Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].Cl.O1[CH2:21][CH2:20][CH2:19][CH2:18]1>[Zn].BrCC1C=CC(C#N)=CC=1>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[CH2:18][C:19]1[CH:2]=[CH:1][C:5]([C:6]#[N:7])=[CH:21][CH:20]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc2ccccc2c1Cl
Reactant: C1CCOC1
Agent: Cl
Agent: N#Cc1ccc(CBr)cc1
Agent: [Zn]
Product: CCCCc1cnc2ccccc2c1Cc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
14 ml of a 0.38M solution of 4-bromomethyl benzonitrile zinc in tetrahydrofuran (prepared by Knochel, J. Org. Chem., (1988) Vol. 53, pages 5789 to 5791) were added to a stirred mixture of 0.720 g of 4-chloro-3-butyl quinoline of Step F with 0.8 ml of tetrahydrofuran and 0.663 g of tetrakis triphenylphosphine palladium. The mixture was stirred for 4 hours at 60° C., then for 16 hours at ambient temperature. The mixture was hydrolyzed with 100 ml of 0.1N hydrochloric acid and then extracted with ethyl acetate. The extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness. The residue was chromatographed on silica (eluant: hexane--ethyl acetate (7-3)) to obtain 0.445 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH2:37][CH3:38])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:47][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH2:37][CH3:38])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)C1CCN(c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)Cc3cc(C(F)(F)F)ccc3OCC)nc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)O)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
Ethyl 1-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carboxylate (110 mg) is dissolved in ethanol (4 ml) and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 1-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carboxylic acid (63 mg). MS (m/z): 651 [M+H]+
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]1[C:16]([OH:18])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:21])=[N-]>CCOCC>[C:1]([O:9][C@H:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]1[C:16]([O:18][CH3:21])=[O:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O[C@@H]1CC=CC[C@@H]1C(=O)O)c1ccccc1
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC=CC[C@@H]1OC(=O)c1ccccc1
Yield: 100 %

Procedure:
A solution of 1-benzoyloxycyclohex-4-ene-2-carboxylic acid (5, 160 mg, 0.645 mmol) in ether (5 ml) is treated with a solution of diazomethane (excess) in ether. The solvent was removed under vacuum to yield methyl cis-2-benzoyloxy-cyclohex-4-enecarboxylate (6, 168 mg, 100%) as a colorless oil. When enantiomerically pure starting material was used, the product of this reaction was >97% enantiomerically pure. [α]D (c 6.35, acetone)=-89.5 for the 1S,2R isomer).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH:19]=O)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.C([BH3-])#N.[Na+].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(C=O)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1c2ncc(CNc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-8-formyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.50 g, 0.16 mmol) was dissolved/suspended in methanol (2 mL) and treated with sodium cyanoborohydride (0.030 g, 0.47 mmol) followed by aniline (0.043 mL, 4.7 mmol). The mixture was stirred for 5 minutes then acetic acid (0.020 mL, 0.35 mmol) was added. After an additional 3 hours at room temperature the mixture was made alkaline with 15% sodium hydroxide and the white suspension was extracted with dichloromethane (3×10 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography then chromatotron (hexane to 1:1 hexanes/ethyl acetate gradient) to give the title compound (0.031 g, 50%), m.p. 79°-80° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.O.NN.[OH-].[K+]>>[NH:16]1[CH2:17][CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:15]1
Reactant: O=C(CCC1CCCNC1)c1ccc2ccccc2n1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2nc(CCCC3CCCNC3)ccc2c1
Yield: 26.4 %

Procedure:
The operation is as in Example 13, but starting from 6 g of 1-(2-quinolyl)-3-(3-piperidyl)-1-propanone, 6 ml of 85% hydrazine hydrate and 5 g of potassium hydroxide pellets. 4.9 g of crude product are obtained. This product is absorbed on a column of 150 g of silica and eluted with a 9/1 chloroform-diethylamine mixture. 1.5 g of 2-[3-(3-piperidyl)-propyl]-quinoline are thus obtained, which melts at 194° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH:23]=O)[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25]([O-])([O-])=O.[K+].[K+]>CO>[C:23]([C@H:13]1[O:12][CH2:11][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14]1)#[CH:25]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [K+]
Solvent: CO
Product: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)CO1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Dimethyl (1-diazo-2-oxpropyl)phosphonate (3.90 mL, 26.0 mmol) was added to tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-formylmorpholine-4-carboxylate (Example 1, step 6) (7.78 g, 21.6 mmol) and K2CO3 (5.98 g, 43.3 mmol) in anhydrous MeOH (216 mL) at ambient temperature. The reaction was stirred for 2 hours then filtered and concentrated in vacuo. Saturated aqueous KH2PO4 was added and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification on silica gel (750 g) eluting with a gradient of 0-30% EtOAc/hexanes afforded the title compound (4.60 g, 12.9 mmol, 60% yield) as a colorless oil, MS (ESI): m/z=256.01 (M+H-Boc).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([O:13][CH3:14])(=[O:12])[C:10]#[CH:11].C(=O)([O-])[O-].[K+].[K+].C1COCC1>O.[Cu]I>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:11]#[C:10][C:9]([O:13][CH3:14])=[O:12])=[N:3][CH:4]=1
Reactant: Nc1cnc(I)cn1
Reactant: C#CC(=O)OC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C#Cc1cnc(N)cn1
Temperature: 65 °C
Yield: 38 %

Procedure:
To a 5 mL of microwave vial was added 5-iodopyrazin-2-amine (100 mg, 0.452 mmol), methyl propiolate (161 μL, 1.810 mmol), potassium carbonate (125 mg, 0.905 mmol), copper (I) iodide (3.45 mg, 0.018 mmol), and THF (1508 μL). The reaction mixture was heated at 65° C. for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (20% EtOAc in DCM) yielding methyl 3-(5-aminopyrazin-2-yl)propiolate (38%). LCMS (m/z): 178.4 (MH+), 0.48 min.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3[S:30][C:29]([C:31]4([OH:39])[CH2:36][O:35]C(C)(C)[O:33][CH2:32]4)=[N:28][CH:27]=3)[CH:22]=[C:23]([CH3:25])[CH:24]=2)[N:13]=1)(C(C)(C)C)(C)C.Cl>O1CCCC1.CO>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3[S:30][C:29]([C:31]([OH:39])([CH2:36][OH:35])[CH2:32][OH:33])=[N:28][CH:27]=3)[CH:22]=[C:23]([CH3:25])[CH:24]=2)[N:13]=1
Reactant: Cc1cc(Nc2nccc(OCCO[Si](C)(C)C(C)(C)C)n2)cc(-c2cnc(C3(O)COC(C)(C)OC3)s2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nccc(OCCO)n2)cc(-c2cnc(C(O)(CO)CO)s2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.3 %

Procedure:
To a solution of 5-[5-(3-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-2,2-dimethyl-1,3-dioxan-5-ol (185 mg, 0.32 mmol) in tetrahydrofuran (1.6 mL) was added hydrochloric acid (1.0 N, 970 μL, 0.97 mmol) at room temperature. The mixture was stirred at room temperature for 2.5 h, then diluted with methanol, filtered, and purified by reverse phase HPLC (10:90 to 90:10 acetonitrile:water with a 0.1% trifluoroacetic acid modifier). The combined fractions were dried on a lyophilizer, dissolved in methanol, and the TFA salt converted to the free base using StratoSpheres SPE PL-HCO3 MP-Resin (0.9 mmol) cartridges to give 2-[5-(3-{[4-(2-hydroxyethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]propane-1,2,3-triol (75 mg, 0.18 mmol, 56% yield) as a white foam. MS ESI: [M+H]+ m/z 419.1. 1H NMR (500 MHz, DMSO-d6) δ 9.65 (dd, J=4.3, 15.1, 1H), 8.21 (d, J=5.7, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.47 (s, 1H), 7.09 (s, 1H), 6.31 (s, 1H), 4.39 (s, 2H), 3.79-3.72 (m, 2H), 3.72-3.63 (m, 4H), 2.30 (s, 3H). rhSYK activity=+++
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH3:15][NH2:16]>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:16][CH3:15])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CN
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1NC
Reaction time: 3 h
Yield: 39797.1 %

Procedure:
To a solution of 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (42 g, 0.181 mol) in EtOH (400 mL) was added MeNH2 (12.3 g, 0.398 mmol) in EtOH (100 mL) at 0° C. and the mixture stirred for 3 h. The mixture was concentrated to remove most of the solvent and then partitioned between H2O (200 mL) and CH2Cl2 (500 mL). The organic layer was washed with brine, dried and concentrated to give 4-(methylamino)-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester as a white solid (36.0 g, 88% yield). 1H NMR (300 MHz, CDCl3): δ 8.59 (s, 1H), 8.18 (brs, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.05 (d, J=4.8 Hz, 3H), 2.52 (s, 3H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]([O:21]CC)=[O:20].[Li+].[OH-].Cl>CO.C1COCC1.O.[Cl-].[Na+].O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1CCC1OCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(-c2ccccc2)sc1CCC1OCCO1
Reaction time: 5 h
Yield: 74.6 %

Procedure:
Ethyl 5-(2-(1,3-dioxolan-2-yl)ethyl)-2-phenylthiazole-4-carboxylate (2.6 g, 7.9 mmol) was dissolved in MeOH/THF (1:1, 60 mL) and a solution of LiOH (378 mg, 15.7 mmol) in H2O (15 mL) was added. The reaction was stirred for ˜5 h and the pH adjusted to ˜3 by the addition of 3N HCl. The mixture was poured into brine and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated. The crude product was crystallized from EtOAc to give 5-(2-(1,3-dioxolan-2-yl)ethyl)-2-phenylthiazole-4-carboxylic acid (1.8 g, 75% yield).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:12])[N:6]([CH3:11])[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH3:11][N:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:12]
Reactant: Cn1ccc(O)c([N+](=O)[O-])c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(OCc2ccccc2)c([N+](=O)[O-])c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To the title compound of step 1 (300 mg, 1.7 mmol) in CH3CN (15 mL) was added K2CO3 (726 mg, 5.2 mmol) at 25° C. under N2. After stirring for 30 min, benzyl bromide (450 mg, 2.6 mmol) was added, and the mixture was heated at 50° C. for 20 h. Following CH2Cl2 extractive work up, the residue was triturated with PE:EA (3:1) to give the title compound (250 mg, 54%) as a yellow solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.43-7.29 (m, 6H), 6.12 (d, J=7.2 Hz, 1H), 5.27 (s, 2H), 3.57 (s, 3H). LCMS: 261.0 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=O)=[N:10]2)=[CH:5][CH:4]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:38]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[S:38])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(C)CC3)cc2-c2ccccc2)cn1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(C(=S)N3CCN(C)CC3)cc2-c2ccccc2)cn1

Procedure:
To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine (173 mg) obtained in Example 62 in toluene (10 mL), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawson reagent, 222 mg) was added. The mixture was refluxed for 14 hours under heat. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, water, and saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel thin-layer chromatography (chloroform-methanol), to thereby give the title compound as an amorphous product (61 mg, 33%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1OC.O[CH2:36]CC1C=CC(C)=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:26][C:21]([S:20][C:17]1[S:16][C:15]([NH:14][C:13]([N:12]([C@H:28]2[CH2:29][CH2:30][C@H:31]([CH3:34])[CH2:32][CH2:33]2)[CH2:11][CH2:10][C:4]2[CH:5]=[CH:6][C:7]([CH3:36])=[CH:2][CH:3]=2)=[O:27])=[N:19][CH:18]=1)([CH3:25])[C:22]([OH:24])=[O:23]
Reactant: Cc1ccc(CCO)cc1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1F
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: Cc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-{2-[3-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 1-(2-hydroxy-ethyl)-4-methyl-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][C:17]([NH:19][C:20](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])SC)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl.[Hg](Cl)Cl>[C:27]([O:26][C:24]([NH:23][C:20](=[N:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[NH:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: Nc1cc2ccccc2cn1
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cc2ccccc2cn1
Reaction time: 26 h
Yield: 84 %

Procedure:
Mercury (II) chloride (192 mg, 0.707 mmol) was added in one portion to a stirred mixture of 3-aminoisoquinoline (84.5 mg, 0.586 mmol), N,N′-di-t-butoxycarbonyl-S-methylisothiourea (Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1987, 52, 1700-1703) (204 mg, 0.703 mmol), and triethylamine (250 μL, 1.79 mmol) in CH2Cl2 (3.0 mL) under N2 at 23° C. The mixture was stirred for 26 hours and then directly purified by column chromatography upon silica gel using hexanes-EtOAc (98:2 to 95:5) as eluant to give 3-(N′,N″-di-t-butoxycarbonyl-N-guanidinyl)isoquinoline (189.4 mg, 0.492 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH:16]([C:20]1[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[N:24][CH:25]=1)[CH:17]([CH3:19])[CH3:18])[C:13](Cl)=[O:14].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][N:7]([CH3:8])[C:13]([N:12]([CH3:11])[CH:16]([C:20]2[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[N:24][CH:25]=2)[CH:17]([CH3:19])[CH3:18])=[O:14])=[CH:4][CH:3]=1
Reactant: CNCc1ccc(Cl)cc1
Reactant: CC(C)C(c1cncnc1C(F)(F)F)N(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(c1cncnc1C(F)(F)F)N(C)C(=O)N(C)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 53 %

Procedure:
0.16 g (1.0 mmol) of (4-chlorobenzyl)-methylamine was dissolved in 30 ml of pyridine, and 0.3 g (1.0 mmol) of N-methyl-N-(2-methyl-1-(4-trifluoromethyl-pyrimidin-5-yl)-propyl]-carbamoyl chloride was dropwise added, followed by stirring at room temperature for 10 hours. To the reaction solution, 50 ml of water was added, followed by extraction with diethyl ether. The obtained organic phase was washed twice with 30 ml of a dilute citric acid aqueous solution, followed by drying over anhydrous magnesium sulfate. Diethyl ether was distilled off under reduced pressure, and the obtained crude product was purified by silica gel chromatography (developing solvent/n-hexane:ethyl acetate=8:1 to 3:1) to obtain 0.22 g (yield: 52%) of 1-(4-chlorobenzyl)-1,3-dimethyl-3-[2-methyl-1-(4-trifluoromethyl-pyrimidin-5-yl)-propyl]-urea as colorless crystals (melting point: 95-98° C.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]3)=O)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.CC(C)=O.Cl.O>O1CCCC1.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:16]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(COCCc1ccc2ccsc2c1)N1CCC(O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: OC1CCN(CCOCCc2ccc3ccsc3c2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The above 2-(2-(1-benzothiophene-6-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone was dissolved in 7.4 ml of tetrahydrofuran. Thereafter, 7.4 ml of a tetrahydrofuran solution containing a 1 mol/l borane-tetrahydrofuran complex was added dropwise to the obtained solution while cooling on ice, and the obtained mixture was then stirred at a room temperature for 17 hours. Thereafter, 10 ml of acetone was added to the reaction mixture, and the obtained mixture was then stirred for 30 minutes. Thereafter, 1.5 ml of 6 mol/l hydrochloric acid was added thereto, and the obtained mixture was heated to reflux for 2 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto, and a water layer was separated. Thereafter, ethyl acetate was added to the water layer. The pH of the obtained mixture was adjusted to pH 9.5 by addition of a 2 mol/l aqueous sodium hydroxide solution, followed by separation of an organic layer. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under a reduced pressure. The residue was purified by column chromatography (eluent; chloroform:methanol=30:1 to 20:1), so as to obtain 0.53 g of a yellow oil product, 1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:16])[CH3:15]>>[CH3:26][CH:24]([N:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:18][N:17]([CH:14]([CH3:16])[CH3:15])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)NCCN(C(C)C)C(C)C
Product: CC(C)N(CCN(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(C)C

Procedure:
Following the procedure of Example 1, p-nitrobenzenesulfonyl chloride was reacted with N,N',N'-triisopropyl ethylene diamine to obtain the free base as a yellow solid, m.r. 98°-100° C.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5](=[O:14])[C:4]1([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([OH:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1.C(O)C>CO.C(Cl)(Cl)Cl.CO>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([OH:46])[CH2:41][CH2:42][N:43]([CH2:2][CH:3]3[CH2:7][N:6]([CH:8]4[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]4)[C:5](=[O:14])[C:4]3([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:44][CH2:45]2)=[CH:36][CH:35]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C1N(C2CCCCC2)CC(CCl)C1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C1N(C2CCCCC2)CC(CN2CCC(O)(c3ccc(Cl)cc3)CC2)C1(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 39 g. (0.106 mole) of 4-chloromethyl-1-cyclohexyl-3,3-diphenyl-2-pyrrolidinone, 58.5 g. (0.424 mole) of finely ground potassium carbonate, and 22.5 g. (0.106 mole) of 4-(4-chlorophenyl)-4-hydroxypiperidine in 300 ml. of ethanol was heated to 200° C. in a steel bomb for 66 hrs. During the heating the bomb was continuously rotated to produce mild stirring. The contents were filtered and the filtrate concentrated. The residue was heated in 250 ml. of ethylacetate and allowed to stand at room temperature overnight. The mixture was filtered. The filtrate was extracted with dilute hydrochloric acid and dilute sodium hydroxide. The ethylacetate was concentrated and the residue dissolved in ethanol and allowed to stand overnight. The resulting mixture was filtered and the filtrate concentrated. The residue was chromatographed on a 4.5 × 60 cm. silica gel column. The product was obtained from the column using a chloroform-methanol eluate containing increasing amounts of methanol. The product after isolation and crystallization from isopropanol melted at 222°-225° C.