Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCCCBr
Yield: 86.5 %

Procedure:
A mixture of 3.5 g (0.011 mole) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 15.4 ml (0.11 mole) of 1,5-dibromopentane and 1.2 g (0.0087 mole) of anhydrous potassium carbonate in 60 ml of anhydrous acetone was stirred at reflux for 77 hours. During the reflux period additional 1.4 g portions of potassium carbonate were added at 4, 21, 28 and 45 hours. The solvent was removed in vacuo and the residue was purified by HPLC using 17% ethyl acetate-hexane to yield 4.35 g (84% yield) of 4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [N:1]1([C:6](=[C:9]2[S:13][C:12]([CH3:15])(Cl)[CH2:11][S:10]2)[C:7]#[N:8])[CH:5]=[CH:4][N:3]=[CH:2]1>O1CCCC1>[N:1]1([C:6](=[C:9]2[S:13][C:12](=[CH2:15])[CH2:11][S:10]2)[C:7]#[N:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(Cl)CSC(=C(C#N)n2ccnc2)S1
Solvent: C1CCOC1
Product: C=C1CSC(=C(C#N)n2ccnc2)S1
Yield: 79.1 %

Procedure:
In 10 ml of tetrahydrofuran were dissolved 0.52 g (0.002 mole) of the 2-(1-imidazolyl)-2-(4-chloro- methyl-1,3-dithiolan-2-ylidene)acetonitrile obtained in Example 2 and 0.31 g of 1,8-diazabicyclo-[5,4,0]-7-undecene, and the reaction was carried out with heating under reflux for 1 hour. After the reaction solution was allowed to cool, the deposited salt was separated by filtration and the filtrate was concentrated to obtain crude crystals, which were then recrystallized from ethyl acetate-n-hexane to obtain 0.35 g of the desired compound in the form of crystals: melting point 115.7° C., yield 79%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Brc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3cccc(Br)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 34.3 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 198 mg of 4-bromoisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 147 mg of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH:29]([CH3:31])[CH3:30])=[N:11]2)=[CH:6][C:5]=1[NH:32][CH:33]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]1)(=[O:3])[NH2:2].C(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH:29]([C:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:32][CH:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[CH:6]=2)[N:11]=1)([CH3:31])[CH3:30]
Reactant: CC(C)c1nn(-c2ccc(C(N)=O)c(NC3CCN(C(=O)OC(C)(C)C)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NC3CCNCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
Tert-butyl 4-{2-carbamoyl-5-(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenylamino}piperidine-1-carboxylate (0.704 g) was dissolved in trifluoroacetic acid, followed by stirring at room temperature for 1 hr. The reaction solution was distributed between chloroform and saturated sodium bicarbonate water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain (76) (0.600 g, 99%) as a white solid.
Reaction SMILES: [CH2:1]([C:9]([O:11]C(C)(C)C)=[O:10])[O:2]CC[Si](C)(C)C.NC1N=[N:19][C:20]2[C:21]=1N=[CH:23][CH:24]=2.NC1N=NC2C=1N=CC=2.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.Cl.CCN(C(C)C)C(C)C.C[C@H]1CN2CCC[C@H]2CN1C(Cl)=O>CN(C=O)C.O1CCOCC1.C(Cl)Cl.CC(N(C)C)=O>[CH2:24]([C:20]1[CH:21]=[C:1]([C:9]([OH:11])=[O:10])[O:2][N:19]=1)[CH3:23]
Reactant: CC(C)(C)OC(=O)COCC[Si](C)(C)C
Reactant: NC1=C2N=CC=C2N=N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[C@H]1CN2CCC[C@H]2CN1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)O)on1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A 0.25 M solution of SEM-Boc protected aminopyrrolopyrazole, E1(III-2) was prepared using anhydrous DMF as solvent. A 0.25 M solution of 3-ethylisoxazole-5-carboxylic acid was prepared using anhydrous DMF as solvent. A fresh 0.5 M solution of o-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (HATU) was prepared in anhydrous DMF. To the reaction tube were added 320 μL (0.08 mmol, 1 equiv, 0.25M) of the 3-ethylisoxazole-5-carboxylic acid DMF solution prepared, 320 μL (0.080 mmol, 1 equiv, 0.25M) of SEM-Boc protected aminopyrrolopyrazole DMF solution prepared, and 40 μL (0.288 mmol, 3.6 equiv) neat TEA followed by the 160 μL (0.080 mmol, 1 equiv) of the HATU DMF solution. The reaction mixtures were stirred at 60° C. for 16 h. Then the tube was allowed to cool to room temperature. The solvents and volatiles from the tubes were removed in vacuo. To the residue were added 1 mL of EtOAc and 1 mL of 2M aqueous NaOH. After the tube was covered with Parafilm, the covered test tube was vigorously shaken until all residues have dissolved or the mixtures are completely homogenized. The agitation was stopped and the phases were allowed to separate completely. The supernatant organic layer (EtOAc layer) of each test tube was transferred into its corresponding receiving tube. EtOAc (0.5 mL) was added to the tube and extracted the organic layers after the agitation of the mixtures and these procedures were repeated twice. The solvent (EtOAc) and volatiles from the receiving tube were removed in vacuo until they were dry. To the residue was added 0.6 mL (2.4 mmol, 30 equiv) of 4M HCl in dioxane and the mixtures were stirred at room temperature for 2 h. Then the solvent, volatiles and HCl from the tube were removed in vacuo. To the residue were added 500 μL anhydrous DMA, 70 μL neat DIPEA (0.400 mmol, 5 equiv.). A 0.25 M solution of (3S,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carbonyl chloride, E1(VI), in anhydrous CH2Cl2 was prepared.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([N+:26]#[N:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(O)C.O>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26]/[N:27]=[C:8](\[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])/[C:9]([O:11][CH3:12])=[O:10])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: N#[N+]c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC(=O)/C(=N\Nc1ccc(Cl)c(Cl)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of dimethyl 3-oxopentanedioate (3.48 g, 20 mmol) in ethanol (12 mL) and water (40 mL) at room temperature was added sodium acetate (12.0 g, 146 mmol), and was followed by the addition of 3,4-dichlorobenzenediazonium solution (20 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The product was collected by filtration, then washed with water (˜50 mL) and dried overnight under reduced pressure to yield 6.776 g (93%) of (E)-dimethyl 2-(2-(3,4-dichlorophenyl)hydrazono)-3-oxopentanedioate as a yellow solid. MS (ESI) 347 (M+H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@H:28]([CH3:31])[CH2:29][OH:30])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C>C(O)C.CN(C=O)C.O>[N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@H:28]([CH3:31])[CH2:29][OH:30])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.23 g, 0.48 mmol (60% pure)) and triethylamine (0.2 mL, 1.44 mmol) were dissolved in ethanol (8 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (23 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 6 days until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off through celite and the filtrate concentrated in vacuo to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in ethyl acetate. An impurity remained at a level of 40%. This mixture (0.27 g, 0.6 mmol) was dissolved in DMF (5 mL) and imidazole (0.29 g, 4.2 mmol) and tert-butyldimethylsilylchloride (180 mg, 1.2 mmol) were added. After stirring at RT for 20 hours water (30 mL) was added and the mixture extracted into diethyl ether (2×50 mL). The combined extracts were washed with brine (50 mL) dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in ethyl acetate, and then chromatographed by preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant. The chromatography fractions were allowed to stand overnight and the acetonitrile removed in vacuo. The aqueous residue was basified with saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate (2×50 mL) and the combined extracts reduced in vacuo to give the desired compound. (28 mg)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][C@H:14]([CH3:16])[NH:13][CH2:12][C@@H:11]2[CH3:17])=[CH:6][CH:5]=1)([O-])=O.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1([CH2:29][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)[CH2:28][O:27]1>C(O)CCCC>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C@@H:11]([CH3:17])[CH2:12][N:13]([CH2:28][C:26]([C:20]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=3[Cl:18])([OH:27])[CH2:29][N:30]3[CH:34]=[N:33][CH:32]=[N:31]3)[C@@H:14]([CH3:16])[CH2:15]2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: C[C@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1
Solvent: CCCCCO
Product: C[C@H]1CN(c2ccc(N)cc2)[C@@H](C)CN1CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 23.1 %

Procedure:
A mixture of the product of part (i) (2.7 g, 11 mmole) and 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl) oxirane (2.7 g, 10 mmole) in n-pentanol (30 ml) was heated under reflux for 48 hours. The solvent was then removed under reduced pressure and the residue suspended in hot ethyl acetate. After cooling, the insoluble material was removed by filtration to yield diastereomer I of the title compound (1.1 g, 22%), m.p. 212°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH3:25]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][CH3:25])=[O:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: COC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C

Procedure:
19.54 g of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid are dissolved in 350 ml of MeOH, 0.97 g of paratoluenesulfonic acid is added and the mixture is then refluxed for 18 hours. After evaporation of the solvent, the residue is taken up with AcOEt and washed with saturated NaHCO3 solution and then with saturated NaCl solution. It is dried over MgSO4, the insoluble material is filtered off and the filtrate is then concentrated to dryness to give 18.53 g of the expected compound, m.p.=133° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1.BrCCC[CH2:21][Cl:22].OC1C=CC2C(=O)C=COC=2C=1>>[Cl:22][CH2:21][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1
Reactant: O=c1ccoc2cc(OCCCCl)ccc12
Reactant: ClCCCCBr
Agent: O=c1ccoc2cc(O)ccc12
Product: O=c1ccoc2cc(OCCCCCl)ccc12

Procedure:
The title compound, mp 75°-78° C. was prepared as described above for 7-(3-chloropropoxy)-4H-1-benzopyran-4-one, starting from 1-bromo-4-chlorobutane and 7-hydroxy-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[NH:1][CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14])#[N:5]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: N#Cc1ccc(F)cc1N
Agent: Br
Product: CC(Nc1cc(F)ccc1C#N)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 43.1 %

Procedure:
2-amino-4-fluorobenzonitrile (111 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(2-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (40 mg, 42%) as a white solid. Mass Spectrum: M+H+ 465.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 197.8 %

Procedure:
(3,5-dihydroxy-phenyl)-acetic acid methyl ester (5 g, 27.4 mmol) in anhydrous DMF (20 mL) was treated with K2CO3 (11.4 g, 82.5 mmol) and benzyl bromide (6.5 mL, 55 mmol). The resultant mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the aqueous layer extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a brown solid (9.82 g, 99%).
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1>CO>[NH:2]([C:6]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:5])[NH2:3]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 90.09 %

Procedure:
Hydrazine hydrate was added to a solution of terephthalic acid monomethyl ester (1 g, 5.5 mmol) in MeOH (10 mL) and stirring was continued for 1 hr. The reaction mixture was concentrated to afford 900 mg (90.09% Yield) of 4-hydrazinocarbonyl-benzoic acid. p-Toluene sulfonic acid (48 mg, 0.277 mmol) was added to a solution of 4-hydrazinocarbonyl-benzoic acid (500 mg, 2.77 mmol) in triethylorthoformate (7.5 mL, 44.0 mmol) and stirring was continued with heating at 100° C. for 3 hrs. The reaction mixture was diluted with water, the solid was collected to afford 200 mg (37.9% Yield) of 4-[1,3,4]oxadiazol-2-yl-benzoic acid.
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.[NH:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH2:32])=[O:31])N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30]([NH2:32])=[O:31])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1cccc(C(N)=O)c1
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(C(N)=O)c3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 3-hydrazino-benzamide according to example 43 gave the desired product. MS: M=436.7 (M+H)+
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Cl:15])O1.Cl[C:18]1[N:23]=[C:22]([NH2:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][CH:19]=1>>[Cl:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:18]1[CH:19]=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([NH2:24])[N:23]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccncc2Cl)OC1(C)C
Product: Nc1nc(-c2ccncc2Cl)ccc1[N+](=O)[O-]
Yield: 99 %

Procedure:
Following the same procedure as in Intermediate 1 (step a), but using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-chloropyridine, 6-chloro-3-nitropyridin-2-amine was transformed into the title compound as a white solid (2.14 g, 99%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH:18]1[CH:25]2[CH2:26][C:21]3([CH2:28][OH:29])[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2>>[OH:29][CH2:28][C:21]12[CH2:20][CH:19]3[CH2:27][CH:23]([CH2:24][CH:25]([CH:18]3[NH:17][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH2:26]1)[CH2:22]2
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Product: O=C(NC1C2CC3CC1CC(CO)(C3)C2)c1cccc(Oc2ccccc2)c1

Procedure:
Prepared from 3-phenoxy benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 7.31-7.49 (m, 5H), 7.08-7.18 (m, 2H), 7.02 (d, 2H), 6.29-6.43 (m, 1H), 4.13-4.23 (m, 1H), 3.24 (d, 2H), 2.09-2.18 (m, 2H), 2.01 (br. s., 1H), 1.55-1.92 (m, 10H), 1.44 (d, 1H).
Reaction SMILES: C(OC([N:8]([C:11]1([C@@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10])=O)(C)(C)C.C(N(CC)CC)C.F[C:27]1[C:36]([CH3:37])=[C:35]2[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]2[C@@H:38]2[CH2:40][C@@H:39]2[F:41])=[CH:29][CH:28]=1>CS(C)=O>[CH2:9]([NH:8][C:11]1([C@@H:14]2[CH2:18][CH2:17][N:16]([C:27]3[C:36]([CH3:37])=[C:35]4[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]4[C@@H:38]4[CH2:40][C@@H:39]4[F:41])=[CH:29][CH:28]=3)[CH2:15]2)[CH2:12][CH2:13]1)[CH3:10]
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CCN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3C)C2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclopropyl]pyrrolidine (2.16 g, 8.40 mmol) and triethylamine (4 ml) to dried dimethyl sulfoxide (10 ml), 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.95 g, 7.00 mmol) was added thereto and heated under reflux in an oil bath of 100° C. for 51 hour under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (150 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml) and saturated saline solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (10 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (20 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (100 ml×5), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (150 ml×4) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by recrystallization from ethanol and then dried under a reduced pressure. 1.61 g (55%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:35])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1>ClCCl.CO>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:35][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(N)ccc1OCCN1CCC(C)CC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC(C)CC1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 3-methoxy-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylamine. Yield: 70 mg (23.5% of theory); melting point: 207° C.-209° C.; C25H26ClF3N2O3 (M=494.94); calc.: molecular ion peak (M+H)+: 495/497; found: molecular ion peak (M+H)+: 495/497; Rf value: 0.45 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[C:24]([O:25]C)=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.Br>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cccc(OC)c1-2
Agent: Br
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cccc(O)c1-2

Procedure:
Reaction of 5-amino-N,N-diethyl-10-methoxy-2H[1]-benzothiopyrano[4,3,2-cd]indazole-2-ethanamine with 48% HBr as described in Example 64 gave the product.