Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([OH:20])[N:17]=[C:16]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]=[C:16]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[N:17]=[C:18]([OH:20])[CH:19]=2)[CH2:10][CH2:9]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(O)nc(N3CCCCC3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1cc(C2CCNCC2)nc(N2CCCCC2)n1

Procedure:
A suspension of 4-(6-hydroxy-2-piperidin-1-yl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.05 mol) in 15% HCl in dioxane (100 mL) was stirred at reflux for 2 hours. After reaction was completed the mixture was cooled, precipitate was filtered, washed with dry ether and dried to obtain 6-Piperidin-4-yl-2-piperidin-1-yl-pyrimidin-4-ol as hydrochloride (12 g, 82%).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=1[F:49]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:44]=[CH:45][C:40]([Cl:39])=[C:41]([F:49])[CH:42]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
5-(tert-Butyl)-4′-chloro-3′-fluoro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 4-chloro-3-fluorophenylboronic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][C:43]=1[F:44])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38](=[O:40])[CH3:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[C:38]([NH:37][C:35]1[N:36]=[C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]3[CH:41]=[CH:42][C:43]([F:44])=[C:24]([NH:23][C:8]([C:6]4[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=4)=[O:10])[CH:25]=3)=[N:33][N:32]2[CH:34]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Reactant: CCc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(C)=O)cn4n3)ccc2F)n(C)n1
Yield: 50.1 %

Procedure:
Using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (215 mg, 1.39 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (122 μL, 1.39 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (300 mg, 1.00 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 238, the title compound (219 mg, 50%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: NCCCCO
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCCCO)ccc21
Yield: 44.1 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (4-hydroxy-butyl)-amide (37 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), 4-amino-butan-1-ol (20 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 429.6.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=1[O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.C(=O)([O-])O.[Na+].[CH:26]1([C:32]2[C:33]3[S:48][C:47]([C:49]([O:51][CH3:52])=[O:50])=[CH:46][C:34]=3[NH:35][C:36]=2B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]1([C:32]2[C:33]3[S:48][C:47]([C:49]([O:51][CH3:52])=[O:50])=[CH:46][C:34]=3[NH:35][C:36]=2[C:2]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=2[O:4][CH2:5][CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=[N+]([O-])c1cccc(Br)c1OCCOC1CCCCO1
Reactant: COC(=O)c1cc2[nH]c(B3OC(C)(C)C(C)(C)O3)c(C3CCCCC3)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc2[nH]c(-c3cccc([N+](=O)[O-])c3OCCOC3CCCCO3)c(C3CCCCC3)c2s1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
To a solution of 2-[2-(2-bromo-6-nitrophenoxy)ethoxy]tetrahydropyran (1.29 g, 3.72 mmol) in water (10 ml) and ethylene glycol dimethyl ether (20 ml) were added sodium hydrogen carbonate (1.23 g, 14.8 mmol) and tetrakis(triphenylphosphine)palladium (430 mg, 0.372 mmol). Methyl 6-cyclohexyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.60 g, 4.10 mmol) obtained in Step 1 was divided in 4 portions and added every 30 min while stirring at 90° C. with heating. After the completion of addition, the mixture was further stirred at 90° C. for 4 hr. The reaction mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1-3:1) to give methyl 6-cyclohexyl-5-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-thieno[3,2-b]pyrrole-2-carboxylate (863 mg, yield 44%).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2)(=[O:3])[CH3:2]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc3[nH]ccc3c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a stirred solution of 80 mg (9.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 55 mg (0.417 mmol) of 5-aminoindole was added. The resulting mixture was stirred at room temperature for one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (97 mg, 93.3% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C@H:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:7]21[CH3:18])[CH3:2].F[B-](F)(F)F.[O:24]=[N+:25]=[O:26]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([N+:25]([O-:26])=[O:24])[CH:12]=1)[N:9]([CH3:13])[C@H:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:7]21[CH3:18])[CH3:2]
Reactant: CCOc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOc1cc([N+](=O)[O-])c2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Reaction time: 0.33 h

Procedure:
A degassed solution, under nitrogen, of 3.70 g of (3aS-cis)-5-ethoxy-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-pyrrolo[2,3-b]indole in 50 ml of dry chloroform was treated with 2.00 g of nitronium tetrafluoroborate at a reaction temperature of +10°. After 20 minutes, the reaction was quenched by the addition of ice and saturated sodium bicarbonate solution with vigorous stirring. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to an oil. This was purified by chromatography over silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to an oil which crystallized from hexane to afford crystals of pure (3aS-cis)-5-ethoxy-1,2,3,3a,8,8a-hexahydro-7-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole, mp 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]23O[C:6]2([CH:12]=1)[C:7](=O)[CH2:8][CH2:9][O:10]3.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:1].[Cl:1][C:2]1[CH:12]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][CH2:9][CH2:8][CH:7]2[N:27]1[CH2:26][CH2:25][C:24]2([N:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][NH:22][C:23]2=[O:30])[CH2:29][CH2:28]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C1CCOC23C=CC(Cl)=CC12O3
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCOc3ccc(Cl)cc31)CC2

Procedure:
The title compound, m.p.>250° C. and MS: m/e=398.2 (M+H+) was prepared in accordance with the general method of example 11 from 6-chloro-2,3 -dihydro-4H-1-benzopyran-4-one oxide and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[NH:27][C:28]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29]
Reactant: COc1cccc(N=C=O)c1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2cccc(OC)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[NH2:10].C(=O)([O-])[O-].[K+].[K+].[F:20][CH:21]([F:32])[C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([F:30])[N:24]([CH3:31])[N:23]=1>C(#N)C>[CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[NH:10][C:27]([C:26]1[C:22]([CH:21]([F:32])[F:20])=[N:23][N:24]([CH3:31])[C:25]=1[F:30])=[O:28]
Reactant: NC1CCCCC1C1CC1C1CC1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1nc(C(F)F)c(C(=O)NC2CCCCC2C2CC2C2CC2)c1F
Temperature: 25 °C
Yield: 41.2 %

Procedure:
To a mixture of 0.489 g (2.73 mmol) 2-[1,1′-bi(cyclopropyl)-2-yl]cyclohexanamine and 0.565 g (4.09 mmol) potassiumcarbonate in 30 ml Acetonitrile was added 0.638 g (3.00 mmol) 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride and stirred at ambient temperature over night. At the end of the reaction the reaction mixture was extracted with ethylacetate and water. The organic layer was dried with natriumsulfate and the solvent was removed by vacuum. The crude product was purified by column chromathography (Solvent: Cyclohexane/ethylacetate gradient). Finally 0.40 g (33%) of N-{2-[1,1′-bi(cyclopropyl)-2-yl]cyclohexyl}-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide with a purity of 87% LC-MS was isolated. log P (acid) of 4.02.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>>[CH3:15][C:16]([CH3:20])([CH3:19])[CH2:17][O:18][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)(C)CO
Product: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and 2,2-dimethyl-propan-1-ol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 285.1 ([M−H]−, 100%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58]O)[CH:53]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.C1COCC1.O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:58][C:54]4[CH:53]=[N:52][CH:57]=[CH:56][CH:55]=4)[CH:13]=[CH:12][C:11]=3[N+:10]([O-:30])=[CH:9][C:8]=2[N:18]=1)[CH3:2]
Reactant: OCc1cccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCn1c(COCC)nc2cnc3ccc(O)cc3c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCc4cccnc4)cc3c21
Reaction time: 4 h

Procedure:
2-Ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (680 mg, 2.38 mmol) was dissolved in dichloromethane and mCPBA (60%, 750 mg, 2.62 mmol) was added. The reaction was monitored by TLC and when all of the starting material was determined to be consumed, 20 mL of 2% aqueous sodium carbonate was added. The organic layer was extracted with 2 additional portions of 2% sodium carbonate. The aqueous fractions were combined and concentrated hydrochloric acid was added dropwise until the pH reached 1. The pH was then adjusted to 5 with the portionwise addition of 2% sodium carbonate. A precipitate formed and was collected by filtration to give crude 2-ethoxymethyl-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol as an off-white powder. The solid was combined in 50 mL of anhydrous THF with triphenylphosphine (1.2 g, 4.76 mmol) and pyridine-3-methanol (390 mg, 3.57 mmol). Diisopropyl azodicarboxylate (1.2 g, 5.95 mmol) was added dropwise. After 4 hours, additional portions of triphenyphosphine and pyridine-3-methanol followed by diisopropyldicarboxylate were added and the reaction was stirred for one hour. Water (1 mL) was added and the reaction stirred overnight. The reaction mixture was concentrated under reduced pressure and the resulting solid was dissolved in dichloromethane and washed 3 times with 50 mL portions of 2% aqueous sodium carbonate. The aqueous fractions were combined and extracted with chloroform. The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated to give crude 2-ethoxymethyl-5-oxido-1-propyl-8-(pyridin-3-ylmethoxy)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[C:4](Cl)[N:3]=1.N1C(C)=CC=CC=1C.[NH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.[CH:31]1([C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][CH:38]=2)=[O:35])[CH2:33][CH2:32]1>O1CCOCC1.C(OCC)(=O)C>[CH:31]1([C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([S:43][C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([NH:24][C:25]4[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=4)[N:3]=3)=[CH:41][CH:42]=2)=[O:35])[CH2:32][CH2:33]1
Reactant: O=C(Nc1ccc(S)cc1)C1CC1
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(N)n[nH]1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1nc(Sc2ccc(NC(=O)C3CC3)cc2)nc(Nc2cc(C)[nH]n2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To compound 3 (1.00 g, 3.76 mmol, 1 equiv) and 2,6-lutidine (1.31 mL, 11.25 mmol, 3 equiv) in dioxane (5 mL) at room temperature was added 3-amino-5-methyl-pyrazol (0.38 g, 3.95 mmol, 1.05 equiv, in 5 mL dioxane) drop wise. After stirring at room temperature for 0.5 hr, 4-cyclopropanecarboxamido-thiophenol (0.87 g, 4.5 mmol, 1.2 equiv) was added. The reaction was stirred at room temperature for overnight. The mixture was diluted with ethyl acetate and washed with 1 N HCl (50 mL) and saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure, and purified by flash column chromatography to yield compound 6 as a yellow solid (1.2 g, 70%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.[N+](C=C(SC)SC)([O-])=O.[N+:20]([CH:23]=[C:24](SC)[NH:25][CH2:26]CSCC1C=CON=1)([O-:22])=[O:21].CN>>[N+:20]([CH:23]=[C:24]([NH:25][CH3:26])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)([O-:22])=[O:21]
Reactant: NCCSCc1ccon1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccon1
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole (from the dihydrobromide (3.8 g) with 1-nitro-2,2-bis-methylthioethylene (2.0 g) by the procedure of Example 4(i) and treatment of the resultant 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene with methylamine according to the procedure of Example 3(ii) gives 1-nitro-2-methylamino-2-[2-(3-isoxazolylmethylthio)ethylamino]-ethylene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O.[Pd]>[ClH:16].[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc(Br)cc1)C1CCNCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: Cl
Product: O=C(c1ccc(-c2cccc(Cl)c2)cc1)C1CCNCC1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
A round bottom flask was charged with (4-bromophenyl)(piperidine-4-yl)methanone (20.0 g, 74.6 mmol), 3-chlorophenyl boronic acid (17.4 g, 111 mmol, 1.5 eq), and palladium encapsulated catalyst (Aldrich, Pd EnCat-TPP®, catalyst species PdCl2(PPh3)2) (5.2 g, 0.187 mmol, 0.05 eq). These solids were suspended in isopropanol (570 ml) and allowed to stir for five minutes. To the mixture was added potassium carbonate (30.8 g, 224 mmol, 3 eq) dissolved in H2O (30 ml). The reaction mixture was heated to 80° C. for 16 hours and deemed complete by LC/MS. The suspension was filtered through a small bed of Celite® and the filtrate was concentrated to dryness. The resulting solids were dissolved in isopropyl acetate (400 ml) and washed with water (3×75 ml). The organic layer was then cooled to 0° C. (ice/water bath) and to this stirring solution was added slowly 6 N HCl until solids crystallized. The solids were filtered and dried in a vacuum oven for 16 hours at 50° C. to afford 16.9 g of compound 2 (68% yield) in >98% HPLC purity. MH+=300, 302 (about 3:1). Palladium: 3 ppm.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:17]1C=CC=C[CH:18]=1>C(Cl)Cl>[CH:5]1[C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][CH2:9][CH2:8][C:7]=2[C:2]([C:18]#[N:17])=[CH:3][CH:4]=1
Reactant: c1ccncc1
Reactant: Clc1cccc2c1CCCc1ccccc1-2
Solvent: ClCCl
Product: N#Cc1cccc2c1CCCc1ccccc1-2

Procedure:
Under a dry nitrogen atmosphere a mixture of 4-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene (1.6 grams, 0.007 mole), cuprous cyanide (0.95 gram, 0.011 mole), and pyridine (0.8 gram, 0.01 mole) was stirred and heated at 195° for approximately 16 hours. The mixture was cooled, dissolved in methylene chloride (150 ml), and the resultant solution was washed with three 70 ml portions of concentrated ammonium hydroxide. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give a brown solid. Recrystallization from n-hexane give 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carbonitrile (mp 109°-111°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:32]([NH:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]2)=[S:33])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CN1CCN(CCCN)CC1
Reactant: S=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc(C)c(NC(=S)NCCCN4CCN(C)CC4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 24.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, 1-(3-aminopropyl)-4-methylpiperazine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 16 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (20 mg, yield 24%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C)C=O>[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:18])([CH3:3])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: CC1(C)c2ccccc2Nc2ccccc21
Reactant: BrCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2N(Cc2ccccc2Br)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.7 g (0.243 mol) of NaH, 60% in mineral oil, are dissolved in 500 ml of dimethylformamide under protective atmosphere. 22.1 g (0.106 mol) of 9,9-dimethyl-9,10-dihydroacridine are dissolved in 500 ml of DMF and added dropwise to the reaction mixture. After 1 h at room temperature, a solution of 60.6 (242 mmol) of 2-bromobenzyl bromide in 500 ml of DMF is added dropwise. The reaction mixture is stirred at room temperature for 1 h, then poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene and recrystallised from toluene/n-heptane. The yield is 37 g (94%).