Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:8]3[O:28][C:27]([CH2:29][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:41]1[N:46]2[CH:47]=[CH:48][N:49]=[C:45]2[CH:44]=[CH:43][CH:42]=1>O1CCOCC1.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.C1C=C(C([O-])=O)SC=1.[Cu+]>[N:49]1[CH:48]=[CH:47][N:46]2[C:41]([C:11]3[N:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:8]4[O:28][C:27]([CH2:29][N:30]5[CH2:31][CH:32]([N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)[CH2:33]5)=[CH:26][C:9]=4[N:10]=3)=[CH:42][CH:43]=[CH:44][C:45]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2oc(CN3CC(N4CCOCC4)C3)cc2n1
Reactant: Brc1cccc2nccn12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: c1cc(-c2nc(N3CCOCC3)c3oc(CN4CC(N5CCOCC5)C4)cc3n2)n2ccnc2c1
Yield: 47.5 %

Procedure:
A mixture of 4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)-2-tributylstannanylfuro[3,2-d]pyrimidine (227 mg, 0.35 mmol), 5-bromoimidazo[1,2-a]pyridine (84 mg, 0.43 mmol), tetrakis(triphenylphosphine)palladium (40 mg, 10 mol %) and CuTC (16 mg, 24 mol %) in 1,4-dioxane (4 mL) was purged with argon gas then subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g); the cartridge was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:NH3/MeOH (2 M); gradient from 100:0 to 96:4)), followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to afford 250 as a cream foam (79 mg, 47%). LCMS (Method G): RT=3.22 min, M+H+=476. 1H NMR (CDCl3, 400 MHz) δ 9.14 (s, 1 H); 7.87 (dd, J=7.2, 1.2 Hz, 1H); 7.77 (d, J=8.9 Hz, 1 H); 7.74 (d, J=1.2 Hz, 1 H); 7.31 (dd, J=8.9, 7.2 Hz, 1 H); 6.76 (s, 1 H); 4.10 (t, J=4.7 Hz, 4 H); 3.89 (t, J=4.7 Hz, 4 H); 3.84 (s, 2 H); 3.74 (t, J=4.5 Hz, 4 H); 3.62 (t, J=6.2 Hz, 2 H); 3.15-3.02 (m, 3 H) and 2.35 (m, 4 H)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[NH:11][C:12](=[O:15])[CH2:13]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:28].[Na+]>CC(=O)CC>[CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[NH:11][C:12](=[O:15])[CH2:13][I:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(CCl)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(CI)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 99.3 %

Procedure:
A solution of N-α-chloroacetyl-L-aspartic acid dibenzyl ester (111 g, 0.285 mol) and sodium iodide (59.5 g, 0.40 mol) in 2-butanone was heated at reflux for a period of 1.5 hours. The reaction mixture was concentrated to dryness and the residue was added to a separatory funnel containing ethyl acetate (about 500 mL). The aqueous phase was removed and the organic phase was first extracted with brine (about 250 mL) and then dried over sodium sulfate. The resulting solution was then concentrated in vacuo to provide product 12 (136 g, 0.283 mol, 99%) as a viscous brown oil which slowly crystallized over a period of several days at room temperature. Satisfactory 1H NMR data were obtained for this material. This material was not further purified but was instead used directly in the preparation of 9.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]1[CH2:26][CH:25]([C:27]([NH2:29])=O)[CH2:24][CH2:23][N:18]12>O1CCOCC1>[CH:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]1[CH2:26][CH:25]([C:27]#[N:29])[CH2:24][CH2:23][N:18]12
Reactant: NC(=O)C1CCn2c(cc3ccccc32)C1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CC1CCn2c(cc3ccccc32)C1
Yield: 80.8 %

Procedure:
991 mg of trifluoroacetic anhydride were added dropwise to a suspension of 1.0 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide in 15 ml of dioxane at 10° C. The mixture was partitioned between dichloromethane and water and the organic phase was dried. The solvent was removed under reduced pressure to give an oil which was subjected to chromatography on silica gel with ethyl acetate/petroleum ether (1:1). There were obtained 740 mg of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carbonitrile of melting point 116°-118° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[Cl:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:27]([C:22]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=1)(=[O:29])=[O:28]
Reactant: COC(=O)Cc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
2-Aminophenylacetic acid methyl ester (10.2 g, 39.45 mmol) was dissolved in DCM (200 ml). There were then added first pyridine (12.4 ml, 151.71 mmol) and 3,4-dichlorobenzenesulfonyl chloride (11.8 ml, 75.87 mmol) in DCM (50 ml). The reaction solution was stirred overnight and then diluted with DCM and washed in succession with 0.5 M KHSO4 solution, saturated NaHCO3 solution and saturated NaCl solution, dried over sodium sulfate and concentrated. Purification was carried out by column chromatography on silica gel (DCM).
Reaction SMILES: O.O.[Br-:3].[Ca+2].[Br-].CC1C=CC(S(O[C:17]2[CH2:21][CH:20]([C:22](=[O:39])[NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[C:31](=[O:38])[NH:32][CH:33]([CH:35]3[CH2:37][CH2:36]3)[CH3:34])[N:19]([C:40]3[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[N:18]=2)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>O>[Br:3][C:17]1[CH2:21][CH:20]([C:22]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[C:31](=[O:38])[NH:32][CH:33]([CH:35]2[CH2:37][CH2:36]2)[CH3:34])=[O:39])[N:19]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=2)[N:18]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Agent: O=C([O-])O
Agent: [Ca+2]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Temperature: 90 °C
Yield: 172.5 %

Procedure:
0.25 g of calcium bromide dihydrate was added to a mixed liquid comprising 1.0 g of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl 4-methylbenzenesulfonate and 10 ml of toluene, followed by heating at about 90° C. for 6.5 hours. After the reaction liquid was stood to cool, 0.41 g of sodium hydrogen carbonate and 10 ml of water were added to the reaction liquid, followed by stirring. After liquid-liquid separation, the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.96 g of the crude desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([NH2:17])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N4C(=O)c5ccccc5C4=O)on3)s2)c(Cl)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2ncc(-c3cc(C(C)N)on3)s2)c(Cl)c1
Temperature: 60 °C
Yield: 96 %

Procedure:
To a solution of Example 30E (510 mg, 1.06 mmol) in ethanol (6 mL) was added hydrazine monohydrate (0.31 mL, 6.3 mol). The reaction was heated at 60° C. for 45 minutes and filtered. The filtrate was concentrated and purified by flash chromatography on silica gel eluting with 90:8:2 dichloromethane/methanol/concentrated ammonium hydroxide to provide 358 mg of the title compound,
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[S:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br>C(#N)C>[CH3:21][S:20][C:11]1[CH:12]=[C:13]([C:16]([F:18])([F:19])[F:17])[CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[N:1]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:22]
Reactant: BrCCOCCBr
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCCC[C@@H]1N1CCOCC1
Yield: 68.6 %

Procedure:
cis-N-(2-Amino-cyclohexyl)-2-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate G) (264 mg, 0.79 mmol) was dissolved in 15 mL acetonitrile. Potassium carbonate (549 mg, 4 mmol) and bis(2-bromoethyl)ether (239 mg, 1 mmol) were added and the reaction mixture was refluxed overnight. The solvent was evaporated off. The residue was taken up in water and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->140:10:1) yielded cis-2-methylsulfanyl-N-(2-morpholin-4-yl-cyclohexyl)-4-trifluoromethyl-benzamide as a light yellow gum (218 mg, 68%), MS: m/e=403.3 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:19])[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[CH3:19][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([C:24]3[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=3)=[CH:3][CH:4]=2)[CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1Cc2ccc(Br)cc2CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 97.7 %

Procedure:
A mixture of tert-butyl 7-bromo-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.326 g, 1.00 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.31 g, 1.50 mmol, Aldrich, Cat. No. 595314), in 1,4-dioxane (4.0 mL) was stirred at r.t. for 10 min. Potassium carbonate (415 mg, 3.00 mmol) in water (2.0 mL) was added to give a deep red solution. The mixture was degassed and refilled with nitrogen three times. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (35.0 mg, 0.0424 mmol) was added and the mixture was degassed and refilled with nitrogen three times and then heated at 120° C.)(oil bath temperature) for 3 h. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in DCM (0-10%) to give the desired product (320 mg, 97.7%). LCMS (M+H)+: m/z=328.1.
Reaction SMILES: C(O[K])(C)(C)C.[S:7]1[C:14]2[C:13]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][NH:11][C:10]=2[CH:9]=[CH:8]1.[CH:21]1([S:24](Cl)(=[O:26])=[O:25])[CH2:23][CH2:22]1.[OH-].[Na+]>C1COCC1>[CH:21]1([S:24]([N:11]2[CH:12]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[C:14]3[S:7][CH:8]=[CH:9][C:10]2=3)(=[O:26])=[O:25])[CH2:23][CH2:22]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCOC(=O)Cc1c[nH]c2ccsc12
Agent: CC(C)(C)O[K]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cn(S(=O)(=O)C2CC2)c2ccsc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 3.11 %

Procedure:
A solution of tBuOK (0.1 mL, 1.2 equiv, 1.0 M in THF) was added to a solution of ethyl 2-(4H-thieno[3,2-b]pyrrol-6-yl)acetate (0.024 g, 0.11 mmol, 1.0 equiv.) in THF (0.5 mL) in a 20 mL vial. This vial was capped and shaken at room temperature for 10 min. To the mixture a solution of cyclopropanesulfonyl chloride (0.7 mL, 1.2 equiv, 0.2 M in THF) was added and the reaction was shaken at room temperature for 4 h. After which time NaOH (aqueous) (1.0 mL, 1.0 M, 9.5 equiv) was added and the reaction was shaken at room temperature overnight. The crude reaction mixture was then concentrated to dryness under reduced pressure and taken up in 1.5 mL 1:1 DMSO/MeOH and purified by reverse phase HPLC (Table 1, Method h) to give the title compound (0.001 g, 3.11%): LC/MS (Table 1, Method e) Rt=1.29 min; MS m/z 285.9 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:24][S:25](O)(=[O:27])=[O:26]>>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=[C:9]([S:25]([Cl:24])(=[O:27])=[O:26])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2cccc(OCc3ccc([N+](=O)[O-])cc3)c2o1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)c1cc2c(S(=O)(=O)Cl)ccc(OCc3ccc([N+](=O)[O-])cc3)c2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Acetyl-7-p-nitrobenzyloxybenzofuran (3 g) was added to chlorosulfonic acid at -15° C. for 30 minutes. After the reaction mixture was stirred at -10° to -5° C. for 1 hour, the resultant was gradually added dropwise to ice-water. The solution was extracted with ethyl acetate, washed with water and dried, ethyl acetate being distilled away under reduced pressure to give 2.7 g of crude 2-acetyl-4-chlorosulfonyl-7-p-nitrobenzyloxybenzofuran.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]=[O:13].[CH3:14][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([OH:13])[CH3:14]
Reactant: O=Cc1cc2cccnc2cc1F
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cc2cccnc2cc1F
Reaction time: 2 h

Procedure:
To a solution of 7-fluoroquinoline-6-carbaldehyde (4.0 g, 22.84 mmol) in THF (30 ml) at 0° C., was added methylmagnesium bromide (2.85M in THF, 8 mL, 22.84 mmol) dropwise. The solution was stirred for 2 h, and NH4Cl was added to quench the reaction. The resulting mixture was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 and NH4Cl, and dried over Na2SO4, filtered and concentrated to give the crude product, which was purified with Analogix gel silica using hexanes:EtOAc to afford 1-(7-fluoroquinolin-6-yl)ethanol (i). LCMS (method B): [MH]+=192, tR=1.84 min.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12.[Br:25][CH:26](Br)[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH:26]([Br:25])[C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=4)=[CH:31][CH:32]=3)[N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12
Reactant: Fc1ccc(-c2ccc(C(Br)Br)cc2)nc1
Reactant: CN1C(=O)c2c(n[nH]c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2c(nn(C(Br)c3ccc(-c4ccc(F)cn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (35 mg, 0.109 mmol), 2-(4-(dibromomethyl)phenyl)-5-fluoropyridine, and K2CO3 (15 mg, 0.109 mmol) in DMF (3 mL) is stirred at room temperature overnight. The mixture is filtered through a 0.45 μm microfilter, and the filtrate is purified by a semi-preparative HPLC to give product as white powder. MS (ESI) m/z 585.9 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: [H][H]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(F)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccc(F)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 34 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (22 mg in 2 ml ethanol) was added 6 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 45 minutes, the mixture was filtered over Celite, concentrated and purified by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (7.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[O:33]1[CH2:38][CH2:37][N:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.O1CCOCC1.C(OCC)(=O)C>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39]([N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[O:40])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)N1CCOCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (339 mg), triethylamine (0.18 ml), 4-dimethylaminopyridine (5 mg) and morpholinocarbonyl chloride (0.15 ml) in 1,4-dioxane (4 ml) was stirred at 80° C. for 2 hours. Then the mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (ethyl acetate) to give 2-benzyl-4-[3-(morpholinocarbonylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (242 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:26])[CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[C:5]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:4]=1>>[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:26])[CH2:16][CH2:17][NH2:18])[CH2:13][CH2:14]2)[CH:6]=[C:5]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:4]=1
Reactant: COc1ccc(Cc2cc(C3CCN(C(=O)CCNC(=O)OC(C)(C)C)CC3)nc(N)n2)cc1
Agent: Cl
Product: COc1ccc(Cc2cc(C3CCN(C(=O)CCN)CC3)nc(N)n2)cc1
Yield: 94.9 %

Procedure:
By a procedure similar to that described in Example 284, the titled compound (127 mg) as hydrochloride was prepared from 2-amino-4-[1-(3-t-butoxycarbonylaminopropanoyl)-4-piperidinyl]-6-(4-methoxyphenylmethyl)pyrimidine (170 mg) obtained in Example 176.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([Cl:12])[CH:3]=1.S(Cl)(Cl)=O.N.[CH2:18](O)[CH3:19]>>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:12])[CH3:19]
Reactant: O=C(O)Cc1ccc(Br)cc1Cl
Reactant: CCO
Agent: N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(Br)cc1Cl

Procedure:
(4-Bromo-2-chlorophenyl)-acetic acid (18, 44.03 g, 0.18 mol) was dissolved in ethanol (440 mL) and thionyl chloride (44.0 mL, 0.61 mol) was added dropwise. The mixture was refluxed for 1 h, and evaporated. The residue was taken up in toluene and evaporated (2×100 mL). The crude oily product was dissolved in dichloromethane (300 mL) and washed with water (2×100 mL), dried over sodium sulfate, filtered and evaporated. The residue was dried in high vacuum (0.2 mmHg) at room temperature, solidifying to a light yellow low melting crystalline solid (45.5 g, 0.16 mol, 93%) ESMS m/z 294 [M+H+NH3]+; 1H NMR (300 MHz, CDCl3): δ 7.55 (d, J=2 Hz, 1H), 7.37 (dd, J=8, 2 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 4.18 (q, J=7 Hz, 2H), 3.71 (s, 2H), 1.26 (t, J=7 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[C:16]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[SH:25])#[N:17]>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[C:16]#[N:17])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1c(S)cccc1Cl
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Solvent: CCOCC
Product: N#Cc1c(Cl)cccc1SSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 86.3 %

Procedure:
30.7 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 500 ml of diethyl ether is reacted in a stirred apparatus with 17 g of 2-cyano-3-chlorothiophenol for 4 hours at 30° C. There is obtained 38 g (86% of theory) of (4-nitro-2-trichloromethylphenyl)-(2-cyano-3-chlorophenyl)-disulfide; m.p.: 137° C.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=O.Br[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].[OH-].[Na+].[Cl-].[Na+]>CO.C(Cl)Cl>[NH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=[CH:11][CH:12]=1
Reactant: O=C(NCc1ccc(O)cc1)C(F)(F)F
Reactant: N#Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cccc(Oc2ccc(CN)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.9 %

Procedure:
Use a method similar to Preparation 40 (Step 2), using 2,2,2-trifluoro-N-(4-hydroxybenzyl)-acetamide (1.0 g, 5.5 mmol) and 3-bromobenzonitrile (673 mg, 3.7 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 3:1). Concentrate in vacuo. Dissolve the residue (287 mg, 0.89 mmol) in methanol (25 mL) and add 5N NaOH (7 mL). Stir at room temperature for 4 h. Dilute with DCM and add solid sodium chloride to the mixture. Extract the aqueous layer three times with DCM. Combine organic extracts, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (94:6) to obtain the title compound (124 mg, 62%). MS (ES+) m/z: 500 (M+H)+.