Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:42])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32]([C:35]([NH:37]C(C)(C)C)=[O:36])=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O.CO>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:42])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32]([C:35]([NH2:37])=[O:36])=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnc(-c2cnc(C(=O)NC(C)(C)C)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Agent: O=S(=O)(O)O
Solvent: CO
Product: COc1cnc(-c2cnc(C(N)=O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
The compound of Example 15, 1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimethylethylaminocarbonyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (20 mg) was dissolved in 1 drop of concentrated sulfuric acid. After 30 minutes, the mixture was diluted with 2 mL of methanol. The resulting solution was injected into a Shimadzu automated preparative HPLC System and the HPLC purification afforded the compound of Example 55, 1-benzoyl-4-[(4-methoxy-7-(2-aminocarbonyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (1 mg); MS m/z: (M+H)+ Calc'd for C26H24N7O5: 514.78; found 514.22. HPLC retention time: 1.44 minutes (column B).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[Br:38][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a stirred solution of 2-(benzyloxy)ethanol (17.0 g, 111.84 mmol) and PPh3 (35.0 g, 134.21 mmol) in DCM (170 mL) at −10° C. to −5° C., NBS (23.88 g, 134.21 mmol) was added slowly in portions maintaining the temperature at −10° C. to −5° C. After addition, the reaction mixture was allowed to stir at RT for 1 h until complete consumption starting material, as evidenced by TLC analysis. The reaction mixture was concentrated, the obtained crude compound was purified by CC using 5% EtOAc in PE as eluent to afford ((2-bromoethoxy)methyl)benzene (13.5 g, 56.2%) as pale yellow liquid (TLC solvent system: 30% EtOAc in PE; Rf: 0.7).
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[CH:11][C:10]2[N:9]([CH3:13])[C:8](=[O:14])[C@@H:7]([CH2:15][CH3:16])[N:6]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:5]=2[N:4]=1.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[CH:27][C:26]=1[O:36][CH3:37]>C(O)C.O>[F:22][C:19]1([F:23])[CH2:20][CH2:21][C@@H:17]([N:6]2[C:5]3[N:4]=[C:3]([NH:24][C:25]4[CH:35]=[CH:34][C:28]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[CH:27][C:26]=4[O:36][CH3:37])[N:12]=[CH:11][C:10]=3[N:9]([CH3:13])[C:8](=[O:14])[C@H:7]2[CH2:15][CH3:16])[CH2:18]1
Reactant: CCNC(=O)c1ccc(N)c(OC)c1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(Nc2ncc3c(n2)N([C@@H]2CCC(F)(F)C2)[C@H](CC)C(=O)N3C)c(OC)c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
Concentrated hydrochloric acid (42 μl) was added to a mixture of (R)-2-chloro-8-((R)-3,3-difluorocyclopentyl)-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (80 mg, 0.24 mmol) and 4-amino-N-ethyl-3-methoxybenzamide (70.47 mg, 0.36 mmol) in ethanol (1.2 mL) and water (4.8 mL). The reaction mixture was heated to 95° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up with dichloromethane, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the desired compound as a white solid (89 mg, 75% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(O)(=O)C>CO.[Zn]>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1cc(F)cnc1Cl

Procedure:
At RT, 44 g (210.58 mmol) of 2,6-dichloro-5-fluoronicotinamide were added to a suspension of 21.9 g (335.35 mmol) of zinc in methanol (207 ml). Acetic acid (18.5 ml) was then added, and the mixture was heated with stirring at reflux for 24 h. The contents of the flask were then decanted from the zinc, and ethyl acetate (414 ml) and saturated aqueous sodium hydrogen carbonate solution (414 ml) were added, followed by intense extractive stirring. Subsequently the reaction mixture was filtered with suction through kieselguhr and the filter product was washed three times with ethyl acetate (517 ml each time). The organic phase was separated off and the aqueous phase was washed with ethyl acetate (258 ml). The combined organic phases were washed once with saturated aqueous sodium hydrogen carbonate solution (414 ml), dried and concentrated under reduced pressure. Dichloromethane (388 ml) was added to the crystals obtained in this manner, and the mixture was stirred for 20 min. The mixture was once more filtered off with suction, washed with diethyl ether and sucked dry.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:2]=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:32])[NH:25][CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=1)=[O:16]>ClCCl>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][NH:25][C:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:9][CH2:10]2)=[O:16])=[CH:23][CH:22]=1)=[O:32]
Reactant: c1cncc(CN2CCNCC2)c1
Reactant: CC(C)(C)CCNC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)CCNC(=O)c1ccc(OC(=O)N2CCN(Cc3cccnc3)CC2)cc1
Reaction time: 16 h

Procedure:
The title product was prepared from 1-pyridin-3-ylmethyl-piperazine was dissolved in dichloromethane (5 ml). 4-(3,3-Dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (method C) (88%, light yellow oil). HPLC-MS m/z=425.4 (M+1), Rt: 2.33 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:29]([NH:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(NCc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.33 h

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (10 mg, 0.026 mmol), benzaldehyde (2.8 mg, 0.026 mmol) and acetic acid (0.5 ml) in 1,2-dichloroethane (1.0 ml) were stirred at RT. After 20 minutes, NaBH(OAc)3 was added and the reaction mixture was stirred for additional 15 minutes, quenched with saturated NH4OH (4.0 ml), extracted with dichloromethane (3×3 ml), dried over Na2SO4, concentrated and purified by silica gel flash chromatography to isolate 376 as a yellow film (1.3 mg, 11%). [M+H]+=446.2.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:37][CH:36]([C:38]([OH:40])=[O:39])[CH2:35]1>>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:37][CH:36]([C:38]([OH:40])=[O:39])[CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)C1CNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][NH:26][CH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1([CH2:42][C:43](O)=[O:44])[CH:41]=[CH:40][N:39]=[CH:38]1>>[CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][N:26]([CH2:27][CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[C:43](=[O:44])[CH2:42][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1)=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Reactant: O=C(O)Cn1ccnc1
Product: CCC(CC)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1)C(=O)Cn1ccnc1

Procedure:
In a manner analogous to that described in Example 8 from (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methylvalerohydrazide and using imidazole-1-acetic acid in place of N-tert-butoxycarbonyl-β-alanine there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-2′-[2-(1H-imidazol-1-yl)acetyl]-4-methylvalerohydrazide in the form of a gum.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[C:27]([CH3:34])=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[C:27]([CH3:34])=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: Cc1c(Cl)cccc1NN
Product: Cc1c(Cl)cccc1-n1nccc1-c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-chloro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=441.0 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH:7]=1
Reactant: Fc1ccccn1
Reactant: O=c1[nH]nc2ccc(Br)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1n(-c2ccccn2)nc2ccc(Br)cn12
Temperature: 160 °C
Yield: 51 %

Procedure:
A mixture of 6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.467 mmol), K2CO3 (129 mg, 0.94 mmol), and 2-fluoropyridine (1 mL) was placed in a sealed microwave vial and heated to 160° C. in a microwave reactor for 90 minutes. The reaction was cooled, diluted with water/EtOAC and the layers were separated. The organic layer was washed with NaHCO3 and brine. The organics were dried (MgSO4), filtered, concentrated and purified by flash chromatography (Rf=0.23, 1:2 hexanes:EtOAc) to afford 70 mg (51% y) 6-bromo-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one, which was used directly in the next reaction (M+1=292.1). Compound 34 was synthesized according to the procedure disclosed in Example 1, however the reaction was done in 24 hours (28% y). C18H11F3N4O2, m/z (ESI)=373.2 [M+H]+. 1H NMR (δ, d6-DMSO, 400 MHz) 8.54-8.57 (m, 1H), 8.22 (t, J=1.2 Hz, 2H), 7.98-8.07 (m, 2H), 7.88 (dt, J=2.0, 8.4 Hz, 2H), 7.72 (dd, J=2.0, 9.6 Hz, 1H), 7.43-7.47 (m, 3H), 7.36-7.40 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13].O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N+:12]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]([F:9])([F:10])[F:11])([O-:14])=[O:13]
Reactant: Cc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 15 °C

Procedure:
2 gms of 3-methyl benzotrifluoride is dissolved in 5 mls of methylene chloride and added dropwise with stirring at -20° C. to -25° C. to 6 gms of 98% HNO3 dissolved in 10 ml methylene chloride. After addition, the reaction was allowed to finish by warming the mixture to 15° C. After treatment with ice and water followed by sodium bicarbonate wash, near quantitative yield was recovered. Isomer distribution was as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
A 3-neck flask was charged with 3-nitro-4-phenylaminobenzoic acid (see Synthesis Example 1-1) (1.67 g, 6.70 mmol), palladium/carbon (Pd:10%, 0.170 g), and tetrahydrofuran (34 mL), the atmosphere was replaced with hydrogen using three cycles of vacuum/hydrogen purge, and this was stirred at room temperature for 2.5 hours. After substituting in nitrogen, distilled water (20 mL) was added and this was stirred for 10 minutes, insoluble material was filtered off through a Celite layer (20 mm thickness), and this same layer was further washed with tetrahydrofuran (20 mL, 3 times). The filtrate and the wash solutions were combined, and the solvent was distilled off under reduced pressure. This was successively extracted with ethyl acetate (approx. 50 mL, 4 times), washed with distilled water (30 mL), and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and further drying under reduced pressure yielded the title compound (1.45 g, 95.3% yield) as a pale yellow solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16].O>C(O)(=O)C>[F:16][C:10]1[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5](=[O:7])[CH3:6]
Reactant: Nc1ccc(O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (1.3 ml, 13.8 mmol) was added dropwise to a solution of 4-amino-3-fluorophenol (1.0 g, 7.9 mmol) in acetic acid (25 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h and water (2 ml) was added and the stirring was continued for 30 minutes at room temperature. The mixture was evaporated to dryness in vacuo. The yield of the crude product was 1.3 g (100%) and it was used without further purification.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[C:32](#[N:35])[CH2:33]O>CO>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:33][C:32]#[N:35]
Reactant: N#CCO
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC#N)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in methanol (10 ml) is added glycolonitrile (50%, 0.19 ml) and the mixture is stirred at room temperature for 20 minutes, and then refluxed for 30 minutes. Thereto is added additional glycolonitrile (0.5 ml) and the mixture is refluxed for 5.5 hours. The reaction solution is concentrated and to the resulting residue is added ethyl acetate. The precipitated crystal is collected by filtration, and recrystallized from acetonitrile to give 5-(N-methyl-N-cyanomethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.32 g) as colorless needles, m.p. 227-228° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(O)C(N)(CO)CO.[N-]=C=O>C(Cl)Cl>[C:33]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)(=[O:35])[CH3:34]
Reactant: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-(1,2,3,4-tetrahydroquinolin-7-yl)-1,1′-biphenyl-4-carboxamide (Example 24) (66 mg, 0.2 mmol) in DCM (1 ml) was added triethylamine (42 ul, 0.3 mmol) followed by acetyl chloride (20.5 ul, 0.3 mmol). The reaction was stirred at ambient temperature for 15 mins then treated with polymer supported trisamine resin (31 mg, 0.1 mmol) and polymer supported isocyanate resin (20 mg, 0.04 mmol). After 5 mins the resins were removed by filtration and the filtrate was washed with 2M hydrochloric acid, dried over MgSO4 and concentrated in vacuo to give the title compound as an off-white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.94 (d, 2H), 7.84 (d, 1H), 7.78 (br, 1H), 7.72 (d, 2H), 7.64 (d, 2H), 7.45 (m, 4H), 7.15 (d, 1H), 3.80 (t, 2H), 2.74 (t, 2H), 2.33 (s, 3H), 1.98 (qn, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH3:16])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CCCCNC
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: O=S(Cl)Cl
Product: CCCCN(C)C(=O)c1ccc(Br)c(C)c1

Procedure:
From 4-bromo-3-methylbenzoic acid (400 mg), thionyl chloride (0.4 ml) and N-methyl-1-butanamine (0.8 ml).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#C.Br[C:17]1C=C2C(C(C)(C)CCC2=O)=C[CH:18]=1>>[C:17]([C:12]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]2=[O:13])=[CH:4][CH:3]=1)#[CH:18]
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Product: C#Cc1ccc2c(c1)C(=O)CCC2(C)C

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1 (2H)-one (Compound K), 7 g (27.6 mmol) of 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) was converted into the title compound using 39 ml (36.6 mmol) of (trimethylsilyl)acetylene, 0.97 g (1.3 mmol) of his (triphenylphosphine) palladium(II) chloride, 0.26 g (1.3 retool) of cuprous iodide and 0.6 g (4.3 mmol) of K2CO3.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1>C(O)(=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:23])=[CH:4][CH:3]=[C:2]([N:1]2[CH:26]=[CH:30][CH:29]=[CH:28]2)[CH:11]=3)=[O:13])=[CH:17][CH:18]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(-n3cccc3)ccc2c1O
Temperature: 25 °C

Procedure:
A mixture of 100 mg of 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide and 0.043 mL 2,5-dimethoxytetrahydrofuran in 1 mL of acetic acid is refluxed for four hours. (The mixture rapidly turned very dark.) It is cooled to 25° C. and the precipitate is collected by filtration. It is washed with three 1 mL portions of acetic acid and dried in a stream of air. After drying at 75° C. the product is obtained as 20 mg of a brown powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[C:4]=1[S:11]([NH2:14])(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[C:4]=1[S:11]([NH:14][C:26]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])(=[O:12])=[O:13]
Reactant: CSc1cccc(SC)c1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCNC(=O)NS(=O)(=O)c1c(SC)cccc1SC
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A stirred suspension of 5.0 g (0.02 mol) of 2,6-bis(methylthio)benzenesulfonamide, 8.3 g (0.06 mol) potassium carbonate and 3.4 ml (0.03 mol) n-butyl isocyanate was heated at reflux for four hours. After stirring at 25° overnight, the mixture was poured into ice and 30 ml 10% HCl. The resulting precipitate was collected, washed several times with water and air dried to provide 6.5 g of the title compound, m.p. 151°-154°.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: CNCCOC
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: COCCN(C)Cc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with N-(methoxyethyl)methylamine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3-(((2-methoxyethyl)(methyl)amino)methyl)-6,7-dihydro-5H-5,7-methanobenzo [c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 24 mg (26%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[[2-methoxyethyl(methyl)amino]methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=441.