Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6]CC)=[O:5].[CH3:18][N:19]([CH3:21])N>>[CH3:18][N:19]([CH3:21])[NH:6][C:4](=[O:5])[C:3]1[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:11]=[C:12]([Cl:13])[C:2]=1[Cl:1]
Reactant: CN(C)N
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Product: CN(C)NC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Yield: 81 %

Procedure:
The acid prepared in Example 203 was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with 1,1-dimethylhydrazine using General Method E1 to afford the title compound. Purification by recrystallization from ether/hexanes gave 0.62 g of the title compound as off-white crystals in 81% yield. m.p. 144-145° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH:8]=[CH:9][CH:10]=1)[C:2]#[CH:3]>C(N(CC)C1C=CC=CC=1)C>[O:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[CH:6]=2)[CH:3]=[CH:2][CH2:1]1
Reactant: C#CCOc1cccc(CCCNC(=O)C2CC2)c1
Solvent: CCN(CC)c1ccccc1
Product: O=C(NCCCc1ccc2c(c1)OCC=C2)C1CC1
Yield: 3.9 %

Procedure:
A solution of cyclopropanecarboxylic acid [3-(3-prop-2-ynyloxy-phenyl)-propyl]-amide (415 mg) in N,N-diethylaniline (2 ml) was heated at 215° C. for 24 h. The cooled mixture was purified by column chromatography on silica. Elution with hexane/ethyl acetate 3:1 gave the title compound (A) as a colourless solid (16 mg)
Reaction SMILES: FC(F)(F)C(N1CCC([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)CC1)=O.IC1C=NN([C@H:42]2[CH2:47][CH2:46][C@H:45]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][C:49]3=[O:54])[CH2:44][CH2:43]2)C=1>>[CH3:33][N:31]1[CH:32]=[C:28]([C:24]2[CH:23]=[C:22]([C:19]3[N:20]=[CH:21][C:16]([C:14]4[CH:13]=[N:12][N:11]([CH:42]5[CH2:43][CH2:44][CH:45]([N:48]6[CH2:53][CH2:52][O:51][CH2:50][C:49]6=[O:54])[CH2:46][CH2:47]5)[CH:15]=4)=[CH:17][N:18]=3)[CH:27]=[CH:26][CH:25]=2)[CH:29]=[N:30]1
Reactant: O=C1COCCN1[C@H]1CC[C@H](n2cc(I)cn2)CC1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C(=O)C(F)(F)F)CC5)c4)cn3)c2)cn1
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCC(N6CCOCC6=O)CC5)c4)cn3)c2)cn1

Procedure:
The title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 230 mg; 0.73 mmol; 1.0 eq.) and trans-4-[4-(4-Iodo-pyrazol-1-yl)-cyclohexyl]-morpholin-3-one (intermediate 26; 274 mg; 0.73 mmol; 1.0 eq.). The crude was purified by recrystallisation in methylisobutylketone. The title compound was obtained as a beige solid (16 mg, 5%). 1H NMR (300 MHz, DMSO) δ 9.16 (s, 2H), 8.54 (s, 2H), 8.40-8.06 (m, 3H), 7.93 (s, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 4.31 (d, J=39.6 Hz, 2H), 4.05 (s, 2H), 3.95-3.71 (m, 5H), 2.20 (d, J=11.5 Hz, 2H), 2.03-1.49 (m, 6H), 1.23 (s, 1H), 0.84 (t, J=7.3 Hz, 1H). HPLC (Condition A): Rt 3.31 min (purity 99.2%). MS (ESI+): 484.4.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C([NH:39][C:40]1C=[CH:44][C:43]([C:46](=[O:51])NCCC)=[CH:42][CH:41]=1)=O)C2>>[N:39]1[CH:40]=[CH:41][CH:42]=[C:43]([C:46]([N:5]2[CH2:6][CH2:7][CH:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])[CH2:9][CH2:10]2)=[O:51])[CH:44]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(NCCCOC1CCNCC1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(NCCCOC1CCN(C(=O)c2cccnc2)CC1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting nicotinoyl chloride for acetyl chloride and N-(3-(piperidin-4-yloxy)propyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.51-8.70 (m, 2H) 7.75-7.88 (m, 1H) 7.46 (dd, J=7.73, 4.96 Hz, 1H) 7.20-7.38 (m, 3H) 6.28 (t, J=5.35 Hz, 1H) 4.57 (s, 4H) 3.83-4.01 (m, 1H) 3.40-3.63 (m, 6H) 3.16 (q, J=6.35 Hz, 2H) 1.35-1.95 (m, 7H); MS (ESI(+)) m/e 409 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][CH2:21][NH:22][S:23]([C:26]1[C:27]2[CH:28]=[CH:29][N:30]=[CH:31][C:32]=2[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH:35]=1)(=[O:25])=[O:24])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)(C)(C)C.[ClH:44]>C(Cl)Cl.CO>[ClH:44].[ClH:44].[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][NH:7][CH2:20][CH2:21][NH:22][S:23]([C:26]2[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[CH:33]=[C:34]([C:36]3[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=3)[CH:35]=2)(=[O:25])=[O:24])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNS(=O)(=O)c1cc(-c2ccc(O)cc2)cc2cnccc12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCNCCNS(=O)(=O)c2cc(-c3ccc(O)cc3)cc3cnccc23)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To {2-[7-(4-hydroxy-phenyl)-isoquinoline-5-sulfonylamino]-ethyl}-[3-(4-nitro-phenyl)-propyl]-carbamic acid tert-butyl ester, (0.090 g, 0.148 mmol) in 6 ml (1:1) CH2Cl2/MeOH bubble HCl (g) for several minutes, then stir for 1 h and filter to give 0.0859 g of 7-(4-hydroxy-phenyl)-isoquinoline-5-sulfonic acid {2-[3-(4-nitro-phenyl)-propylamino]-ethyl}-amide dihydrochloric acid in 100% yield. ES Positive Ion MS [M+H]+ ion observed: m/z 507. 1H-NMR (DMSO-d6) δ9.62 (s, 1H), 8.93 (br s, 2H), 8.75 (s, 1H), 8.69-8.71 (m, 2H), 8.61 (s, 1H), 8.52 (d, J=6.2 Hz, 1H), 8.15 (d, J=8.8 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 3.10-3.15 (br m, 2H), 2.90-3.00 (br s, 2H), 2.87 (br s, 2H), 2.75 (t, J=7.5 Hz; 2H), 1.87-1.90 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].C(=O)(O)[O-].[Na+].Cl[S:24]([C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:26])=[O:25]>O1CCOCC1>[CH3:32][O:31][C:29]([C:28]1[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=1[S:24]([NH:10][C@@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)(=[O:26])=[O:25])=[O:30]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 9 h
Yield: 71.6 %

Procedure:
2.3 g of p-nitro-D-phenylalanine are suspended in 25 ml of dioxan and treated with 10ml of 1N sodium hydroxide solution and 1.7 g of sodium bicarbonate. A solution of 2.6 g of methyl 2-chlorosulfonylbenzoate in 22 ml of dioxanl is added dropwise thereto and the mixture is stirred at room temperature for 9 hours. The reaction mixture is poured into ice-cold 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated. There are obtained 3.2 g of N-[[o-(methoxycarbonyl)phenyl]sulfonyl]-3-(p-nitrophenyl)-D-alanine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH2:15]([S:22][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(SCc2ccccc2)nc1
Yield: 72.8 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-chloro-5-methyl pyridine (200 mg, 1.5 mmol), K2CO3 (325 mg, 2.3 mmol), benzylmercaptan (292 mg, 2.3 mmol) and DMSO (1.5 ml) at 150° C. for 4 h gave the title compound (235 mg, 69%) which was used in the next step without further purification.
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].[OH:14][C@H:15]([CH2:35][NH:36][C:37]([CH3:50])([CH3:49])[CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[CH2:16][O:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[OH:14][C@H:15]([CH2:35][NH:36][C:37]([CH3:49])([CH3:50])[CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[CH2:16][O:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([C:32]([O:34][CH:3]([O:2][C:1]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:13])[CH3:4])=[O:33])=[CH:30][CH:31]=1)[CH3:19]
Reactant: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(OC(=O)OC1CCCCC1)OC(=O)c1ccc(-c2ccccc2C(C)OC[C@H](O)CNC(C)(C)Cc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
1-Chloroethyl cyclohexyl carbonate (149 mg) obtained in Step 1 was dissolved in N,N-dimethylformamide (5.0 ml), 2′-[1-[(2R)-2-hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-4-carboxylic acid (300 mg) obtained in Step 2, potassium carbonate (99 mg) and potassium iodide (50 mg) were successively added and the mixture was stirred at 60° C. for 1 day. Water was added to the reaction mixture and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with water (3 times) and brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=15:1) to give the title compound (381 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:5]([O:18][CH3:19])[CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:5]([O:18][CH3:19])[CH:4]=1)=[O:2]
Reactant: CCOC(=O)CCCOc1ccc(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(C=O)ccc1OCCCC(=O)O
Yield: 58.3 %

Procedure:
4-(4-Formyl-2-methoxyphenoxy)butanoic acid, ethyl ester (240 mg, 0.90 mmol) is dissolved in 3 mL of methanol/water (3:2) and treated with 435 mg (3.15 mmol) of potassium carbonate according to the procedure described for Example 4 to give 125 mg (58%) of 4-(4-formyl-2-methoxyphenoxy)butanoic acid as a white powder: m.p. 143°-148°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3575, 3500, 1720, 1700, 1680, 1600, 1585 cm-1 ; MS (CI (low res)) m/e 239 (M+H), 221, 207, 153.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:31][CH2:32][CH2:33][NH2:34]>>[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:31][CH2:32][CH2:33][NH:34][C:18]([C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:8](=[O:21])[NH:9]2)=[CH:14][CH:13]=1)=[O:19]
Reactant: CC1CCCCN1CCCN
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Product: CC1CCCCN1CCCNC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
65 mg (52%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mol) obtained in Example 1 and 3-(2-methyl-piperidine-1-yl)-propylamine (103 mL, 0.598 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:19]O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:19])=[O:6]
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1C
Reactant: CO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(C)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of 3,4-dimethyl-2-nitrobenzoic acid (13 g) and thionyl chloride (11.8 g) in toluene (100 ml) was refluxed for 4 h. The reaction mixture was cooled at 0° C., treated with methanol (15 ml) and the solvent was removed under vacuum. The reaction mixture was treated water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 3,4-dimethyl-2-nitrobenzoate (10 g). 1H-NMR (400 MHz, CDCl3): 2.19 (s, 3H), 2.38 (s, 3H), 3.87 (s, 3H), 7.25 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.C[O:17]C1C=C2C(=CC=1)C=C([C@H](C)C(O)=O)C=C2>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:10]1([NH:9][C:8]([NH:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DCC (0.56 g, 2.7 mmol) in CH2Cl2 (20 mL) was added dropwise to a stirred solution of the product of Example 13d (0.5 g, 2.45 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (0.56 g, 2.45 mmol), and DMAP (0.05 g) in CH2C2 (20 mL) at room temperature. The resulting suspension was stirred for 1 hour at room temperature. The precipitate was removed by filtration and washed with CH2Cl2 (25 mL). The filtrate was concentrated to give a green oil which was chromatographed on silica gel eluting with 1:9 MeOH:CH2Cl2 to afford a green solid (contaminated with dicyclohexyl urea). The solid was triturated with hexane (50 mL) and filtered. The filtrate was concentrated to give the title compound (0.7 g, 69%) as a viscous green oil. 1H NMR (300 MHz, CDCl3) δ 7.50-7.65 (mult, 3H), 7.01-7.29 (mult, 3H), 4.18 (t, J=6.5 Hz, 2H), 3.83 (s, 3H), 3.72 (q, J=7.0 Hz, 1H), 2.51 (t, J=6.6 Hz, 2H), 2.13 (s, 3H), 2.00-2.60 (mult, 8H), 1.45 (d, J=7.2 Hz, 3H), 1.47 (d, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 157.7, 135.4, 133.7, 129.2, 128.9, 127.2, 126.1, 126.0, 119.0, 105.6, 61.1, 57.6, 55.3, 51.4, 51.3, 46.0, 45.4, 40.8, 36.5, 36.4, 18.2; mass spectrum (API-TIS) m/z 415 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[CH:48][C:47]([Cl:52])=[CH:46][N:45]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:44]([Cl:43])=[N:45][CH:46]=[C:47]([Cl:52])[CH:48]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1cc(Cl)cnc1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(Cl)cnc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2,5-dichloro-3-(chloromethyl)pyridine and isolated as light-yellow gum. MS (m/e): 442.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:15]([OH:17])=O)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].CCN(C(C)C)C(C)C.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:15](=[O:17])[NH:36][CH2:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:29][CH:30]=1)[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH3:2]
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)NCCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the compound of example 70 (1.55 g, 5.96 mmol) in anhydrous DMF (5 mL) was treated successively with DIEA (5.2 mL), 4-biphenylethyl amine (2.40 g, 11.92 mmol) and TBTU (2.76 g, 8.34 mmol). The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was treated with HCl (1M, excess) and the mixture was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was flashed with 30% ethyl acetate in hexanes and the desired product was obtained as a white solid. 1H-NMR(CDCl3, 400 MHz: 1.22(t, J=7.2, 3H); 1.42(s, 9H); 2.32-2.42(m, 2H); 2.60-2.75(m, 2H); 2.83(t, J=7.1 Hz, 2H); 3.02(m, 1H); 3.53(m, 2H); 4.11(m, 2H); 6.25(m, t, 5.1 Hz, 1H); 7.30(m, 3H); 7.43(m, 2H); 7.57(m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41])=[CH:34]2>CN(C)C=O>[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([S:40]([N:43]1[CH2:48][CH2:47][N:46]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[N:3]=4)=[CH:17][CH:16]=3)=[O:15])[CH2:45][CH2:44]1)(=[O:42])=[O:41])=[CH:34]2
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Reactant: Cn1nc(-c2ccc(C(=O)O)cc2)ccc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)cc2)ccc1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.2 %

Procedure:
To a solution of 4-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoic acid, (0.637 g, 2.76 mmol) in N,N-dimethylformamide was added 1,1′-carbonyldiimidazole (0.930 g, 5.74 mmol, 2.07 eq.). The resulting solution was stirred at room temperature for 5 hours, whereupon 5-chloro-2-(piperazin-1-ylsulphonyl)-1H-indole (see WO 99/57113, 0.622 g, 2.08 mmol, 1.11 eq.) was added. The reaction mixture was stirred at 25° C. for 14 h and then evaporated in vacuo. The residue was purified by flash column chromatography: first eluting with ethyl acetate:toluene (2:1), then with ethyl acetate. During concentration of the desired fraction, a white solid precipitated. The solid was triturated with hot ethyl acetate (50 mL) to remove a trace of impurity. After drying, pale yellow solid were isolated. De-colorization on charcoal using hot methanol together with the re-crystallization in methanol, gave 0.79 gram 6-{4-[4-(5-chloro-1H-indole-2-sulphonyl)-piperazine-1-carbonyl]-phenyl}-2-methyl-2H-pyridazin-3-one as fine white crystals (yield 56%).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](O)(=[O:21])[C:18](O)=[O:19].Cl>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]1)[NH:15][C:18](=[O:19])[C:17](=[O:21])[NH:16]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(F)c(-n2ccc(=O)cc2)cc1N
Agent: Cl
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2F)cc1
Yield: 73.7 %

Procedure:
First, 4.266 g of 4-fluoro-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine, and 1.927 g of oxalic acid were added to 48 ml of 4N hydrochloric acid. The mixture was refluxed by heating for 2.5 hours. After the reaction, precipitated crystals were filtered, washed with water, and dried to give 3.920 g of 6-fluoro-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:33])([CH3:32])[C:28]([O:30]C)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+].[CH3:37]O>O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:33])[C:28]([OH:30])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][C:6]([CH3:37])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of methyl 2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate and corresponding acid (100 mg, 0.22 mmol) was treated with 1 M of lithium hydroxide in water (2 mL) and methanol (0.37 mL). The reaction was stirred at room temp for 12 h. Acidified by 10% aqueous citric acid to pH=5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried and concentrated to give 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid 216. 1H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.39 (s, 0H), 8.37 (s, 1H), 7.98 (s, 1H), 7.92 (s, 2H), 7.45 (dd, J=8.4, 1.8, 1H), 7.36 (d, J=1.7, 1H), 5.90 (dt, J=13.2, 6.6, 1H), 4.53 (q, J=6.0, 4H), 1.72 (d, J=42.8, 6H), 1.50 (d, J=6.6, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=[O:25]>CO>[CH3:22][NH:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1)=[O:25]
Reactant: Nc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Reactant: CN=C=O
Solvent: CO
Product: CNC(=O)Nc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Reaction time: 8 h

Procedure:
The mixture of 0.7 g of 2-(p-aminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, 1.4 g of methylisocyanate and 25 ml of methanol is refluxed for 7 hours and allowed to stand at room temperature overnight. It is evaporated, the residue treated with diluted aqueous sodium hydroxide and diethyl ether, the aqueous solution separated, washed with diethyl ether and its pH adjusted to 8.5 with ammonium chloride. The precipitate formed is collected, washed with methanol, then with diethyl ether and dried, to yield the 2-(p-methylcarbamoylaminophenyl)-pyrazolo[4,3-c]quinolin3(5H)-one, showing IR-peaks of 895, 869, 850, 825, 816, 812, 785, 780, 767 and 738 cm-1.