Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:21]3[C:22]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:18]=[CH:19][CH:20]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1Cc2cccc(-c3cccc4ccccc34)c2C1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Using a method similar to Example 15b), 2.5 g (13.8 mmol) of 7-chloro-2-methyl-1-indanone (1), 2.97 g (17.3 mmol) of naphthylboronic acid and 3.66 g (34.6 mmol) of sodium carbonate were placed in 40 ml of o-xylene/5 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 1.55 mg (0.0069 mmol) of palladium acetate and 7.3 mg (0.027 mmol) of triphenylphosphine, the reaction mixture was stirred for 8 hours at 100° C. After 2, 4 and 6 hours, the same amount of palladium acetate and triphenyl phosphine were added again each time. After addition of 40 ml of water, the phases were separated, the aqueous phase was extracted 3 times with 40 ml each time of ether, the combined organic phases were washed with 40 ml of water and 40 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 3.26 g of (16) as solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]#N)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[ClH:24].C(OC(=O)[C@H](CCCCNC=NOCC)[NH:32][C:33](OC(C)(C)C)=[O:34])(C)(C)C.Cl.C(OC(=O)[C@H](CCCNCOC=N)NC(OC(C)(C)C)=O)(C)(C)C.CO>ClCCl>[ClH:24].[C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][O:34][CH:33]=[NH:32])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCON=CNCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC#N)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](CCCNCOC=N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNCOC=N)C(=O)OC(C)(C)C

Procedure:
From 1.6 g (4.89 mmol) N2-(tert-butoxycarbonyl)-N6-(cyano)-L-lysine tert-butyl ester was prepared 1.5 g (75%) of foamy solid N2-(tert-butoxycarbonyl)-N6-(ethoxyiminomethyl)-L-lysine tert-butyl ester hydrochloride by the method described for N2-(tert-butoxycarbonyl)-N5-(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride. TLC (methanol:dichloromethane/1:9) Rf=0.36. Mass spectrum (CI) 360 (MH+, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[C:28]([O:31][CH2:32][CH2:33]O)(=[O:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:28]([O:31][CH2:32][CH2:33][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])[N:10]=2)=[CH:14][CH:15]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCCO
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)OCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
5-(4-Chlorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-hydroxyethyl acetate, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(2-acetoxyethyloxy)phenyl)-5-(4-chlorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C(OC(=O)[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](C=O)C=1)(C)(C)C.C1(NC(C2CCNCC2)=O)CCCC1>>[CH:34]1([NH:33][C:4]([CH:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=3)[CH2:10][CH2:11]2)=[O:5])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C=O)c1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Agent: O=C(NC1CCCC1)C1CCNCC1
Product: Nc1cccc(CN2CCC(C(=O)NC3CCCC3)CC2)c1

Procedure:
The title compound is prepared according to the reactions 1.001a and 1.001d described above using (3-formyl-phenyl)-carbamic acid tert-butyl ester and piperidine-4-carboxylic acid cyclopentylamide: LC-MS A: tR=0.45 min; [M+H]+=302.40.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:19]3[C:20]([C:24]#[C:25][Si](C)(C)C)=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=[CH:33][C:15]=3[CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:24]([C:20]1[C:19]2[N:13]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:38])([F:39])[F:1])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH2:14][C:15]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[N:30][C:16]=3[NH:17][C:18]=2[CH:23]=[CH:22][CH:21]=1)#[CH:25]
Reactant: C[Si](C)(C)C#Cc1cccc2c1N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cccc2c1N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-7-[(trimethylsilyl)ethynyl]-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (414 mg, 0.75 mmol) in MeOH (40 mL) was added K2CO3 (306 mg, 3.00 mmol). The reaction was stirred at rt for 1.5 h, diluted with H2O, and the product was extracted with EtOAc. The combined organic extracts were washed with H2O, brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography to give the title compound. 1H NMR (500 MHz, (CD3)2CO): δ 8.50 (s, 1H), 7.76 (d, 1H), 7.40 (m, 4H), 7.27 (m, 1H), 7.15 (d, 3H), 5.27 (d, 1H), 4.70 (d, 1H), 3.81 (s, 1H). LCMS: m/z 514.1 (m+H).
Reaction SMILES: [OH-:1].[Li+].[CH2:3]([C:9]1[C:14]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH:20]3[CH2:24][CH:23]([C:25]([O:27]C)=[O:26])[NH:22][C:21]3=[O:29])=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl>O.O1CCCC1>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH:20]([C:21]([OH:29])=[O:1])[CH2:24][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:22])=[CH:30][CH:31]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CCCCCCc1ccccc1-c1ccc(OC2CC(C(=O)OC)NC2=O)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc(CCCCCCc2ccccc2)cc1)C(=O)O)C(=O)O
Temperature: 58 °C
Reaction time: 3.8 h
Yield: 27.3 %

Procedure:
A mixture of lithium hydroxide (0.712 g) in water (9.3 ml) and tetrahydrofuran (29 ml) was treated with methyl 3-[4-(6-hexylphenyl)phenoxy]-2-pyrrolidone-5-carboxylate (3.91 g), and heated to 58° C. After about 3.8 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was then treated with 5N HCl (5.94 ml). The resulting light suspension was sonicated then stirred at room temperature for fifteen minutes . Insolubles were collected by filtration, washed with 1:1 tetrahydrofuran:water (10 ml), then tetrahydrofuran (10 ml) and finally water (10 ml). The title compound crystallized out from the filtrate and was collected by filtration. This material was dried in vacuo to give 1.077 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:9][C:10]([C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7].[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:9][C:10]([C:12]1[N:13]=[N:14][C:15]([N:23]2[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]2)=[CH:16][CH:17]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)NC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: COC(=O)C(CC(C)C)NC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 2-[(6-chloropyridazine-3-carbonyl)amino]-4-methylpentanoic acid methyl ester in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (36% yield). 1H NMR (400 MHz, CDCl3) δ 8.16, 8.04, 7.85, 7.66-7.53, 7.28, 7.00, 4.82-4.77, 4.14-3.68, 3.58-3.51, 1.83-1.60, 1.03-0.95.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[CH:10]([NH2:13])[CH2:11][O:12][C:8]=2[CH:7]=1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[CH:10]([NH:13][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: NC1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)CNC1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of 6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-amine (127.3 mg) and THF (4.0 mL) were added TEA (0.172 mL) and ethyl 2-bromoacetate (0.055 mL) at 0° C. The mixture was stirred at room temperature for 4 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (32.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:26])=[O:15])=[CH:12][CH:13]=2)=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=1
Reactant: Nc1ccc(-c2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccc(N)cc2C(F)(F)F)cc1
Yield: 50 %

Procedure:
Crude 4'-amino-2'-trifluoromethylbiphenyl-4-carboxylic acid (D33, 0.31 g, 0.078 mol) was dissolved in methanol (200 ml) and treated with conc. H2SO4 acid (1 ml). The mixture was heated at reflux under argon for 2 hrs, then concentrated in vacuo. The resultant yellow solid was basified with 10% aqueous Na2CO3 solution, extracted with dichloromethane, then the extract dried (Na2SO4) and concentrated in vacuo. The resultant yellow solid was purified by preparative TLC on silica gel plates eluting with 1:1 pet ether/ether to afford the title compound as an off-white solid (161 mg, 50%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)=[O:9].[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36](Cl)=[O:37].C[N+]([O-])=O>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([NH:10][C:8](=[O:9])[C:7]3[C:20]([F:31])=[CH:21][CH:22]=[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[C:6]=3[F:5])[CH:12]=2)[NH:17][CH:18]=1)=[O:37]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)c4ccc(Cl)c(Cl)c4)c3c2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 21.4 %

Procedure:
A slurry of aluminum trichloride (0.078 g, 0.59 mmol) was added to a slurry of 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.029 g, 0.074 mmol) in DCM (1.2 mL) at 0° C., and the reaction mixture was allowed to stir at 0° C. for 40 minutes. 3,4-Dichlorobenzoyl chloride (0.023 g, 0.11 mmol) was added, and the mixture was allowed to slowly warm to room temperature overnight. CH3NO2 (300 μL) was added, and the reaction mixture was sonicated for 2 minutes. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was quenched with ice and then partitioned between aqueous sodium bicarbonate and EtOAc. The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residual solids were triturated with 5% MeOH/EtOAc to provide N-(3-(3,4-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (9 mg, 22%). 1H NMR (400 MHz, CD3OD) δ 8.98-8.99 (m, 1H), 8.66-8.68 (m, 1H), 8.09 (s, 1H), 7.63-7.79 (m, 3H), 7.13-7.17 (m, 1H), 3.11-3.15 (m, 2H), 1.85-1.91 (m, 2H), 1.05-1.09 (m, 3H); m/z (APCI-pos) M+1=567.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([OH:17])=O)[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N+:34]([C:37]1[CH:55]=[CH:54][C:40]([CH2:41][O:42][C:43]([NH:45][C:46]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[NH:47])=[O:44])=[CH:39][CH:38]=1)([O-:36])=[O:35].C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:51]3[CH2:52][CH2:53][N:48]([C:46](=[NH:47])[NH:45][C:43]([O:42][CH2:41][C:40]4[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:55][CH:54]=4)=[O:44])[CH2:49][CH2:50]3)=[O:17])[CH2:10]2)=[CH:18][CH:19]=1
Reactant: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=N)NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C)C2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
480 mg of (2S, 4S)-4-(4-methoxybenzylthio)-1-methylpyrrolidine-2-carboxylic acid were suspended in 20 ml of dry acetonitrile, and 325 mg of N,N'-carbonyldiimidazole were added to this suspension, after which the mixture was stirred at 40° C. for 1 hour. At the end of this time, the reaction mixture was cooled with ice, and 980 mg of 1-(4-nitrobenzyloxycarbonylamidino)piperazine bis(trifluoroacetate) [prepared as described in step (a) above] and 320 μl of diisopropylethylamine were added to the mixture, which was then stirred at room temperature overnight. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium hydrogencarbonate, with water (4 times) and with an aqueous solution of sodium chloride, in that order. The ethyl acetate solution was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted with a 4:1 by volume mixture of ethyl acetate and methanol. The fraction containing the desired compound was concentrated by evaporation under reduced pressure, to obtain 860 mg of the title compound, as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]([NH:9][C:10]1[C:11](Cl)=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]>S1(CCCC1)(=O)=O.S(=O)(=O)(O)O>[CH3:17][N:5]1[C:6]2[C:7](=[O:8])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=3[NH:1][C:2]=2[CH:3]=[N:4]1
Reactant: Cn1ncc(N)c1C(=O)Nc1cccnc1Cl
Agent: O=S(=O)(O)O
Solvent: O=S1(=O)CCCC1
Product: Cn1ncc2c1C(=O)Nc1cccnc1N2

Procedure:
An amount of 25.0 gm (0.099 mol) of 4-amino-N-(2-chloro-3-pyridinyl)-1-methyl-1H-pyrazole-5-carboxamide was dissolved in 100 ml of sulfolane and, after addition of 5 drops of concentrated sulfuric acid, heated for 1 hour to 120° C. The cold reaction mixture was filtered, and the filtration residue was suspended with 5% aqueous ammonia solution and again filtered. The product obtained was thoroughly washed with water, stirred with methanol, and subjected to cold suction filtration. After drying, 14.6 gm (68.5% of theory) of colorless crystals were obtained (m.p.: 304°-305° C.).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[OH-].[Na+]>CO>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[O:23])=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N(CCCCCCCCCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1

Procedure:
As described in example 1(b), the reaction is carried out with 31.2 g (68 mmol) of 11-[4-chloro-N-(4-methoxyphenyl)-benzamido]-undecanoic acid methyl ester, 4.4 g (0.11 mol) of sodium hydroxide and 200 cc. of methanol. Reaction time: 15 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])(O)=[O:2].Cl.C([N:31]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25])(=[O:2])[NH2:31]
Reactant: CCOc1c(C(=O)O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(N)=O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 3-carboxy-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (153 mg) in dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg) and 1-hydroxybenzotriazole (76.5 mg), and the mixture was stirred for 2 hours at ambient temperature. To the mixture was added conc. ammonia solution (0.2 ml) with stirring, and the mixture was stirred for 6 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 3-carbamoyl-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (128.3 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:20]1[NH:25][C:24](=[O:26])[C:23]2=[C:27]([CH3:35])[N:28]=[C:29]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:22]2[N:21]=1)[CH3:2].[ClH:36]>C(OCC)C>[ClH:36].[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:19][CH:14]2[CH3:15])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:20]1[NH:25][C:24](=[O:26])[C:23]2=[C:27]([CH3:35])[N:28]=[C:29]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[N:22]2[N:21]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: Cl
Solvent: CCOCC
Product: CCOc1ccc(S(=O)(=O)N2CCNCC2C)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
220 mg (0.42 mmol) of 2-[2-ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,-f][1,2,4]-triazin-4-one (Example 1) are suspended in 20 ml of diethyl ether and, after addition of 20 mg (0.462 mmol) of 1 molar ethereal HCl solution, stirred at room temperature for 30 minutes. The solvent is distilled off under reduced pressure and the residue is dried under high vacuum.
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]([OH:8])[CH2:5][CH:6]=[CH2:7].[CH2:9](Br)[CH:10]=[CH2:11]>CN(C)C=O>[CH2:11]([O:8][C@@H:4]([CH3:3])[CH2:5][CH:6]=[CH2:7])[CH:10]=[CH2:9]
Reactant: C=CC[C@H](C)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H](C)CC=C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (21 g, 34 mmol) in N,N-dimetylformamide (100 mL) was dropwise added (S)-pent-4-en-2-ol (10 g, 116 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. After that, allyl bromide (14.0 g, 116.2 mmol) was dropwise added to the mixture at 0° C. The resultant mixture was stirred at 0° C. for another 3 h, and the mixture was quenched by saturate ammonium chloride solution (500 mL). The aqueous layer was extracted with tert-butyl methyl ether (200 mL×3), and the combined organic layers were washed with water (100 mL×3) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford (S)-4-(allyloxy)pent-1-ene (˜20 ml tert-butyl methyl ether solution), which was used in the next step without further purification.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:14](C(OC(C)(C)C)=O)[C:15]([O:17]C(C)(C)C)=[O:16])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[N+:9]([O-:11])=[O:10]>C(O)(=O)C>[F:2][C:3]1[CH:4]=[C:5]([CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(F)c1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(CC(=O)O)cc(F)c1[N+](=O)[O-]

Procedure:
Acetic acid (7 ml) and concentrated hydrochloric acid (7 ml) were added to di-tert-butyl 3-fluoro-5-methoxy-4-nitrophenylmalonate (4.88 g, 12.7 mmol). The mixture was heated under reflux for 15 hours under stirring. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. To the residue were added 1N NaOH (200 ml) and ether (200 ml) to separate it into layers. The water layer thus obtained was acidified with 1N HCl, followed by extraction with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (2.83 g, 97%) was obtained as a pale brown solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>CCO.[Pd]>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:4]2[CH:3]=[CH:2][N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2ccn3nccc3n2)cc1
Yield: 67.5 %

Procedure:
A mixture of 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.5, step 2) (1.06 g, 4.0 mmol), triethylamine (0.84 mL), and 5% Pd—C (0.1 g) in EtOH (40 mL) was stirred in an atmosphere of hydrogen for 1.5 h. The catalyst was filtered off, the solution was evaporated in vacuo and the residue was crystallized from EtOAc/cyclohexane to give 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (0.62 g, 67%) as a pale-yellow solid. MS (ISP) 230.4 [(M+H)+]; mp 178-180° C.