Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH2:10])[CH2:5][CH2:4]1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COC1CCC(CN)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(4-Methoxyphenyl)methanamine (1 g, 1.29 mmol) in ethanol (10 ml) was treated with 5% Rh—Al2O3 (99.8 mg, 0.048 mmol) under H2 atmosphere (500 psi) at 50° C. for 16 hours. Additional 5% Rh—Al2O3 (0.4 g) was added. The resulting mixture was stirred under H2 atmosphere (500 psi) at 60° C. for 2 hours. The insoluble material was filtered off and the filtrate was concentrated to provide a mixture of cis and trans product as an oil, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1>[Pt]>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]([C:13]([F:15])([F:14])[F:16])[CH2:3][CH2:2]2
Reactant: FC(F)(F)c1cc(Cl)c2cc(Cl)ccc2n1
Agent: [Pt]
Product: FC(F)(F)C1CCc2cc(Cl)ccc2N1

Procedure:
4.6-Dichloro-2-trifluoromethylquinoline was reduced with platinum on carbon to give 6-chloro-2-trifluoromethyltetrahydroquinoline.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Mg].[CH:23]1[C:36]2[C:35](=O)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.Cl>C(OCC)C.O1CCCC1>[CH:23]1[C:36]2[C:27](=[CH:28][C:29]3[C:34]([C:35]=2[C:15]2[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:12]([C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:2]=[CH:3][CH:4]=4)=[CH:13][CH:14]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2Cc2ccccc21
Reactant: Brc1ccc(-c2cccc3ccccc23)c2ccccc12
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc2c(-c3ccc(-c4c5ccccc5cc5ccccc45)c4ccccc34)cccc2c1

Procedure:
4-bromo-1,1′-binaphthyl and magnesium were refluxed in diethylether for one hour, which was then added to a solution of anthrone in tetrahydrofuran. The resulting mixture was heated for two hours, which was then poured into diluted hydrochloric acid. After being extracted by diethylether, organic layer was separated and dried over magnesium sulfate. It was purified according to conventional method, whereby 1-(9-anthryl)-4-(1-naphthyl)-naphthalene was obtained. This was dissolved in chloroform to which was added two equivalent amounts of N-bromosuccinimide, and they were stirred at room temperature for one day. The product was purified according to conventional method and 1-(10-bromo-9-anthryl)-4-(4-bromo-1-naphthyl)-naphthalene was obtained. With this pdoruct, diphenylamine was reacted in nitrobenzene at 180° C. for 40 hours together with potasium carbonate and copper powder. After nitrobenzene was removed by vacuum distillation, the reaction mixture was purified according to conventional method, whereby the target compound (18) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH:41]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:17])=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)[CH:41]=1)#[N:25]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCCN)CCC(c1ccc(F)cc1)c1ccccn1
Product: CN(CCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 0.99 g (2.5 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=614 ([M+H]+, 3), 214 (50.2), 154 ([m-NO2 -benzylOH], 100); IR (KBr): 2163 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 105°-110° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1csc(/C=C/c2ccccc2)n1
Product: C(=C/c1nc(COc2ccc(CCCn3ccnc3)cc2)cs1)\c1ccccc1
Yield: 58 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-phenylethenyl]thiazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]thiazole. The yield was 58%. Recrystallization from ethyl acetate gave colorless prisms, mp 129-130° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:41][N:40]([CH3:42])[CH2:39][CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1cccc(N)c1
Product: CN(C)CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.12) according to general procedure II. Yellow solid. MS (ISP) 601.3 [(M+H+]; mp 224° C.
Reaction SMILES: [Br:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][CH2:7][CH:8]([OH:34])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.I[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]([O:34][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:35][CH:36]=1
Reactant: CCCCCI
Reactant: OC(COc1ccc(Br)cc1)COc1ccc(C(CCCc2ccccc2)OC2CCCCO2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCOC(COc1ccc(Br)cc1)COc1ccc(C(CCCc2ccccc2)OC2CCCCO2)cc1

Procedure:
A mixture of the product (0.57 g) of Step 3, 0.3 mL of 1-iodopentane and 80 mg of Nail in 20 ml of 1:1 THF/DMF was refluxed for 4 hrs. The mixture was then quenched with 5 mL of MeOH, 20 mL of Sat. NH4Cl, and extracted with 50 mL of Et2O. The extract was dried over NaSO4 and concentrated. The residue was purified by flash chromatography eluted with EtOAc and hexanes (7:1) to give 0.6 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH3:10])[CH:3]=1.O.[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[N:13])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)ccc1I
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1cc(Cl)ccc1C#N
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of Example 59A (2.68 g, 10 mmol), Zn(CN)2 (0.654 g, 5.5 mmol), and Pd(PPh3)4 (0.577 g, 0.5 mmol) in DMF (15 mL) was stirred at 90° C. for 6 hours and cooled to room temperature. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate several times. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide 1.34 g (90%) of the desired product. MS (DCI) m/e 168 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=8.1 Hz, 1H), 6.97-7.03 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:12](=[O:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([O:9]CC)=O.[H-].[Na+].[C:24]([O:33][CH2:34][CH3:35])(=[O:32])/[CH:25]=[CH:26]\[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[CH2:34]([O:33][C:24]([CH:25]1[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:7](=[O:9])[C:6](=[C:2]2[S:1][CH:5]=[CH:4][S:3]2)[C:12](=[O:21])[N:13]1[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)=C1SC=CS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1C(=O)C(=C2SC=CS2)C(=O)N(Cc2ccccc2)C1C(=O)OCC
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (1.0 g) and dimethylformamide (25 ml) is added dropwise to a suspension of sodium hydride (63% dispersion in oil, 144 mg) in dimethylformamide (10 ml). Said addition is carried out under ice-cooling. The mixture is stirred at the same temperature for 30 minutes. A solution of diethyl maleate (0.6 ml) in dimethylformamide (10 ml) is added dropwise thereto. The mixture is stirred at room temperature overnight. The mixture is poured into water, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The mixture is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=1:2) to give 1-benzyl-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-2,3-dicarboxylic acid diethyl ester (196 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:19][CH:18]=[CH:17][N:13]3[C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1.[I:20]I.O>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:19][CH:18]=[CH:17][N:13]3[C:14](=[O:16])[C:15]=2[I:20])=[CH:4][CH:3]=1
Reactant: II
Reactant: O=c1cc(/C=C/c2ccc(Cl)cc2)nc2sccn12
Solvent: O
Solvent: CC#N
Product: O=c1c(I)c(/C=C/c2ccc(Cl)cc2)nc2sccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Step 2 intermediate (3.0 g, 0.018 mmol), iodine (2.75 g, 0.018 mmol) and ceric ammonium nitrate (CAN) (4.93 g, 0.009 mmol) in CH3CN (30 ml) was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to room temperature. Distilled water (50 ml) was added to the residue obtained after concentration of the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was filtered, dried under vacuum to give 5.30 g of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 6.87 (d, J=15.6 Hz, 1H), 6.94 (d, J=4.8 Hz, 1H), 7.33 (d, J=9.0 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.73 (d, J=15.6 Hz, 1H), 7.90 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 289.37 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:10]2)=[N:6][CH:7]=1.[O-]CC.[Na+].O>CCO>[CH3:31][N:8]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10]1)[C:5]1[CH:4]=[N:3][CH:2]=[CH:7][N:6]=1
Reactant: CN(c1cnc(Br)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(c1cnccn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Yield: 51.7 %

Procedure:
A solution of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (55 mg, 0.10 mmol) and sodium ethoxide (680 mg, 10 mmol) in EtOH (10.5 mL) was stirred at refluxing temperature for 5 days. It was then treated with water and extracted with EtOAc (2×30 mL). The combined extracts were concentrated and the residue was purified by chromatography on silica gel (PE/EtOAc=1/1). The first compound from the column was collected and confirmed to be (R)-5-ethoxy-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine [MS (m/z), 470 (M+1)+, 21 mg, 41.1% yield) and the later compound from the column was isolated and concentrated to give the title compound (22 mg, 47.8% yield). MS (m/z), 426 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:17][CH:16]=3)=[O:13])=[CH:25][CH:26]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc1
Reaction time: 8 h

Procedure:
The product from Example 3 (300 mg, 0.87 mmol) and triethylamine (0.6 mL, 4.3 mmol) in CH2Cl2 (10 mL) were treated with methanesulfonyl chloride (0.2 mL, 2.58 mmol) at room temperature and stirred overnight. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with H2O (3×5 mL) and brine (5 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (99:1 CH2Cl2:CH3OH) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.81 (dd, J=4.6 Hz, 1.6 Hz, 1H), 8.25 (dd, J=8.1 Hz, 1.4 Hz, 1H), 8.11-8.14 (m, 2H), 7.61-7.77 (m, 5H), 7.37-7.41 (m, 2H), 3.19 (s, 6H), 1.29 (s, 9H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=O.Br[C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=1>CN1CCCC1>[CH2:10]([O:9][C:3]([C:4]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([Br:19])[N:18]=2)[NH:20][C:5]=1[CH3:7])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ncc(Br)nc1Br
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(C)[nH]c2ncc(Br)nc12
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 9.5 %

Procedure:
To a flask charged with 20 mL of anhydrous N-methylpyrrolidine at 0° C. was added 60% NaH (840 mg, 21 mmol). After stirring 15 min, ethyl acetoacetate (2.73 g, 10.8 mmol) was added slowly. After stirring an additional 20 min 3,5-Dibromo-pyrazin-2-ylamine (5.04 g, 20 mmol). The reaction vessel was then removed from the ice bath and heated to 140° C. for 3 days. The dark mixture was cooled to rt and diluted with diethyl ether and water. The mixture was filtered and then partitioned. The organic layer was washed with water and then brine, dried over Na2SO4, filtered, and concentrated to afford a dark red oil. This was purified by silica gel chromatography (4:1 Hexanes:EtOAc) to afford 290 mg of 2-Bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[N:11]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: O
Product: c1ccc2c(N3CCOCC3)nc(N3CCOCC3)nc2c1

Procedure:
Eight grams of 2,4-dichloroquinazoline was cautiously added to 25 ml of morpholine; a vigorous reaction ensued upon mixing. After the initial reaction subsided, the mixture was then heated to 110° overnight. The reaction mixture was poured into water, and the resulting aqueous solution was extracted with several portions of ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from aqueous ethanol, giving 8 g of 2,4-bismorpholinoquinazoline; m.p. 172°-174°. The following analytical data were obtained:
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-])=O)[CH:14]=2)[CH2:8][C:7]1=[O:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[O:25]1CC[CH2:27][CH2:26]1>[Pd].[C]>[C:26]([NH:21][C:15]1[CH:14]=[C:13]([CH:9]2[CH2:10][C:11](=[O:12])[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:7]([OH:24])[CH2:8]2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20])(=[O:25])[CH3:27]
Reactant: CCCC(=O)C1C(=O)CC(c2ccc(OC)c([N+](=O)[O-])c2)CC1=O
Reactant: C1CCOC1
Agent: [Pd]
Product: CCCC(=O)C1=C(O)CC(c2ccc(OC)c(NC(C)=O)c2)CC1=O
Reaction time: 16 h
Yield: 55 %

Procedure:
5.3 g of 2-butyryl-5-(3-nitro-4-methoxyphenyl)cyclohexane-1,3-dione in 300 ml of tetrahydrofuran were hydrogenated in the presence of 3 g of Pd/carbon (10%) under atmospheric pressure at 25° C. After 0.9 l of hydrogen had been absorbed, the mixture was dried over sodium sulfate and filtered, 1.3 g of sodium bicarbonate were added and the mixture was reacted with 1.2 g of acetyl chloride. After the mixture had been stirred for 16 hours, it was filtered and evaporated down. The remaining oil was brought to crystallization with diethyl ether, and the crystals were filtered off under suction. 3 g (55% yield) of 5-(3-acetylamino-4-methoxyphenyl)-2-butyryl-3-hydroxycyclohex-2-en-1-one of melting point 102°-106° C. were obtained.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:17][C:11]=3[C:10]=2[CH:22]=1)(=[O:5])=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31]>S1(CCCC1)(=O)=O.Cl>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([S:18]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30](=[O:32])(=[O:31])[NH2:33])(=[O:20])=[O:19])=[CH:17][C:11]=3[C:10]=2[CH:22]=1)(=[O:5])=[O:4]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CNS(=O)(=O)c1ccc2sc3ccc(S(=O)(=O)Cl)cc3c2c1
Agent: Cl
Solvent: O=S1(=O)CCCC1
Product: CNS(=O)(=O)c1ccc2sc3ccc(S(=O)(=O)Nc4ccccc4S(N)(=O)=O)cc3c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
8-(Methylsulfamoyl)dibenzo[b,d]thiophene-2-sulfonyl chloride (200 mg) was added to a solution of 2-aminobenzenesulfonamide (191 mg) in sulfolane (2 ml). The mixture was stirred at RT for 20 h then diluted with 1N hydrochloric acid. The solid was recovered, washed with 1N hydrochloric acid and dried to give the title compound (196 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH:28]([N:27]([CH3:33])[CH3:26])[CH2:29]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CN(C)C1CCNC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(N(C)C)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-3-dimethylaminopyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.69 minutes; C23H25Cl2N5O2 (474.39); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH2:14])[CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH2:23][CH:22]=[CH2:21])[CH2:6]2
Reactant: COc1cc2c(cc1OC)[C@@H](CN)C2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCNC[C@H]1Cc2cc(OC)c(OC)cc21
Reaction time: 60 h

Procedure:
To 3.9 g (20 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine in 40 mL of acetone, at ambient temperature, there are added, all at once, 4.1 g (30 mmol/1.5 eq.) of potassium carbonate, and then there are quickly added dropwise 1.9 mL (22 mmol/1.1 eq.) of allyl bromide. Stirring is carried out at ambient temperature for 60 hours; the salts are then filtered off and the filtrate is concentrated. The residue (4.8 g) is chromatographed over 300 g of silica (eluant: dichloromethane/ethanol/ammonia: 98/2/0.2) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: NCCCN1CCCC1=O
Product: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Yield: 84 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (35.26 g, 123.8 mmol) was treated with 1-(3-aminopropyl)pyrrolidin-2-one (19.1 mL, 136.2 mmol) according to the method described in Part E of Example 1 to provide 40.87 g of 1-[3-(7-bromo-3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[CH:19]=2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH3:26][O:25][C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:15]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: COc1ccc2cc(Br)cnc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3c2)cc1

Procedure:
Followed Step 1 of Compound IV-1, starting from 4-(methoxycarbonyl)phenylboronic acid and Intermediate 13, and where the base used was Na2CO3, the solvent DME/H2O (8: 2), and the reaction was run at 100° C. for 2 h.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=3)[C:7]=12
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: Cc1ccc(CCl)cc1
Product: Cc1ccc(Cn2c(C)c(C)c3ccnc(Cl)c32)cc1
Yield: 75 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 4-methylbenzyl chloride, the titled compound was obtained as a white solid. (Yield: 75%)