Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([O:14][C@@H:15]([C@H:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH3:16])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH:9]1([N:6]2[C:5]3[C:12]([O:14][C@@H:15]([C@@H:17]4[CH2:18][C:19](=[O:22])[NH:20][CH2:21]4)[CH3:16])=[CH:13][C:2]([C:39]4[CH:38]=[CH:37][C:36]([N:33]5[CH2:32][CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:35][CH2:34]5)=[CH:41][CH:40]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:11][CH2:10]1
Reactant: C[C@@H](Oc1cc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C

Procedure:
Intermediate 2.75 (120 mg, 0.33 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (180 mg, 0.59 mmol), K3PO4 (240 mg, 1.1 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (12 mg, 0.017 mmol) were taken up in 1,4-dioxane (5.3 mL) and water (0.53 mL). The stirred reaction mixture was heated to 100° C. for 2 h and was then cooled and partitioned between EtOAc, water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-25% MeOH in DCM) to provide tert-butyl 4-(4-(1-cyclopropyl-7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H40N5O4: 546.3; found: 546.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:10][C@@H:9]2[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[C@H:9]([OH:10])[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: OC[C@H]1O[C@@H]1c1cccc(Cl)c1
Product: OC[C@@H](O)[C@H](c1cccc(Cl)c1)N1CCc2ccccc21
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
[(2R,3R)-3-(3-chlorophenyl)oxiran-2-yl]methanol (4.8 g, 26 mmol) and indoline (d 1.063, 2.9 mL, 26 mmol) were heated neat at 135° C. in a sealed flask. After 1.5 hours, the cooled mixture was pre-adsorbed on silica gel (25 g). Flash column chromatography (silica 375 g, 20%, 40%, 80% ethyl acetate/hexanes) provided (2S,3S)-3-(3-chlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-diol (5.8 g, 73%) as a white solid. MS (ES) m/z 304 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O>>[CH2:8]([C:4]1[CH:3]=[C:2]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:9]
Reactant: OB(O)c1cccs1
Reactant: CCc1cccc(Br)c1
Product: CCc1cccc(-c2cccs2)c1

Procedure:
1-Bromo-3-ethylbenzene and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(3-ethylphenyl)thiophene as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7](OS(C(F)(F)F)(=O)=O)=[CH:8][C:9]=2[S:11]([CH3:13])=[O:12])[S:4][C:3]=1[C:22](=[O:24])[NH2:23].[O:25]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>CN(C=O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:32]3[CH2:33][CH2:34][C:29]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:30][CH2:31]3)=[CH:8][C:9]=2[S:11]([CH3:13])=[O:12])[S:4][C:3]=1[C:22]([NH2:23])=[O:24]
Reactant: CS(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2sc(C(N)=O)c(N)c12
Reactant: C1CC2(CCN1)OCCO2
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)c1cc(N2CCC3(CC2)OCCO3)nc2sc(C(N)=O)c(N)c12
Temperature: 70 °C
Yield: 42.4 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-amino-2-carbamoyl-4-methanesulfinyl-thieno[2,3-b]pyridin-6-yl ester (3.00 g, 7.44 mmol) in DMF (100 mL) was added 1,4-dioxa-8-azaspiro[4,5]-decane (2.20 g, 15.4 mmol). The mixture was heated to 70° C. for 1 h. The mixture was cooled to room temperature, diluted with H2O, and washed with CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 1.25 g (42.2%) of 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methanesulfinyl-thieno[2,3-b]pyridine-2-carboxylic acid amide as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12]CC2C=CC(OC)=CC=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:3]=1[F:30].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[C:11]([SH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:3]=1[F:30]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N)c(F)c1Nc1ccccc1F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(S)c(N)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 23 h
Yield: 75 %

Procedure:
To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate (9.79 g, 22.7 mmol) in anisole (12 mL) was added CF3COOH (20 mL). After stirring at ambient temperature for 23 h, the solvent was removed in vacuo. To the residue was added water (30 mL). The mixture was neutralized with 25% aqueous ammonia and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL×3) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated to give the desired product (white solid, 5.28 g, 75% yield). The product was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C@@H:10]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].[Br-].[CH2:50]([C:52]1[CH:67]=[CH:66][C:55]([CH2:56][C:57]2[CH:58]=[C:59](B(O)O)[CH:60]=[CH:61][CH:62]=2)=[CH:54][CH:53]=1)[CH3:51].[Cl-].[Na+]>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.O.O1CCOCC1.O>[CH2:50]([C:52]1[CH:67]=[CH:66][C:55]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:12]3[C@H:13]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C@@H:10]([CH2:39][O:40][CH2:41][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:11]=3)[CH:58]=2)=[CH:54][CH:53]=1)[CH3:51]
Reactant: O=S(=O)(OC1=C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)C(F)(F)F
Reactant: CCc1ccc(Cc2cccc(B(O)O)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(Cc2cccc(C3=C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Reaction time: 26 h
Yield: 72.7 %

Procedure:
In a nitrogen stream, dioxane-water (10:1)(12 mL) was added to a mixture of trifluoromethanesulfonic acid (3R,4R,5S,6R)-4,5,6-trisbenzyloxy-3-(benzyloxymethyl)cyclohex-1-enyl ester (656 mg, 0.981 mmol), K3PO3 (250 mg, 1.18 mmol), KBr (140 mg, 1.18 mmol), 3-(4-ethylbenzyl)phenylboronic acid (283 mg, 1.18 mmol) and Pd(PPh3)4 (56.6 mg, 0.049 mmol), and the reaction mixture was heated and stirred at a temperature of 100° C. to 105° C. for 26 hours. After cooling the reaction mixture, a saturated sodium chloride aqueous solution and water were added thereto. The resulting solution was extracted with ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10 to 1:8) to obtain the title compound (510.0 mg, 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22](OC)=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>C1COCC1.O>[OH:23][CH2:22][CH:13]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CO)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alaninate (80 g, 230 mmol) in THF (800 mL) was added lithium borohydride (20 g, 920 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was diluted with water and filtered. The filtrate was concentrated under reduced pressure to give benzyl tert-butyl (3-hydroxypropane-1,2-diyl)biscarbamate. MS ESI calc'd. for C16H25N2O5 [M+H]+ 325. found 325. 1H NMR (400 MHz, CDCl3) δ 7.38-7.35 (m, 5H), 5.11 (s, 2H), 4.70 (s, 1H), 4.13-4.11 (m, 1H), 3.66-3.28 (m, 4H), 2.04 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:23][C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Br:31])=[CH:26][C:25]=2[O:32][CH3:33])=[C:13](/[C:15](/[CH3:22])=[CH:16]\[C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:23]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Br:31])=[CH:26][C:25]=1[O:32][CH3:33])[C:17](=[O:18])[CH:16]=[C:15]2[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C(/C)c1cc(SCc2ccccc2)ccc1Nc1cc(Cl)c(Br)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(Cl)cc1-n1c(=O)cc(C)c2cc(SCc3ccccc3)ccc21

Procedure:
The crude residue from step 3 was dissolved in 6 mL THF, was treated with potassium tert-butoxide 1N in THF (3.05 ml, 3.05 mmol) and was heated to reflux for 20 minutes. The reaction mixture was then concentrated. The crude residue was used in the next step without purification. m/z (ESI) 502.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[NH3:17].C1COCC1>S(Cl)(Cl)=O.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([NH2:17])=[O:16])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2ccncc2)CC1
Reactant: N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)[C@H]1CC[C@@H](Nc2ccncc2)CC1
Reaction time: 1 h

Procedure:
cis-4-(Pyridin-4-ylamino)cyclohexanecarboxylic acid (600 mg, 2.74 mmol) was dissolved in thionyl chloride (2 ml) at room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to yield the crude acid chloride, which was added to liquid ammonia/THF (1:1, 15 ml) and allowed to stir at room temperature. The reaction mixture was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure to afford 400 mg (68%) of cis-4-(pyridin-4-ylamino)cyclohexanecarboxamide as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10].[CH2:18]([S:21][CH2:22][C:23]([NH2:25])=[O:24])[CH2:19][CH3:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:5]([CH3:8])=[CH:6][C:7]=1[CH:22]([S:21][CH2:18][CH2:19][CH3:20])[C:23]([NH2:25])=[O:24]
Reactant: Cc1ccc(N)c(C(=O)c2ccc(F)cc2)c1
Reactant: CCCSCC(N)=O
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSC(C(N)=O)c1cc(C)cc(C(=O)c2ccc(F)cc2)c1N
Temperature: -70 °C
Yield: 85.6 %

Procedure:
To a mixture of 45.8 g (0.2 mole) of (2-amino-5-methylphenyl)(4-fluorophenyl)methanone and 26.6 g (0.2 mole) of 2-(1-propylthio)acetamide and 700 ml of methylene chloride cooled to -70° C. was added 23 g (0.2 mole) of 95% t-butoxychloride over a 40 minute period. The mixture was kept at -70° C. for 2 additional hours and then 21 g (0.2 mole of triethylamine was added dropwise. The mixture was allowed to warm to room temperature and was washed with water. The organic layer was concentrated and the residue was triturated with isopropyl ether to give 61.7 g (86%) of the titled compound as yellow crystals, m.p. 130.5°-132.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6]Cl)[CH3:3].[Mg].[CH2:9]1[CH2:19][C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1>O1CCCC1>[CH3:1][N:2]([CH3:3])[CH:4]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:19][CH:9]=1)[CH2:5][CH3:6]
Reactant: CN(C)CCCCl
Reactant: O=C1CCCc2ccccc21
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(C1=CCCc2ccccc21)N(C)C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
The Grignard reagent from 300 g (2.5 moles) of dimethylaminopropyl chloride and 60 g (2.5 moles) of magnesium turnings is prepared in 2 l. of tetrahydrofuran. To this is added 300 g (2.0 moles) of α-tetralone in 1 l. of tetrahydrofuran, at a rate to maintain reflux. After the addition the reflux is continued for 1.5 hours, then the mixture is cooled in ice and quenched with 500 ml of saturated ammonium chloride. The layers are separated, and the aqueous diluted with water and reextracted with ether. The organics are evaporated, then treated with a mixture of 350 ml of concentrated HCl and 1400 ml of glacial acetic acid at reflux for 1/2 hour. The solvents are removed in vacuo, and the residue taken up in water, and the aqueous extracted with benzene. Basification liberates the product which is extracted with benzene, dried over carbonate, the solvent evaporated, and the product distilled at 129° C., 0.3 mmHg to give 250 g (58%) of a light yellow liquid, 1-dimethylaminopropyl-3,4-dihydronaphthalene.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>CC(C)=O>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:13]=[C:14]([NH:18][C:19]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 250 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 18.7 g. 3-(trifluoromethyl)phenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from acetonitrile 17.9 g. of the hydrochloride of 1-[3-(trifluoromethyl)phenyl]-3-(pentanimidoyl)urea; m.p. 167°-169°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:20]([F:23])([F:22])[F:21])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1.CCOCC>[ClH:24].[CH3:19][C:17]1[N:18]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:15][C:16]=1[C:20]([F:23])([F:21])[F:22]
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1nc(N2CCNCC2)sc1C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 1.45 mmol 4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml dioxane was added dropwise 21.8 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90° C. for 2 h. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as a white crystalline solid (yield 68%). MS (m/e): 252.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:7].[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:23][OH:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:7]
Reactant: COCCOC(=O)Nc1cccc(C)c1COc1cccn2c(C=O)c(C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCOC(=O)Nc1cccc(C)c1COc1cccn2c(CO)c(C)nc12
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 72.7 %

Procedure:
A suspension of 3.7 g (9.3 mmol) of 8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzyloxy}-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde in 40 ml of methanol is treated at RT with 362 mg (9.3 mmol) of 97% sodium borohydride and stirred for 75 min. It is added to ice/water, extracted with dichloromethane and concentrated in a Rotavapor. The residual oil is crystallized using 5 ml of isopropyl alcohol, 5 ml of toluene and diisopropyl ether. 2.7 g (72.7%) of the title compound of m.p. 121°-123° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:18][C@@H:17]1[C:32]([O:34]C)=[O:33].[ClH:36]>CO.[OH-].[Na+].O>[ClH:36].[ClH:36].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:18][C@@H:17]1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@H]1CN(CCSc2cccc(F)c2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCSc4cccc(F)c4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of 0.54 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-carboxylate in 4 cm3 of methanol and 0.8 cm3 of 5N aqueous sodium hydroxide was heated with stirring at 60° C. for 20 hours. After evaporating the solvents under reduced pressure (5 kPa) at a temperature in the region of 40° C. the residue obtained was taken up in 10 cm3 of water and then acidified with 0.4 cm3 of concentrated hydrochloric acid. The solution was evaporated under the same conditions and then the residue obtained was triturated in a dichloromethane/methanol (90/10 by volume) mixture. The insoluble material was filtered off and washed with 5 cm3 of dichloromethane. The filtrate was dried over sodium sulfate and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue was triturated in 10 cm3 of diisopropyl ether and then 1 cm3 of a 5N solution of hydrochloric acid in diisopropyl ether was added with stirring. The crystals were separated by filtration and then washed with 2 times 5 cm3 of diisopropyl ether. After drying in the air, 0.45 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio) ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of an amorphous solid with a pale yellow color which melts in the region of 140° C. with softening.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([OH:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[N:2].N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>Cl>[C:30]([O:23][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[C@@H:20]([OH:22])[CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[C:1]#[N:2])[CH2:13]1)(=[O:32])[CH3:31]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](C#N)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](C#N)CC[C@@H]32)C1
Reaction time: 72 h

Procedure:
A solution of 17β-cyano-5α-androstane-3α,11β-diol (20 mg) in acetic anhydride (0.5 ml) containing pyridine (0.5 ml) was kept at room temperature for three days. The mixture was diluted with 2N-hydrochloric acid and extracted with ethyl acetate. Evaporation of the organic extract afforded title compound (21 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.O=S(Cl)[Cl:14]>>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(CBr)cc1

Procedure:
A solution of 4-bromomethyl-benzoic acid (8.6 g, 0.04 mol) in 7.23 mL SOCl2 (0.1 mol) is heated to reflux for 5 h. SOCl2 is removed, and the residue is recrystalized from hexane to afford 4-bromomethyl-benzoyl chloride as a white crystalline solid.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[C:32]5C=CC=CC=5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[C:41]1([CH:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)C=CC=CC=1>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][N:48]5[CH2:41][CH2:47][CH2:51][CH2:50][CH2:49]5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: c1ccc(C2CCCN2)cc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5c5ccccc5)c4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5CN5CCCCC5)c4)cc23)CC1
Yield: 32 %

Procedure:
The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting 1-(2-pyrrolidinylmethyl)piperidine (168.3 mg, 1.0 mmol) for 2-phenylpyrrolidine to afford 21 mg of the title compound (32%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.Cl>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: Cc1cc(OCCN(C)C)ccc1NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(OCCN(C)C)ccc1NC(=O)c1ccc(N2CCNCC2)cc1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar and a gas dispersion tube was added N-(2-methyl-4-(2-(N,N-dimethylamino)ethoxy)phenyl)-4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)benzamide (0.295 g, 0.61 mmol) and 50 mL of dry EtOAc. This well stirred solution was cooled in an ice bath and saturated with HCl gas over 15 min. The mixture was aged 1 h at 0° C. and the excess HCl was then removed with a stream of argon. The EtOAc was removed in vacuo and the crude product was partitioned between EtOAc and NaHCO3 solution. The layers were separated, the organic phase was washed with brine and dried (MgSO4). Filtration, removal of the solvent in vacuo and recrystallization from EtOAc gave 0.145 g of N-(2-methyl-4-(2-(N,N-dimethyl)aminoethoxy)phenyl)-4-(1-piperazinyl)benzamide, as a white crystals. mp: 139-141° C. 1H NMR (CDCl3): d 1.66 (br s, 1H), 2.28 (s, 3H), 2.33 (s, 6H), 2.72 (t, j=6 Hz, 2H), 3.05 (m, 4H), 3.27 (m, 4H), 4.05 (t, j=6 Hz, 2H), 6.77 (m, 2H), 6.93 (d, j=9 Hz, 2H), 7.45 (s, 1H), 7.63 (d, j=9 Hz, 1H), 7.77 (d, j=9 Hz, 2H).