Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([I:41])[CH:36]=1>CN(C)C=O.C(OCC)(=O)C.O>[I:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]2=[N:3][C:2]=3[NH2:1])=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCc4cccc(I)c4)cc3C)cc12
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (B-4), 1.0 equiv. in dimethylformamide (0.10 M) at 22° C. was added cesium carbonate (1.5 equiv.) and the resulting mixture was allowed to stir for 30 minutes. At this point, 1-(bromomethyl)-3-iodobenzene (1.5 equiv.) was added to this mixture. The reaction mixture was allowed to stir at 55° C. for 18 hours, after which it was diluted with ethyl acetate and water. The biphasic layers were separated and the organic layer was washed twice with water. The organic layer was dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexanes gradient to provide 2-(4-(3-iodobenzyloxy)-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (4-1) as a solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1
Reactant: Cc1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncc(-c2cc(Oc3ccc(N)nc3)ccn2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.5 %

Procedure:
A 0° C. mixture of 2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)oxazole (323 mg, 1.083 mmol) and NH4Cl (2.317 g, 43.3 mmol) in MeOH (8 mL) and THF (8 mL) was treated portion-wise with zinc dust (708 mg, 10.83 mmol), allowed to warm to RT and stirred overnight. The mixture was diluted with EtOAc, warmed slightly, the solids removed via filtration through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to dryness, treated with EtOAc, heated to reflux, the solids removed via hot filtration and the filtrate concentrated to dryness to afford 5-((2-(2-methyloxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (324 mg, 112%). 1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J=5.7 Hz, 1 H), 7.83 (d, J=2.9 Hz, 1 H), 7.60 (s, 1 H), 7.31 (dd, J=8.9, 3.0 Hz, 1 H), 7.06 (d, J=2.5 Hz, 1 H), 6.83 (dd, J=5.7, 2.5 Hz, 1 H), 6.53 (d, J=8.9 Hz, 1 H), 6.07 (s, 2 H), 2.46 (s, 3 H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:15])[C:4]=1[F:16].[K+].[Br-].[CH3:19]O>>[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([O:9][CH3:19])=[O:8])=[C:5]([F:15])[C:4]=1[F:16]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Reactant: CO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Reaction time: 23 h
Yield: 70 %

Procedure:
Hydrogen chloride gas was dissolved in anhydrous methanol (30 ml) until the solution was warm. The solid 4-amino-2,3-difluoro-5-nitrobenzoic acid (0.47 g; 0.00215 mol) was dissolved in this solution and the reaction mixture was brought to reflux with vigorous stirring for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool slowly on the bench. A yellow precipitate formed and was collected by vacuum filtration and dried with suction to afford 0.35 g of yellow microfilaments; 70% yield; m.p. 183.5–184° C.; 1H-NMR (400 MHz; DMSO) δ 8.36 (dd, 1H, J=7.3, 1.7 Hz), 8.06 (s, 2H), 3.78 (s, 3H); 19F-NMR (376 MHz; DMSO) δ −128.85 to −128.92 (m), −153.29 (d); MS (APCl−) 231 (M−1, 100); IR (KBr) 3433, 3322, 1700, 1650, 1549, 1343, 1285 cm−1; Anal. calcd/found for: C8H6F2N2O4 C, 41.39/41.40; H, 2.61/2.50; N, 12.07/11.98; F, 16.37/16.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[C:14]1[CH:15]=C(C=C(OC(C)C)[CH:23]=1)C(OC)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]([CH3:15])[CH3:23])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(OC(C)C)c1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1

Procedure:
Prepared from methyl 3-chloro-4-hydroxybenzoate according to the procedure for methyl 3-bromo-5-isopropoxybenzoate. LCMS-ESI (m/z) calculated for C11H13ClO3: 228.7; found 229.1 [M+H]+, tR=3.90 min. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=2.1 Hz, 1H), 7.89 (dd, J=8.7, 2.2 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 4.67 (dt, J=12.2, 6.1 Hz, 1H), 3.89 (s, 3H), 1.37 (dd, J=34.4, 30.1 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:23])[CH:14]=2)=[N:4][C:5]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH3:32]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:23])[CH:14]=2)=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:31][CH3:32])[CH:12]=2)=[CH:6][N:7]=1
Reactant: CCBr
Reactant: COC(=O)c1ccc(-c2nc(-c3cn[nH]c3)cnc2N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2cnc(N)c(-c3ccc(C(=O)OC)c(F)c3)n2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.7 %

Procedure:
To methyl 4-(3-amino-6-(1H-pyrazol-4-yl) pyrazin-2-yl)-2-fluorobenzoate (45 mg, 0.115 mmol) in DMF (2 mL) was added potassium carbonate (47.6 mg, 0.345 mmol), followed by bromoethane (0.017 mL, 0.230 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixtures was partitioned between ethylacetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, evaporated and purified by flash chromatography eluting with 0-60% of EtOAc (contains 10% of MeOH)/heptane to yield the desired product (25 mg, 64%, 80% purity). LCMS (m/z): 342.0 (MH+), 0.73 min.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(Cl)(=O)[C:22](Cl)=[O:23].[I:27][C:28]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[C:29]=1C(O)=O>>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])[C:22](=[O:23])[C:36]4[CH:35]=[C:34]([O:37][CH3:38])[C:33]([O:39][CH3:40])=[CH:29][C:28]=4[I:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)CCCNc1ccnc2cc3c(cc12)OCO3
Reactant: COc1ccc(I)c(C(=O)O)c1OC
Product: COc1cc(I)c(C(=O)N(CCCN(C)C)c2ccnc3cc4c(cc23)OCO4)cc1OC
Yield: 79 %

Procedure:
Prepared from N′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane-1,3-diamine (273 mg, 1.0 mmol), in 79% yield with a reaction time of 12 h, from the acid chloride prepared using 4.0 mmol of oxalyl chloride and 1.36 mmol of 2-iodo-5,6-dimethoxybenzoic acid. Compound 7e had: IR(CHCl3) 1650; 1H NMR (CDCl3) δ 1.93 (m, 1H), 2.16 (m, 1H), 2.34 (s, 6H), 2.58 (m, 1H), 3.31 (s, 3H), 3.47 (m, 1H), 3.75 (s, 3H), 3.95 (m, 1H,), 4.55, (m, 1H), 6.16 (s, 1H), 6.39 (s, 1H), 7.04 (s, 1H), 7.28 (d, 1H, J=5.0), 7.31 (s, 1H), 7.38 (s, 1H), 8.56 (d, 1 h, J=5.0); 13C NMR (CDCl3) δ 25.8, 45.1, 47.2, 55.5, 56.1, 26.9, 82.7, 98.1, 102.3, 107.0, 110.1, 120.1, 121.5, 122.5, 133.5, 145.5, 148.1, 148.4, 148.6, 149.2, 149.7, 151.1, 170.1; HRMS calcd for C24H26IN3O5H, 564.0995; found 564.0990.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1.[N:19]1([C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[CH3:18][O:17][C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:22]1[CH2:23][CH2:24][N:19]([C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:20][CH2:21]1)=[O:16]
Reactant: COC(=O)c1ccc2[nH]cc(CCCCCl)c2c1
Reactant: c1cc2c(cc1N1CCNCC1)OCCO2
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1

Procedure:
A solution of 3.6 g of 3-(4-chlorobutyl)-5-methoxycarbonylindole [obtainable by reaction of 5-methoxycarbonylindole with 4-chlorobutyryl chloride to give 3-(4-chlorobutyryl)-5-methoxy indole and subsequent reduction with diborane to give 3-(4-chlorobutyl)-5-methoxycarbonylindole] and 3.4 g of 6-piperazino-1,4-benzodioxane ("A") in 200 ml of acetonitrile is stirred at room temperature for 14 hours and worked up in the conventional manner to give 6-[4-(4-(5-methoxycarbonyl indol-3-yl)butyl)piperazino]-1,4-benzodioxane, m.p. 177-179° (dihydrochloride).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=4)=[N:15][N:14]4[CH2:24][CH2:25][CH2:26][C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CCCC)CCCC)CCC.[C:40]([O:44][CH3:45])(=[O:43])[CH:41]=[CH2:42].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C)C=O>[CH3:45][O:44][C:40](=[O:43])[CH:41]=[CH:42][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=4)=[N:15][N:14]4[CH2:24][CH2:25][CH2:26][C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(Br)ccc24)CCC3)n1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Nitrogen is bubbled through a solution of 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline (0.050 g, 0.12 mmol), tributylamine (0.032 mL, 0.17 mmol), methyl acrylate (0.027 mL, 0.24 mmol), and N,N-dimethylformamide (0.5 mL) in toluene (1.0 mL) for 20 min. Pd(OAc)2 (0.002 g, 0.006 mmol) and tri(o-tolyl)phosphine (0.007 g, 0.021 mmol) are added and nitrogen bubbled through the reaction mixture for 10 min. The mixture is heated to 80° C. for 24 h. An additional portion of Pd(OAc)2 (0.002 g, 0.006 mmol) and tri(o-tolyl)phosphine (0.007 g, 0.021 mmol) is added and heating continues for another 24 h. The reaction is cooled and concentrated in vacuo and the residue chromatographed on SiO2 (2% methanol in methylene choloride) to yield the title compound, 0.49 g (97%), as a yellowish solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClC1C=CC(N(C2CCNCC2)C(=O)[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47]C)[CH:42]=2)=CC=1.C12OC1CCCC2>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C@@H:42]3[CH2:41][CH2:46][CH2:45][CH2:44][C@H:43]3[OH:47])[CH2:13][CH2:12]2)[C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:26][CH:27]=1
Reactant: COc1cccc(C(=O)N(c2ccc(Cl)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COc1cccc(C(=O)N(c2ccc(Cl)cc2)C2CCNCC2)c1
Agent: C1CCC2OC2C1
Product: COc1cccc(C(=O)N(c2ccc(Cl)cc2)C2CCN([C@@H]3CCCC[C@H]3O)CC2)c1

Procedure:
The title compound, MS (ISP): m/e=519.4 (M+H+), white foam, was prepared as for example 98, steps (A) to (F). Step (A) was performed using 4-chloro-aniline, and yielded 4-(4-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester which was acylated to 4-[(4-chloro-phenyl)-(3-methoxy-benzoyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester in step (B). This was then deprotected to N-(4-chloro-phenyl)-3-methoxy-N-piperidin-4-yl-benzamide (C), and reacted with cyclohexene oxide to give (+/−)—N-(4-chloro-phenyl)-N-[trans-1-(2-hydroxy-cyclohexyl)-piperidin-4-yl]-3-methoxy-benzamide [step (D)]. Oxidation to (+/−)-N-(4-chloro-phenyl)-3-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzamide in step (E) and reaction with phenyl lithium [step (F)] led to the title compound of the example.
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH2:14].[Cl-].[C:16]([O:27][CH3:28])(=[O:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21]([O-])=[O:22])=[CH:19][CH:18]=1.Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:21]([C:20]1[CH:24]=[CH:25][C:17]([C:16]([O:27][CH3:28])=[O:26])=[CH:18][CH:19]=1)=[O:22]
Reactant: Nc1cc2c3c(c1)CCCC3CCC2
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A solution of 5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.260 g) in anhydrous benzene (10 ml) and pyridine (3 ml) was added with monomethyl terephthalate chloride (0.304 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.460 g, yield: 95%) as colorless needles (melting point: 217-218° C.).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH2:5])=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(#N)C>[Cl-:1].[NH2:5][C:3](=[O:4])[CH2:2][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)CCl
Reactant: c1ccncc1
Solvent: CC#N
Product: NC(=O)C[n+]1ccccc1
Product: [Cl-]
Temperature: 90 °C
Reaction time: 10 h
Yield: 87.5 %

Procedure:
To a suspension of 2-chloroacetamide (50.00 g, 524.01 mmol) in 100 mL of acetonitrile was added pyridine (41.45 g, 524.01 mmol). After being stirred at 90° C. for 10 h, the suspension was cooled to 22° C., suction-filtered and washed with 100 mL of hexanes. The product, 1-(2-amino-2-oxoethyl)pyridinium chloride (79.10 g, yield: 87%, mp 205.2° C.), was obtained as colorless crystals after being recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17]CN(C(C)(C)C(N(C)C)=O)C[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:32][N:33]([CH3:40])[CH:34]1[CH2:39][CH2:38]CNC1>>[Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][CH2:38][CH2:39][CH:34]([N:33]([CH3:40])[CH3:32])[CH2:17]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C1CCCNC1
Reactant: CN(C)C(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CN(C)C1CCCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1

Procedure:
Prepared using the method used in the preparation of 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-isobutyramide using dimethyl-piperidin-3-yl-amine in place of N,N-dimethyl-2-piperazin-1-yl-isobutyramide. The title compound was obtained as an off-white solid (180 mg, 76%).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=O)[S:14][CH:15]=2)=[CH:8][CH:7]=1.[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].C([O-])(=O)C.[Na+]>O>[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:26]3[S:20][C:21](=[S:22])[NH:23][C:24]3=[O:25])[S:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1cc(Cc2ccc(Cl)cc2)cs1
Temperature: 80 °C
Yield: 81 %

Procedure:
To a 20-mL scintillation vial fitted with a magnetic stir bar was added 3 mL of glacial acetic acid (AcOH). The vial was capped tightly and heated to 80° C. To the hot AcOH was added 4-(4-chlorobenzyl)thiophene-2-carbaldehyde (example 1.1.a); 0.37 g, 1.56 mmol, 1 equiv) and rhodanine (0.23 g, 1.7 mmol, 1.1 equiv) with stirring until a solution was formed. To the mixture was then added anhydrous sodium acetate (0.45 g, 5.5 mmol, 3.5 equiv), and the vial was capped tightly and heated to 110° C. for approx. 1 h. The reaction vial was cooled to rt and the contents were poured into water. The resulting precipitate was filtered, washed with water and a cold mixture of 1:1 water/ethanol. The solid was dried thoroughly in vacuo at 40° C. to give 5-((4-(4-chlorobenzyl)thiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (451 mg, 81%). 1H NMR (400 MHz, (CD3)2SO) δ (ppm): 7.70 (s, 1H), 7.67 (s, 1H), 7.46 (s, 1H), 7.34-7.38 (m, 2H), 7.25-7.29 (m, 2H), 3.96 (s, 2H).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]([CH:13](P(OC)(OC)=O)[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12].[CH3:31][Si:32]([CH3:50])([CH3:49])[CH2:33][CH2:34][S:35]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([CH:47]=O)=[CH:44][CH:45]=2)[CH:40]=[CH:39]1)(=[O:37])=[O:36]>O1CCCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[CH:47][C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:38]([S:35]([CH2:34][CH2:33][Si:32]([CH3:31])([CH3:50])[CH3:49])(=[O:36])=[O:37])[CH:39]=[CH:40]2
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(C=O)ccc21
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,1,3,3-Tetramethylguanidine (0.68 mL, 5.43 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-α-phophonoglycine trimethyl ester (1.88 g, 5.69 mmol) in tetrahydrofuran (40 mL). The mixture was stirred at room temperature for 15 min and cooled to −78° C., and a solution of 1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indole-5-carbaldehyde (1.6 g, 5.17 mmol) in tetrahydrofuran (15 mL) was added slowly. The resulting reaction mixture was stirred at −78° C. for 2 h and then warmed to room temperature in 3 h. Solvents were removed in vacuo and the residue was subjected to flash chromatography on silica gel using methylene chloride/hexanes (1:1.5) with 1% triethylamine as eluent to afford the title compound as a 92:8 Z/E mixture (determined by integration of CO2CH3, for Z isomer at 3.79 ppm, and E isomer at 3.65 ppm). For the Z isomer: 1H-NMR (CD3CN, 500 MHz) δ 7.96 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.56 (d, J=3.7 Hz, 1H), 7.51 (s, 1H), 7.43-7.35 (m, 5H), 7.67 (d, J=3.7 Hz, 1H), 5.16 (s, 2H), 3.79 (s, 3H), 3.42-3.38 (m, 2H), 0.87-0.83 (m, 2H), −0.04 (s, 9H). Mass spec. 515.20 (MH)+.
Reaction SMILES: [N+](C1C=CC(C([NH:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=O)=CC=1)([O-])=O.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:36])=[O:35])=[CH:32][CH:33]=1)([O-:27])=[O:26]
Reactant: O=C(NCCN1CCc2ccccc2C1)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCCN2CCc3ccccc3C2)cc1

Procedure:
The title compound was prepared by Method A using 2-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinoline (described in Example 174) and 4-nitrobenzenesulfonyl chloride to produce the desired product in 98% yield. This material was crystallized from EtOAc to afford a gold-colored solid; mp 142.5°-144.5° C.; IR (KBr) 3372, 3110, 2778, 1929, 1603, 1521, 1305, 1151, 969 and 739 cm-.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21](O)=[O:22])=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1(NC(NC2CCCCC2)=O)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH:9][C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:10]=[CH:11][CH:12]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Product: O=C(Cc1ccc2ncccc2c1)NNc1ccc(Cl)nn1
Temperature: 25 °C

Procedure:
To a suspension of 3-chloro-6-hydrazinylpyridazine (3 g, 20.75 mmol) and 2-(quinolin-6-yl)acetic acid (4.27 g, 22.83 mmol) in 200 ml DCM was added DCC (5.14 g, 24.90 mmol). The solution was stirred at room temperature for overweekend. The title compound as a white solid containing dicyclohexyl urea was filtered and used in the next step without further purification (8 g, 100%). LCMS (method A): [MH]+=314.1, tR=2.85 min.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH3:5].[CH2:6]([NH-:11])[CH2:7][CH:8]([CH3:10])[CH3:9].Cl>O1CCCC1.CO>[CH2:6]([NH:11][CH2:5][CH2:4][CH2:3][S:2][CH3:1])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CC[NH-]
Reactant: CCCSC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CSCCCNCCC(C)C
Reaction time: 8 h

Procedure:
The amide from (a) (1.9 g) in tetrahydrofuran (20 ml) was treated under nitrogen at 0° with boranetetrahydrofuran complex (1 Molar in tetrahydrofuran 20 ml) and stirred overnight. 2 Molar hydrogen chloride in methanol (20 ml) was added and the mixture was boiled for 30 minutes, evaporated and the residue partitioned between ethyl acetate and water. The aqueous layer was basified and extracted with ether. The dried extract was evaporated to give the amine an oil (1.6 g). Rf3A=0.72, Rf7B=0.63, Rf4A=0.74
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[NH2:30].CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[NH:30][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC2=NC(=O)/C(=C/c3ccc4ncncc4c3)S2)c(OC)c1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 2,4-dimethoxy-phenylamine and DIEA to give 2-(2,4-dimethoxy-phenylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 393 (MH+).