Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH:11]([F:13])[CH:10]2[O:14][CH2:15][CH:16]([OH:17])[CH:9]12)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH:47]([C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57])[C@H:48](C(O)=O)[CH2:49][CH:50]([CH3:52])[CH3:51].CCN(CC)CC.C(OC(=O)NC(C(N1CC(F)C2OCC(O)C12)=O)CC(C)C)C1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CN(C=O)C>[CH2:59]([O:58][C:56](=[O:57])[NH:47][CH:48]([C:6]([N:8]1[CH2:12][CH:11]([F:13])[CH:10]2[O:14][CH2:15][C:16](=[O:17])[CH:9]12)=[O:7])[CH2:49][CH:50]([CH3:51])[CH3:52])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(F)C2OCC(O)C21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)N1CC(F)C2OCC(O)C21
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)N1CC(F)C2OCC(=O)C21
Temperature: 2 °C
Reaction time: 1 h

Procedure:
6-Fluoro-3-hydroxy-hexahydro-furo[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester (0.200 g, 0.81 mmol) was dissolved in DCM (4 mL) at 0° C. and TFA (4 mL) added. After stirring at 0-4° C. for 1 h, the solvent was evaporated in vacuo and the residue left under high vacuum for 4 h to afford a brown oil. The residue was dissolved in DMF (5 mL) and WSC.HCl (171 mg, 0.89 mmol), HOBt (137 mg, 1.01 mmol), Cbz-Leu-OH (226 mg, 0.85 mmol) and Et3N (337 μl, 2.43 mmol) added. After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, dissolved in EtOAc (10 mL), washed with H2O (5 mL) and saturated NaHCO3 solution (5 mL), dried (Na2SO4) and evaporated in vacuo to afford a colourless oil (242 mg; [M+H]+ 395). (1-(6-Fluoro-3-hydroxy-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)-3-methyl-butyl]-carbamic acid benzyl ester (242 mg, 0.62 mmol) was dissolved in dry DCM (8 mL) and Dess-Martin periodinane (261 mg, 0.62 mmol) added. The reaction immediately turned light brown. After stirring at room temperature for 2.5 h, the yellow solution was diluted with DCM (8 mL) and washed with saturated NaHCO3 solution (5 mL), dried (Na2SO4) and evaporated in vacuo to afford a yellow residue. Purification by column chromatography (EtOAc: heptane; 1:2) yielded the title compound as a colourless oil, 147 mg; [M+H]+ 393.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:18]2[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:17]2=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:18]2[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:17]2=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1nc1n2CCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1nc1n2CCC1
Yield: 45.6 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.410 g) was added to a solution of methyl 6-amino-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (Intermediate 55, 0.290 g) in pyridine (10 mL) and DCM (10 mL) and the resultant mixture was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15% to give a sandy coloured solid which was triturated with ether and filtered to give methyl 6-(2-bromo-4-fluorobenzenesulfonylamino)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (0.268 g).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:6][CH2:5][N:4]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:3]1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[F:25][C:2]1([F:1])[CH2:6][CH2:5][N:4]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCC(F)(F)C2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC1(F)CCN(c2cccc3c2OCCNC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A mixture of tert-butyl 9-(3,3-difluoropyrrolidin-1-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (110 mg, 0.310 mmol), ethyl acetate (2 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was added to 1N aqueous sodium hydroxide solution (2 ml), and the mixture was extracted with ethyl acetate:tetrahydrofuran (1:1). The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (41.0 mg, 52.0%) as a solid.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([F:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C>Cl.CCO>[NH2:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:16])[F:17])[C:8]([F:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(F)cc1[N+](=O)[O-]
Yield: 65.6 %

Procedure:
A mixture of 3-acetamido-6-fluoro-4-nitrobenzotrifluoride (593 mg, 2.23 mmol) in concentrated HCl (5 mL) and EtOH (5 mL) was refluxed overnight and it was extracted by ethyl acetate (2×5 mL). The extract was dried over Mg2SO4 and evaporated to give 328 mg (66%) of 3-amino-6-fluoro-4-nitrobenzotrifluoride. 1H NMR (CDCl3): δ6.105 (s, 2H); 7.110 (d, 1H, J=6.0 Hz); 7.979 (d, 1H, J=10.2 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:8][CH2:7][C:6]=2[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:28].FC1C=CC(CN2CCC3C(C(OCC)=O)=NC=C(OC)C=3C2=O)=CC=1>>[CH3:28][O:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH2:8][CH2:7][C:6]=2[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(OC)cc1)C2=O
Agent: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)cc1)C2=O
Product: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(OC)cc1)C2=O

Procedure:
The title product was prepared by treating ethyl 4-hydroxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate with TMS-diazomethane, using a method set forth in Step 5 of Example 8 for the preparation of ethyl 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate, except that after quenching with HOAc the reaction was concentrated in vacuo and partitioned between sat aq NaHCO3 and CHCl3. LRMS (M+1)=371.0
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[N:11]([CH2:19][CH3:20])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([O:13][C:12]([N:11]([CH2:19][CH3:20])[C@H:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:12]([O:13][CH3:14])=[O:18])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2ccc(C(=O)OC)cc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
(R)-tert-Butyl 6-bromo-2,3-dihydro-1H-inden-1-yl(ethyl)carbamate (15 g, 44.12 mmol, 1 eq) was dissolved in MeOH (180 ml) and DMSO (30 ml). The mixture was degassed for 30 minutes with argon, and then Pd(OAc)2 (0.513 g, 2.21 mmol, 0.05 eq), 1,3-bis(diphenyl-phosphino)propane (0.911 g, 2.21 mmol, 0.05 eq) and TEA (18.4 ml, 132.35 mmol, 3 eq) were added. The reaction mixture was stirred for 16 hours at 80° C. in an autoclave under CO pressure (80 psi) and then concentrated under reduced pressure. The residue was taken up in water (200 ml) and extracted with ethyl acetate (2×400 ml). The combined org. phases were washed with sat. NaCl solution (500 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 8% ethyl acetate in hexane). Yield: 77% (10.84 g, 33.97 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1>CO.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Oc2cc(Cl)ncn2)cc1

Procedure:
4-Chloro-6(4-nitro-phenoxy)-pyrimidine (Stage 21.2; 3.6 g, 14.3 mmol) dissolved in MeOH (250 ml) is hydrogenated in the presence of Raney-Ni (3 g) at 40° C. for 3 d. The reaction solution is filtered, concentrated under reduced pressure and crystallized from AcOEt/hexane to give the title compound of Stage 21.1: M+H=222/224; 1H-NMR (400 MHz, DMSO-d6): 8.62 (s, 1H), 7.13 (s, 1H), 6.83 (d, 9 Hz, 2H, phenyl), 6.56 (d, 9 Hz, 2H, phenyl), 5.12 (s, 2H, NH2); m.p.=135.5-138.1° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=O)[CH2:19][C:20](=O)[CH3:21])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9].O.[NH2:39][NH2:40].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CO.O>[F:36][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]([CH3:21])[NH:40][N:39]=2)[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: NN
Reactant: CC(=O)CC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(Cl)cc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CO
Solvent: O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(c2cc(C)[nH]n2)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a mixture of N-(3,5-Bis-trifluoromethyl-benzyl)-N-[8-chloro-1-(3-oxo-butyryl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-acetamide (0.13 mmol, 72 mg), hydrazine hydrate (1.3 mmol, 40.0 μL) in MeOH (2 mL) was added P4O10 (0.5 g) at room temperature. The resulting suspension was stirred vigorously at 70° C. for 12 h. After completion, the mixture was diluted with water (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated to dryness. Flash chromatography (EtOAc-Hexane as eluent 1:1) afforded the title compound as viscous foam; Rf 0.28 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 545 (M+H+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.N>ClCCl>[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: N
Solvent: ClCCl
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.5 g (1.5 mmol) of 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone are dissolved in 20 ml of dichloromethane and after the addition of 0.57 g (4.5 mmol) of 4-chloroaniline stirred for 72 hours at ambient temperature. Then 3 ml of methanolic ammonia are added and stirred for 48 hours. After removal of the solvent in vacuo the residue is triturated with ether, suction filtered and dried.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.[N+:28](C1OC(C2C(C(Cl)=O)=CN(C3C=CC=CC=3)N=2)=CC=1)([O-])=O>ClC(Cl)C>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH2:28])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 8 h

Procedure:
Heat 1 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid together with 0.56 g of phosphorus oxychloride and 10 ml of dichloroethane for 2 hours at 80° C. Add 10 ml of a 25% aqueous solution dropwise at 0° C to the thus-obtained solution of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic chloride. Allow the resulting mixture to stand overnight and then vacuum distil it to remove the organic solvent therefrom. Vacuum filter to separate formed precipitate and recrystallize the filter residue from dimethylformamide/methanol to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide [m.p. 236° to 238° C].
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:32][CH2:31][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1>CC(O)C>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4[C:5](=[N:4][CH:3]=[C:2]([N:28]5[CH2:32][CH2:31][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:29]5)[N:7]=4)[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (200 mg, 0.586 mmol), potassium carbonate (243 mg, 1.76 mmol), and (R)-tert-butyl pyrrolidin-3-ylcarbamate (218 mg, 1.17 mmol) in 2-propanol (6.0 mL) was heated in the microwave at 80° C. for 20 minutes. The mixture was allowed to cool and the solids were collected by filtration then purified by flash chromatography using a Horizon purification system eluting with chloroform/ethyl acetate (25-75%) to afford (R)-tert-butyl 1-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrrolidin-3-ylcarbamate, (239 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Cl[CH2:21][CH2:22][C:23]#[N:24]>>[C:23]([CH2:22][CH2:21][N:7]1[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8]1)#[N:24]
Reactant: N#CCCCl
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(CCC#N)c1=O
Yield: 78.9 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 3-chloropropionitrile as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 78.9%.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:14])([O-])=O.[H][H]>[Pd].CO>[F:11][C:10]([F:12])([F:13])[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:14])[C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(F)(F)F)c1N

Procedure:
A slurry of 2-nitro-3-trifluoromethyl-phenylamine (0.678 g, 3.2 mmol) and 10% palladium on carbon (0.067 g) in methanol (20 mL) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered and the solvent was evaporated under vacuum to obtain the title compound as off white solid (0.420 g, 73.17%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[C:19]([C@@H:21]5[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]5)[N:18]=[N:17]4)[CH:14]=3)[N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[NH:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([C:19]2[N:18]=[N:17][N:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[NH:9][N:8]=[C:7]4[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:20]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2cn(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2n[nH]c3ccc(-n4cc([C@@H]5CCCNC5)nn4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the crude (R)-tert-butyl 3-(1-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate dissolved in CH2Cl2 (30 mL) was added TFA (2 mL and Et3SiH (0.2 mL) and stirred at room temperature overnight under a stream of nitrogen. Evaporated the solvent and column purified (10% MeOH in CH2Cl2) to give the (R)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(pyridin-4-yl)-1H-indazole (0.61 g).
Reaction SMILES: [ClH:1].C(O[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1)=[NH:6])C.[CH2:34]([NH2:36])[CH3:35]>C(O)C>[ClH:1].[CH2:34]([NH:36][C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:11][CH:12]=1)=[NH:6])[CH3:35]
Reactant: CCN
Reactant: CCOC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Agent: Cl
Solvent: CCO
Product: CCNC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Into a suspension (4 ml) of N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (169 mg) in ethanol was added ethylamine (1 ml). The resulting mixture was stirred at room temperature for 4 days and was then concentrated. The residue was suspended in ethyl acetate, 4 N hydrochloric acid/ethyl acetate was added and the precipitate was collected by filtration. The precipitate was recrystallized from ethyl acetate/methanol to obtain N-(4-ethylamidinophenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (compound 43) (25 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([N:18]3[CH:23]=[CH:22][CH:21]=[C:20](C4C=C5C(=CC=4)N(C)N=C5)[C:19]3=[O:34])[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:45][N:46]1[C:54]2[C:49](=[CH:50][C:51](C3C=CC(=O)NC=3)=[CH:52][CH:53]=2)[CH:48]=[N:47]1>>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([N:18]3[CH:23]=[C:22]([C:51]4[CH:50]=[C:49]5[C:54](=[CH:53][CH:52]=4)[N:46]([CH3:45])[N:47]=[CH:48]5)[CH:21]=[CH:20][C:19]3=[O:34])[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1ncc2cc(-c3ccc(=O)[nH]c3)ccc21
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-n3cccc(-c4ccc5c(cnn5C)c4)c3=O)sc2c1-c1ccc(Cl)cc1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-n3cc(-c4ccc5c(cnn5C)c4)ccc3=O)sc2c1-c1ccc(Cl)cc1

Procedure:
Compound (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate was prepared following the procedure used to prepare (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate of Example 27, except that 5-(1-methyl-1H-indazol-5-yl)pyridin-2(1H)-one was used instead of 3-(1-methyl-1H-indazol-5-yl)pyridin-2(1H)-one. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O4S: 627.18; Found: 627.2.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[C:8]([O:10]C)=O.[CH:12]([NH2:14])=O>>[Cl:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[NH:14][CH:12]=[N:1][C:2]=2[CH:6]=1
Reactant: COC(=O)c1sc(Cl)cc1N
Reactant: NC=O
Product: O=c1[nH]cnc2cc(Cl)sc12
Temperature: 205 °C

Procedure:
In a 50 ml round bottom flask equipped with a mechanical stirrer and a reflux condenser, a mixture of 7.0 g (0.036 mole) of methyl 3-amino-5-chloro-2-thiophenecarboxylate and 15 ml of formamide was heated at 205° C. for 7 hours. Upon cooling to room temperature, the reaction solution afforded a precipitate which was filtered: yield about 3.3 g. The crude tan solid was taken up in hot methanol, treated with activated carbon, and filtered. Upon cooling to room temperature, the filtrate afforded yellow crystals of 6-chlorothieno[3,2-d]pyrimidin-4(3H)-one: m.p. 238°-239° C.; yield 2.5 g (36%); ir (KBr) 3427 cm-1, 1688, 1659, 1600, 1510, 1476, 1410 among others; 1H-nmr (CDCl3 +some trifluoroacetic acid) delta 7.5 ppm (s, 1H), 9.1 (s, 1H); mass spectrum 186 (molecular ion and parent peak with the expected isotope pattern), 159 (-27), 131 and others.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[O:35][CH:34]=[N:33][CH:32]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[O:35][CH:34]=[N:33][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: COC(=O)Cc1cnco1
Product: COc1ccc(N2CCN(C(=O)Cc3cnco3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 17 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and oxazol-5-yl-acetic acid methyl ester with heating for 5 days to afford the title compound as tan solid (22 mg, 17%). LC/MS (Method B) 3.59 min, [M+1]+ 462.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:16]=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClC1C=CC=CC=1Cl>[CH:5]1[C:4]2[NH:1][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:8]([CH:16]=[O:17])=[CH:7][CH:6]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: O=Cc1cccc2[nH]c3ccccc3c12
Yield: 56.3 %

Procedure:
A 100-mL round-bottom flask was placed a solution of 6-nitrobiphenyl-2-carbaldehyde (6.2 g, 27.31 mmol, 1.00 equiv) in 1,2-dichlorobenzene (60 mL). To the mixture was added PPh3 (17.9 g, 68.32 mmol, 2.50 equiv) and the mixture was heated to reflux for 30 hours. Upon completion, the resulting mixture was concentrated on a rotary evaporator to give a residue that was purified by silica gel column chromatography affording 9H-carbazole-4-carbaldehyde as yellow solid (3 g, 56%).