Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([Cl:12])[N:4]=1)#[N:2].[CH2:13]([SH:15])[CH3:14].N1C=CC=CC=1>CC(C)=O.O>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([Cl:12])=[C:6]([S:15][CH2:13][CH3:14])[N:7]=1)#[N:10]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: CCS
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: CCSc1nc(C#N)c(C#N)nc1Cl
Yield: 29.4 %

Procedure:
2,3-Dicyano-5,6-dichloropyrazine (1.00 g; 0.005 mole) and 0.47 g of ethanethiol were dissolved in 50 ml of acetone. The solution was cooled to -15° to -10° C., and a solution of 0.40 g (0.005 mole) of pyridine in 40 ml of water was added dropwise over the period of 30 minutes. The mixture was worked up in the same way as in Example 26 to afford 0.33 g (yield 29%) of 2,3-dicyano-5-chloro-6-ethylthiopyrazine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([OH:12])=O)=[N:3]1.Cl.[CH3:21][O:22][NH:23][CH3:24].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(N(CC)CC)C>[CH3:21][O:22][N:23]([CH3:24])[C:10](=[O:12])[CH:9]([C:4]1[CH:5]=[C:6]([S:7][CH3:8])[N:2]([CH3:1])[N:3]=1)[CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CNOC
Reactant: CSc1cc(C(CC2CCOCC2)C(=O)O)nn1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(CC1CCOCC1)c1cc(SC)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a mixture of 2-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (1.09 g), N-methoxymethanamine hydrochloride (0.75 g), 1H-1,2,3-benzotriazol-1-ol (0.70 g), triethylamine (1.1 mL) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.88 g) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO1), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (0.80 g, yield 63%) as a colorless oil from the fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 328 (MH+).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:14]([NH2:26])[CH2:15][C:16]1[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[C:18]([O:19][CH3:20])[CH:17]=1.C(N(CC)CC)C>C(OCC)(=O)C.C(OCC)C>[CH3:20][O:19][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][NH:26][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:25]=[CH:24][C:21]=1[O:22][CH3:23]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)C23CC4CC(CC(C4)C2)C3)cc1OC

Procedure:
Subject 2.0 g. of adamantane carboxylic acid chloride 1.8 g. (10.0 mmoles) of homoveratrylamine and 5.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from an ethyl acetate-ethyl ether mixture to obtain the title product, m.p. 132°-133°C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][C:14]=2[O:25][CH3:26])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:27])[NH:7]2.N1C(C)=CC=CC=1C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.[OH-].[Na+].Cl>C1COCC1.CCOC(C)=O.O>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:1][C:2]2[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[O:25][CH3:26])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:27])[NH:7]3)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3[nH]c(=O)ccc3c2N)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(=O)ccc2c1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 25.3 (25 mg, 0.068 mmol) and 2,6-lutidine (0.033 mL, 0.28 mmol) in THF (0.1 mL) was added 4-chlorobenzenesulfonyl chloride (30 mg, 0.14 mmol). The mixture was stirred at 70° C. overnight. After cooling, water (0.1 mL) and 10N NaOH (0.1 mL) were added. The mixture was stirred at room temperature for 5 h. 3N HCl (0.35 mL) and EtOAc were added to the mixture, and the organic layer was separated, dried with MgSO4 and concentrated. Flash column chromatography of the residue afforded 25. MS ESI (pos.) m/z: 544.1 (M+H). 1H NMR (DMSO-d6) δ 12.32 (bs, 1H); 11.74 (s, 1H); 10.14 (s, 1H); 8.06 (d, 1H); 7.68 (d, 2H); 7.50 (d, 2H); 7.16 (d, 1H); 6.96 (s, 1H); 6.72 (m, 2H); 6.56 (d, 1H); 6.27 (d, 1H); 3.66 (s, 3H); 3.54 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9](=O)[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH2:19][C:20]#[CH:21])=[C:12]([O:22][CH3:23])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][NH:8][C:9]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH2:19][C:20]#[CH:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[S:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C#CCOc1c(OC)cc(C(=O)NCC2CCCCC2)cc1OC
Solvent: Cc1ccccc1
Product: C#CCOc1c(OC)cc(C(=S)NCC2CCCCC2)cc1OC
Yield: 63.6 %

Procedure:
To 30 ml of toluene were added 1.2 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3,5-dimethoxybenzamide and 1.8 g of Lawesson's Reagent and the mixture obtained was heated under reflux for 2 hours. Then, the reaction mixture was concentrated. The residue was subjected to silica gel column chromatography to obtain 0.80 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3,5-dimethoxybenzenethioamide (hereinafter, described as the compound 33 of the present invention) represented by the formula:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[C:13](=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[N:15]=[CH:16][N:17]=3)[C:12]1=2)(C(C)(C)C)(C)C.Cl>CO>[N:30]1([CH:27]2[CH2:26][CH2:25][CH:24]([O:23][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:13]=3[C:12]3[C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:29][CH2:28]2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: Cl
Solvent: CO
Product: OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (230 mg, 0.44 mmol, 1.00 equiv) dissolved in methanol (10 mL) was added hydrochloric acid (12 M, 0.5 mL) slowly at 0° C. The resulting solution was stirred for 2 hr at room temperature and then quenched with saturated aqueous sodium bicarbonate, extracted with 3×50 mL of ethyl acetate. The combined organic layers were concentrated under vacuum. The crude product (200 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (25% CH3CN up to 100% in 15 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]ethan-1-ol (94 mg) as a white solid. MS (ES): m/z 404 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.48 (1H, s), 5.29 (1H, m) 3.76 (4H, m), 3.66 (3H, m), 3.10-2.95 (2H, m), 2.72 (5H, m), 2.69 (1H, s), 2.41 (3H, m), 2.36 (1H, m), 2.15 (2H, m), 1.73-1.54 (5H, m).
Reaction SMILES: C=O.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]1)[CH2:9]2)([O-])=O.[CH3:21]C(O)=O.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH3:21][NH:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]1)[CH2:9]2
Reactant: CC(=O)O
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reaction time: 4 h

Procedure:
To a stirred mixture of formaldehyde (0.026 mL of a 37 wt % aqueous solution, 0.32 mmol), (±)-5′-amino-spiro[imidazolidine-4,2′-indane]-2,5-dione (described in Intermediate 45) (50 mg, 0.23 mmol), and AcOH (0.053 mL, 0.92 mmol) in MeOH (3 mL) at ambient temperature was added sodium cyanoborohydride (0.34 mL of a 1 M solution in THF, 0.34 mmol) and the reaction mixture was stirred for 4 h, then concentrated ill vacuo. The residue was partioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was removed, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as an off-white solid. MS: m/z=232 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:15][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[C:22]([Si:19]([O:18][CH2:17][CH2:16][CH2:15][O:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]=1[O:9][CH3:10])([CH3:20])[CH3:21])([CH3:24])([CH3:25])[CH3:23]
Reactant: COc1cc([N+](=O)[O-])c(F)cc1O
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(F)cc1OCCCO[Si](C)(C)C(C)(C)C
Yield: 69.8 %

Procedure:
A mixture of 0.350 g (1.87 mmole) of 5-fluoro-2-methoxy-4-nitro-phenol, 0.568 g (2.25 mmole) of (3-bromo-propoxy)-tert-butyl-dimethyl-silane, 1.29 g (9.35 mmole) of potassium carbonate and 5 mL of dimethylformamide was heated at 60 degrees for 3 hours. The mixture was cooled, poured into 50 mL of dilute ammonium chloride solution and extracted three times with 25 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-hexanes (60:40) to give 0.469 g of tert-butyl-[3-(5-fluoro-2-methoxy-4-nitro-phenoxy)-propoxy]-dimethyl-silane (IV.42) as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:11][C:12]1[C:20]2[C:19]([NH2:21])=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]([CH2:22][C:23]2[S:27][C:26]([CH3:28])=[N:25][CH:24]=2)[N:13]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]3[C:45]([C:48](OCC)=[O:49])=[CH:46][N:47]=[C:41]3[CH:40]=2)[CH2:32][CH2:31]1>C1COCC1.O>[I:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[NH:21][C:48]([C:45]2[N:42]3[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[CH:40][C:41]3=[N:47][CH:46]=2)=[O:49])[N:14]([CH2:22][C:23]2[S:27][C:26]([CH3:28])=[N:25][CH:24]=2)[N:13]=1
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Reactant: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(Cn2nc(I)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Temperature: 25 °C
Yield: 16.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.24 mL) was added dropwise at ambient temperature and under a nitrogen atmosphere to a solution of 3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-amine (40 mg, 0.108 mmol) in anhydrous THF (3 mL). The resulting brown mixture was added via syringe to a cooled (ice-water bath) solution of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation D; 35.9 mg, 0.108 mmol) in anhydrous THF (3 mL). The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with water, and extracted multiple times with dichloromethane. The dichloromethane extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, 7 N ammonia/MeOH:MeOH:DCM in a 3:7:90 ratio as eluent) to afford the product (11.6 mg) as a tan solid. MS (ES+APCI) m/z=657 (M+H).
Reaction SMILES: Cl.C(O[C:5](=[NH:16])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].C(=O)(O)[O-].[Na+].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH:31][NH2:32])=[O:30]>C(Cl)(Cl)Cl>[C:10]1([S:7]([CH2:6][C:5]([NH:32][NH:31][C:29]([C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)=[O:30])=[NH:16])(=[O:8])=[O:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NNC(=O)c1cccs1
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N=C(CS(=O)(=O)c1ccccc1)NNC(=O)c1cccs1

Procedure:
A suspension of 13.2 g (0.05 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 110 ml chloroform was treated with 50 ml 1N aqueous sodium hydoxide. 20 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 7.82 g (0.05 mol) 2-thiophencarboxylic acid hydrazide in 75 ml chloroform for 24 hours at 50° C. The resulting precipitate was filtered off and dried. A quantitative yield thiophene-2-carboxylic acid N′-(2-benzenesulfonyl-1-imino-ethyl)-hydrazide was obtained as white crystals. MS m/e (%): 324 (M+H+, 100).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:10][C:9]=2[CH:20]=1)(=O)C.C([O-])C.[Na+]>C(O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:10][C:9]=2[CH:20]=1
Reactant: CCOC(=O)CC1=COc2ccc(OC(C)=O)cc2O1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1=COc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.84 g (3.78 mmol) of the ester obtained in Step A is dissolved in 20 ml of anhydrous ethanol; the medium is then adjusted to a basic pH using a molar solution of sodium ethanolate (0.5 ml). After 18 hours of stirring under an inert atmosphere and at ambient temperature, the reaction mixture is neutralised with DOWEX X-8 resin (acid form). The solid is then filtered off; the filtrate is then concentrated in vacuo. The residue obtained is purified on a silica column (eluant: AcOEt/PE: 50150) to yield the title compound in the form of a white solid.
Reaction SMILES: [C:1]([CH:4]([NH:16][C:17](=[O:33])[NH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6])(=[O:3])[NH2:2].Br[CH2:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OCC)C>[C:1]([CH:4]([NH:16][C:17](=[O:33])[NH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:35][CH2:36][CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])[CH:8]=1)=[O:6])(=[O:3])[NH2:2]
Reactant: CCOC(=O)n1cc(NC(=O)NC(C(N)=O)C(=O)c2c[nH]c3ccccc23)c2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)n1cc(NC(=O)NC(C(N)=O)C(=O)c2cn(CCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
A solution of 0.10 g (0.223 mmol) of the product from step d), 0.15 g (0.56 mmol) of N-(3-bromopropyl)phthalimide, 0.10 g (0.72 mmol) of K2CO3 and 1.5 ml of DMF. The flask was sealed and heated to 65° C. for 5 hours. The reaction mixture was partitioned between 10 ml of EtOAc and 10 ml of water. The organic phase was collected and the aqueous phase was extracted with an additional 10 ml of EtOAc. The combined organic phases were washed with water and brine. The organic phase was evaporated to give a yellowish solid. The solid was suspended in 20 ml of diethyl ether and stirred for 30 minutes. The precipitate was allowed to settle and the ethereal phase was removed. The residual precipitate was dried in vacuum to give 100 mg (70%) of the sub-title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[OH:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>>[NH2:9][C:8]1[O:19][C:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:26]=3[CH:27]=[CH:28][C:29]=2[CH:6]([C:5]2[CH:12]=[C:13]([O:17][CH3:18])[C:14]([O:15][CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:7]=1[C:10]#[N:11]
Reactant: COc1cc(C=C(C#N)C#N)cc(OC)c1OC
Reactant: Oc1cccc2ncccc12
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ncccc32)cc(OC)c1OC

Procedure:
The title compound was prepared from 3,4,5-trimethoxybenzylidenemalononitrile (244 mg, 1 mmol) and 5-hydroxyquinoline by a procedure similar to that described for Example 145.11H NMR (CDCl3): 8.96 (m, 1H), 8.52 (d, J=8.7, 1H), 7.82 (d, J=9.0, 1H), 7.52 (m, 1H), 7.33 (d, J=8.7, 1H), 6.43 (s, 2H), 4.83 (m, 3H), 3.83 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[O:23][CH3:24].C([O-])(=O)C.[Na+]>OS(O)(=O)=O.C(Cl)(Cl)(Cl)Cl>[Cl:22][C:19]1[CH:18]=[C:17]([O:23][CH3:24])[C:16]([Cl:15])=[CH:21][C:20]=1[C:3]1[CH:5]=[C:6]([Cl:10])[C:7]([Cl:9])=[CH:8][C:2]=1[Cl:1]
Reactant: COc1cc(Cl)ccc1Cl
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Cl)c(-c2cc(Cl)c(Cl)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 22.4 %

Procedure:
To a suspension of 2,4,5-trichloroaniline (1.96 g, 10 mmol) in 30 mL 35% H2SO4 in an ice/salt bath (below 0° C.) was added a solution of sodium nitrite (0.828 mg, 12 mmol) in 50 ml cold distilled water. The yellow mixture was allowed to stir below 0° C. for 45 minutes at which time it was added to a vigorously stirred solution of 2,5-dichloroanisole (1.76 g, 10 mmol) in 100 mL CCl4 below 0° C. Saturated sodium acetate solution was added until a pH≧7 was obtained. The resulting mixture was allowed to warm to room temperature, then stirred 18 h. The reaction was extracted with several portions of CH2Cl2 and the combined organic layers were dried with anhydrous Na2SO4, filtered, then concentrated to a heavy oil. The oil was distilled (150-200° C., 0.2 mm Hg) through a Kugelrhor apparatus to yield 0.8 g of a dark yellow oil. The distillate was further purified via flash chromatography (silica gel, hexane eluent). Fraction 1 (40 mg; Rf=0.38; GC retention time=16.32 minutes) was identified as 2,2′,4′,5,5′-pentachloro-6-methoxybiphenyl. Fraction 2 (262 mg, 7.4% yield; Rf=0.33) was found to contain 2,5,2′,4′,5′-pentachloro-3-methoxy and 2,5,2′,4′,5′-pentachloro-4-methoxybiphenyl in a 17:83 ratio as determined by GC (RT=17.58, 17.75 minutes respectively) and NMR analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C(Cl)(Cl)Cl>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22])[CH3:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.8 %

Procedure:
To a solution of 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 3.0 mL chloroform were added 9.3 mg (0.131 mMol) ethyl isocyanate. The reaction was mixed for 48 hours and to it were then added 0.23 gm (0.131 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 16.1 mg (82%) of the title compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][S:14][C:15]1[C:16]2[CH:23]=[CH:22][S:21][C:17]=2[N:18]=[CH:19][N:20]=1.[I:24]I.[NH4+].[Cl-]>C1COCC1.O>[CH3:13][S:14][C:15]1[C:16]2[CH:23]=[C:22]([I:24])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CSc1ncnc2sccc12
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1ncnc2sc(I)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
Butyllithium (1.6 M in hexane, 32.8 mL) was added dropwise to a stirred solution of diisopropylamine (7.36 mL) in THF (170 mL) at −78° C. under an inert atmosphere. The reaction mixture was warmed to 0° C., stirred for 20 min, recooled to −78° C. and 4-(methylthio)thieno[2,3-d]pyrimidine (J. Heterocycl. Chem. 1975, 12, 921-924) (9.11 g) in THF (17 mL) added. A purple solution resulted and then iodine (19.0 g) in THF (20 mL) was added and stirring at −78° C. continued for 1 hours before warming to ambient temperature and stirring for a further 1.5 hr. Saturated aqueous NH4Cl (3 mL), then water (500 mL) were added and the reaction mixture extracted with DCM (500 mL), the organic layer was washed with Na2S2O3 (2M, aq) (2×50 mL), water (2×200 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was triturated with DCM (50 mL) to afford the title compound as a brown solid (11.8 g, 77%);
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[N:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14][CH2:13]2>C(O)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:15]3[CH:16]4[CH2:19][CH2:20][N:12]([CH2:13][C:14]=3[C:6]=2[CH:5]=1)[CH2:18][CH2:17]4.[ClH:1]
Reactant: O=C1CCN2CCC1CC2
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Brc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of HCl in acetic acid (1 M, 30 mL) was added under nitrogen to a mixture of 4-bromophenylhydrazine hydrochloride (4.33 g, 19.37 mmol; Aldrich) and 1-azabicyclo[3.2.2]nonan-4-one (2.70 g, 19.37 mmol; Example 2A). The mixture was stirred at room temperature for 16 hours, then heated at 75° C. for 3 hours. The mixture was cooled to room temperature and concentrated under vacuum to remove most of the acetic acid. Anhydrous ethanol (100 mL) was added to the residue, and the mixture was heated at reflux for 10 minutes, then cooled to room temperature. The precipitate was collected by filtration, washed with ethanol (25 mL) and dried under vacuum to provide the title compound as its HCl salt (3.02 g). A portion of this salt (400 mg) was partitioned between 20% NaOH (25 mL) and chloroform (50 mL) and the organic phase was dried (sodium sulfate) and concentrated. The residue was crystallized from ethyl acetate-ethanol (5:1) to provide the free base of title compound: 1H NMR (300 MHz, methanol-d4) δ 2.14-2.36 (m, 4H), 3.17-3.25 (m, 1H), 3.33-3.45 (m, 2H), 3.45-3.65 (m, 2H), 4.54 (s, 2H), 7.18 (dd, J=8.8, 1.8 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 7.51 ppm (d, J=2.4 Hz, 1H); MS(DCI) m/z 291/293 (M+H)+.