 g, 62 mmol) in chloroform (80 mL) cooled to 0° C. was slowly added sulfuric acid at a rate such that the temperature did not rise above 8° C. After the addition was over, the ice-water bath was removed and the mixture was heated at 55° C. for 2.5 h. The solvent was decanted into a separation funnel and the residue was stirred and dissolved in water. After a few minutes, the aqueous mixture was made basic to pH 8 by slowly adding solid Na2CO3 and then saturated with solid NaCl. The extra salt was removed by filtration (a portion of the filtrate was sucked into trap and was not recovered) and the filtrate was extracted with CH2Cl2 three times. The combined organic layer was dried over Na2SO4, filtered, concentrated and the residue was triturated in CH2Cl2-ether (1:10, v/v) solvent. The white solid was filtered, washed with CH2Cl2-ether (1:10, v/v) and dried to give 2.70 g of -chloro-5-[(methylsulfonimidoyl)methyl]pyridine (C) in 34% yield as a white solid (m.p. 134.5-136° C.). LC-MS (ELSD): mass calcd for C7H9ClN2OS [M+H]+ 203.67. Found: 203.22.