Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.O>CC(O)=O>[OH:15][C:10]1[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: NNc1ccc(I)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2ccccc2c(O)nn1-c1ccc(I)cc1
Temperature: 125 °C
Yield: 8.3 %

Procedure:
4-Iodo phenyl hydrazine (8.97 g, 36.4 mmol) was added in one portion to a stirred mixture of phthalic anhydride (5.0 g, 33 mmol) in HOAc (40 ml) at RT. The reaction mixture was heated to 125° C. for 2 hours, and then allowed to cool to RT. The suspension was poured into H2O (100 ml) and the resulting solid was removed by filtration. The mother liquor was acidified with conc. HCl. The resulting solid was collected by filtration and dried in vacuum to give the title compound (1.0 g, 8% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO) 11.91 (1H, br. s), 8.30 (1H, d), 7.91-8.03 (3H, m), 7.83 (2H, d), 7.51 (2H, d); MS (ESI+)=365.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([OH:19])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:45][C:46]1[CH:53]=[CH:52][C:49]([NH:50][CH3:51])=[CH:48][CH:47]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([N:50]([C:49]3[CH:52]=[CH:53][C:46]([Cl:45])=[CH:47][CH:48]=3)[CH3:51])=[O:19])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Reactant: CNc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)C12CCC(NC(=O)OC(C)(C)C)(CC1)CC2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-tert-Butoxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (101 mg) was dissolved in dichloromethane (2 mL). To this solution, trichloroacetonitrile (74.0 μL) and triphenylphosphine (196 mg) in dichloromethane (1.5 mL) were sequentially added and the mixture was stirred at room temperature for 2 hours. This was followed by addition of triethylamine (0.18 mL) and 4-chloro-N-methylaniline (98.6 μL) and stirring at room temperature for additional 5.5 hours. The reaction mixture was then poured into aqueous citric acid (5 mL) and was extracted with ethyl acetate (3×10 mL). The ethyl acetate extracts were combined, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant:hexane:ethyl acetate=2:1) to give 4-tert-butoxycarbonylamino-N-(4-chlorophenyl)-N-methylbicyclo[2.2.2]octane-1-carboxamide (91.4 mg) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O.[OH-].[Na+]>N1C=CC=CC=1>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:4][CH:5]=1
Reactant: CN(C)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CN(C)CCNc1ccc(CNS(C)(=O)=O)c2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
4-(Aminomethyl)-1-[[2-(dimethylamino)ethyl]amino]-thioxanthen-9-one (2 g, 6 mmol) in 30 mL of dry pyridine under nitrogen was stirred at room temperature until the solution was complete. The solution was chilled in an ice-bath and 0.52 mL(6.7 mmol) of methanesulfonyl chloride in chilled pyridine was added dropwise and the mixture was stirred for 1 h at room temperature. The reaction mixture was poured into 500 mL of water containing 0.51 g of sodium hydroxide, extracted into chloroform, the organic layer was washed with water (2x) and brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue (2.5 g) was stirred in either, filtered, and dried to afford 2 g of N-[[1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]methane-sulfonamide, m.p. 126°-127° C. The free base was dissolved in MeOH and treated with methane sulfonic acid (0.48 g) to afford 2.0 g (67%) of the product as the methanesulfonate salt, m.p. 168° C. (dec.).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[O:13]1[CH2:18][CH2:17]OCC1.[CH:19]1[C:28]2[C:23](=[CH:24]C=C[CH:27]=2)[CH2:22][CH2:21][C:20]=1N1CCCC1.Cl>CCCCCC.C(OCC)(=O)C>[C:3]1([CH2:2][CH:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:24][CH2:17][C:18]2=[O:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1cccc2ccccc12
Reactant: C1COCCO1
Reactant: C1=C(N2CCCC2)CCc2ccccc21
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2C1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Added to a mixed solution of 30.53 g (124.08 mmol, purity: 90.4%) of 1-(bromomethyl)naphthalene and 180 ml of dehydrated dioxane was 30.27 g (151.89 mmol) of 1-(3,4-dihydronaphthalene-2-yl)pyrrolidine, and the mixture was stirred for 5 hours while heating and refluxing. After cooled down to room temperature, 100 ml of a 5% hydrochloric acid aqueous solution was dropwise added to the reaction mixture and stirred, and the mixture was extracted twice with dichloromethane. The organic phase was dried on anhydrous sodium sulfate and filtered, and then the solvent was removed by distillation. A crude product obtained was refined by column chromatograph (silica gel: hexane/ethyl acetate=10/1) to obtain 20.47 g (purity: 51.8%) of 1-(naphthalene-1-ylmethyl)-3,4-dihydronaphthalene-2(1H)-one.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@@H:49]([CH2:63][C:64]1[CH:69]=[C:68]([F:70])[CH:67]=[C:66]([F:71])[CH:65]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1>C(Cl)Cl>[F:70][C:68]1[CH:69]=[C:64]([CH:65]=[C:66]([F:71])[CH:67]=1)[CH2:63][C@H:49]([NH:48][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:7][CH:8]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(CS(C)(=O)=O)nc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.9 %

Procedure:
To a stirred solution of 6-[(methylsulfonyl)methyl]nicotinic acid (181 mg), diisopropylethylamine (116 mg), and HBTU (341 mg) in methylene chloride (5 mL) was added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (326 mg) and N,N-diisopropylethylamine (233 mg) in methylene chloride (5 mL). The mixture was stirred at room temperature for 15 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 to 10:90 methanol/methylene chloride) provided 165 mg of the title compound: ESI MS m/z 532 [M+H]+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+].CCOCC>C(O)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:32]4[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]5[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc(N)c3)n2)cc1
Temperature: 75 °C

Procedure:
To a solution of N-cyclopentyl-2-(4-methoxyphenyl)-3-[2-(3-nitroanilino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (167 mg, 0.32 mmol) in ethanol (10 mL) was added tin(II)chloride dihydrate (304 mg, 1.60 mmol). The mixture was heated to 75° C. for 8 hours and then cooled to room temperature. Saturated aqueous sodium bicarbonate was added followed by ether. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by flash chromatography (1:1 hexanes-ethyl acetate to 100% ethyl acetate) to provide_N′-{4-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-1,3-benzenediamine (40 mg, 25%) as a yellow solid. 1H NMR (CDCl3): δ 8.15 (d, 1 H), 7.82 (d, 1H), 7.64 (d, 2 H), 7.43 (s, 1 H), 7.34 (t, 1 H), 7.15-7.10 (m, 2 H), 7.03 (d, 2 H), 6.86 (d, 1H), 6.55 (d, 1 H), 6.40 (d, 1 H), 6.11-6.06 (m, 2 H), 4.05 (m, 1 H), 3.91 (s, 3 H)<3.69 (broad, 2 H), 2.18 (m, 2 H), 1.90-1.66 (m, 6 H); MS m/z 492 (M+1).
Reaction SMILES: NCCC1C=CC(O)=C(O)C=1.C[N:13]1[C@H:17]2[C@@H:18]([C:28](OC)=O)[C@@H:19]([C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)[CH2:20][C@@H]1CC2.[ClH:32].[ClH:33].FC1C=CC(C(C2C=CC(F)=CC=2)OCCN2CCN(CCCC3C=CC=CC=3)CC2)=CC=1.C1N(CCCC2C=CC=CC=2)CCN(CCOC(C2C=CC(F)=CC=2)C2C=CC(F)=CC=2)C1>>[ClH:32].[Cl:32][C:25]1[CH:26]=[C:21]([C:19]23[CH2:28][CH:18]2[CH2:17][NH:13][CH2:20]3)[CH:22]=[CH:23][C:24]=1[Cl:33]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Agent: Fc1ccc(C(OCCN2CCN(CCCc3ccccc3)CC2)c2ccc(F)cc2)cc1
Agent: NCCc1ccc(O)c(O)c1
Product: Clc1ccc(C23CNCC2C3)cc1Cl

Procedure:
The dopamine uptake transporter binding assay was performed according to the methods described in Madras et al., 1989, Mol. Pharmacol. 36(4):518-524 and Javitch et al., 1984, Mol. Pharmacol. 26(1):35-44. The receptor source was guinea pig striatal membranes; the radioligand was [3H]WIN 35,428 (DuPont-NEN, Boston, Mass.) (60-87 Ci/mmol) at a final ligand concentration of 2.0 nM; the non-specific determinant 1 μM 1-[2-[bis(4-Fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (“GBR 12909”), a high-affinity dopamine uptake inhibitor; reference compound was also GBR 12909. (−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl was obtained according to the method of Example 5, above. Reactions were carried out in 50 mM TRIS-HCl (pH 7.4), containing 120 mM NaCl and at 0° C. to 4° C. for two hours. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped in the filters was determined and compared to control values in order to ascertain the interactions of the test compound with the dopamine uptake site. The data are reported in Table 1 below.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](C(O)=O)=[CH:31]2.CCN=C=NCCCN(C)C.Cl.CCOC(C)=O.O(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:25][CH2:24][CH:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:16]=2[N:8]([C:6]([C:32]2[NH:33][C:34]3[C:30]([CH:31]=2)=[CH:29][C:28]([O:27][CH3:26])=[CH:36][CH:35]=3)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)cc2c1
Yield: 75.5 %

Procedure:
Deprotection of 13 (260 mg, 0.72 mmol) as in Example C, and reaction with 5-methoxyindole-2-carboxylic acid (145 mg, 0.76 mmol) and EDCI.HCl (344 mg, 1.80 mmol) in DMA (3 mL) gave 14d (237 mg, 76%), mp (2×EtOAc/iPr2O) 241-243° C. 1H NMR [(CD3)2SO] δ 11.73 (d, J=1.3 Hz, 1 H, NH), 9.16 (s, 1 H, H-4), 8.35 (dd, J=7.2, 2.5 Hz, 1 H, H-6), 8.23 (dd, J=6.9, 2.4 Hz, 1 H, H-9), 7.79-7.70 (m, 2 H, H-7,8), 7.42 (d, J=8.9 Hz, 1 H, H-7'), 7.20 (d, J=1.9 Hz, 1 H, H-3'), 7.17 (d, J=2.4 Hz, 1 H, H-4'), 6.94 (dd, J=9.0, 2.4 Hz, 1 H, H-6'), 4.93 (dd, J=10.6, 9.2 Hz, 1 H, H-2), 4.70 (dd, J=10.9, 2.4 Hz, 1 H, H-2), 4.65-4.57 (m, 1 H, H-1), 4.18-4.07 (m, 2 H, CH2Cl), 3.79 (s, 3 H, OCH3).
Reaction SMILES: [C:1](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[N:41]1([C:1]([O:2][C@@H:3]2[CH2:19][C@@H:18]3[C@@:6]([CH3:29])([C@@H:7]4[C@@H:15]([CH2:16][CH2:17]3)[C@:14]3([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]5[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=5)[CH2:12][CH2:13]3)[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)=[O:30])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: C1CNCCN1
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)N3CCNCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 69.1 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (29 mg, 0.054 mmol) in CH2Cl2 was added piperazine (46.4 mg, 0.54 mmol). The resultant mixture was stirred at rt for 16 h and then purified via preparative TLC to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (18.6 mg, 69.2%) as a white solid. LRMS (M+H−) m/z 499.5. 1H NMR (CD3OD, 400 MHz) δ 7.90 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J=9.6 Hz, 1H), 4.89 (m, 1H), 3.41 (m, 4H), 2.77-2.80 (m, 4H), 2.44-2.48 (m, 1H), 1.08-2.15 (m, 21H), 0.88 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](Cl)(Cl)=[O:10])=[CH:5][CH:4]=1.[CH2:13]1[CH2:17]OCC1.[CH:18]([Mg]Br)=[CH2:19]>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:10])([CH:18]=[CH2:19])[CH:13]=[CH2:17])=[CH:5][CH:4]=1
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Reactant: COc1ccc(P(=O)(Cl)Cl)cc1
Solvent: CCOCC
Product: C=CP(=O)(C=C)c1ccc(OC)cc1
Reaction time: 1 h

Procedure:
(4-Methoxyphenyl)phosphonic dichloride (2.00 g, 8.89 mmol) was made 0.1 M in 1:1 THF:ether and stirred at −78° C. To this stirring solution vinyl magnesium bromide (17.8 mL, 17.78 mmol, 1M in THF) was added dropwise. The mixture was stirred for 1 h, then quenched with 2M aq. HCl and extracted with DCM (3×). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to afford the requisite product. MS: cal'd 209 (MH+), exp 209 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][N:6]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:4]=1.CCO>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N2CCN(C)CC2)ncc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.1 %

Procedure:
2-Chloro-4-methoxy-5-nitropyridine (Frontier Scientific, Newark, Del.; 1.02 g, 5.40 mmol) and K2CO3 (895 mg, 6.48 mmol) were purged with argon, treated with DMF (10 mL) followed by 1-methylpiperazine (0.66 mL, 5.94 mmol). The reaction mixture was then heated to 60° C. for 3 h. The reaction mixture was cooled to RT and treated with water, extracted with EtOAc (2×100 mL), washed with brine (2×25 mL) and dried over MgSO4, filtered and concentrated affording crude 1-(4-methoxy-5-nitropyridin-2-yl)-4-methylpiperazine (1.36 g, 5.39 mmol, 99% yield). m/z (ESI, +ve ion) 252.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.88 (1H, s), 5.97 (1H, s), 3.97 (3H, s), 3.70-3.78 (4H, m), 2.47-2.55 (4H, m), 2.36 (3H, s). Pd/C (10 wt. %, 586 mg, 0.55 mmol) and 1-(4-methoxy-5-nitropyridin-2-yl)-4-methylpiperazine (1.36 g, 5.39 mmol) were treated with EtOH (20 mL) and EtOAc (20 mL) and stirred at RT overnight (18 h) under an atmosphere of hydrogen (balloon). The reaction mixture was filtered through a pad of Celite, washed with MeOH, and concentrated to dryness affording 4-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-amine (8a) (1.22 g, 5.77 mmol, 99% yield) as a purple viscous oil. m/z (ESI, +ve ion) 223.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.67 (1H, s), 6.17 (1H, s), 3.87 (3H, s), 3.37-3.45 (4H, m), 3.32 (2H, br. s.), 2.51-2.60 (4H, m), 2.36 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.[N:11]#[C:12][NH2:13].[Na].[CH3:15]I>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:11][C:12]#[N:13])[S:10][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: CI
Reactant: S=C=Nc1cccc(Cl)c1
Agent: [Na]
Solvent: CCO
Product: CSC(=NC#N)Nc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
Ten grams (59 mmol) of 3-chlorophenyl isothiocyanate and 4.15 g (65 mmol) of monosodium cyanamide are mixed in 100 cm3 of absolute ethanol and kept boiling for 2 hours. After elimination of the solvent, the resulting solid residue is washed with 100 cm3 of ethyl ether. The compound is then suspended in a solution of 4.8 cm3 (77 mmol) of methyl iodide in 50 cm3 of ethanol. The mixture is then left at ambient temperature for 20 hours. The final precipitate is filtered and washed with water (2×50 cm3) and ethanol (2×50 cm3) and is then dried in vacuo. A 10.1 gram portion of N-(3-chlorophenyl)-N'-cyano-S-methylisothiourea is obtained with a melting point of 167° C. ##STR88##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:24]3[CH:28]=[C:27]([CH:29]=O)[O:26][CH:25]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:31]#[N:32].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:24]3[CH:28]=[C:27]([CH2:29][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[O:26][CH:25]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:31]#[N:32]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4coc(C=O)c4)c(OC)cc23)c(Cl)cc1Cl
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4coc(CN5CCN(C)CC5)c4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(5-formyl-3-furyl)-6-methoxy-3-quinolinecarbonitrile (200 mg, 0.43 mmol) and 0.24 mL of N-methylpiperazine (2.2 mmol) in 5 mL of dichloromethane and 1 mL of dimethylformamide is cooled to 0° C. Sodium triacetoxyborohydride (470 mg, 2.22 mmol) is added in portions followed by a few drops of acetic acid. The resulting mixture is stirred at 0° C. for 10 minutes then at room temperature for 5.5 hours. The mixture is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 10% methanol in ethyl acetate to 1% ammonium hydroxide in a 1:4 mixture of methanol and ethyl acetate to provide 120 mg (51%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6 methoxy-7-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}-3-quinolinecarbonitrile as a light yellow solid, mp 179-181° C.; 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.23-2.36 (broad s, 4H), 2.38-2.49 (broad s, 4H), 3.54 (s, 2H), 3.87 (s, 3H), 4.06 (s, 3H), 7.01 (s, 1H), 7.33 (s, 1H), 7.74 (s, 1H), 7.94 (s, 1H), 8.10 (s, 1H), 8.28 (s, 1H), 8.43 (s, 1H), 9.82 (s, 1H); MS 552.1, 554.1 (M+H)+; HRMS calcd: 552.15638, found: 552.15599 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].C(NC(C)C)(C)C.Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[C:32]([S:40][CH:41]([CH3:43])[CH3:42])[CH:31]=2)=[CH:26][CH:25]=1>CN(C)C=O.C(OCC)(=O)C>[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C@@H:2]([NH:1][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[C:32]([S:40][CH:41]([CH3:42])[CH3:43])[CH:31]=2)=[CH:28][CH:29]=1)[CH3:12]
Reactant: COC(=O)c1ccc(-c2ccc(OCCBr)cc2)cc1SC(C)C
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)cc1SC(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a solution of 4-[(1R,2S)-2-amino-1-hydroxypropyl]-phenol (75.4 mg) in N,N-dimethylformamide (1 ml) were added diisopropylamine (72.9 μl) and methyl 4′-(2-bromoethoxy)-3-(isopropylthio)-4-biphenylcarboxylate (142 mg) in N,N-dimethylformamide (0.4 ml) at room temperature and stirred at 100° C. for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution, water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography to give methyl 4′-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-amino]ethoxy]-3-(isopropylthio)-4-biphenylcarboxylate (113 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14]>C(#N)C>[BrH:11].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][N:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[S:3][C:2]2=[NH:1])=[CH:16][CH:17]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CC#N
Product: Br
Product: N=c1sc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 7.5 parts of 2-aminobenzothiazole in 80 parts of acetonitrile are added 11.75 parts of 2-bromo-1-(4-chlorophenyl)ethanone and the whole is stirred for about 20 hours at room temperature. The precipitated product is filtered off, washed with acetonitrile, and dried, yielding 11.4 parts of 1-(4-chlorophenyl)-2-(2-imino-3(2H)-benzothiazolyl)ethanone hydrobromide; mp. 261°-272° C.