Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7](C(O)=O)=[CH:6][NH:5][C:4]2[CH:11]=[N:12][NH:13][C:3]1=2>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:1]=[C:2]1[CH:7]=[CH:6][NH:5][C:4]2[CH:11]=[N:12][NH:13][C:3]1=2
Reactant: O=C(O)c1c[nH]c2cn[nH]c2c1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1cc[nH]c2cn[nH]c12

Procedure:
4,7-Dihydro-7-oxo-1H-pyrazolo[4,3-b]pyridine-6-carboxylic acid (7.0 g, 39 mmol) was suspended in Dowtherm A (250 ml) and the mixture was heated under reflux under nitrogen for 2.5 h. After cooling, the mixture was diluted with 60°-80° petrol and filtered. The precipitate was washed well with petrol and dried to give the crude product as an off-white solid (3.9 g, 74%). Recrystallisation from aqueous ethanol/ether gave the title compound as very fine needles, m.p. >320° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]([CH3:10])[CH3:9].[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]#[N:30])[CH:23]=2)=[N:19][C:18]=1[CH3:31])=[O:16])[CH3:13].O>CN(C)C=O>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:7][CH:8]([CH3:10])[CH3:9])=[C:24]([C:29]#[N:30])[CH:23]=2)=[N:19][C:18]=1[CH3:31])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(C#N)c2)nc1C
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (300 g, 2.17 mol) and isobutyl bromide (142.7 g, 1.041 mol) were added to a solution of ethyl-2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate (100 g, 0.347 mol) in dimethylformamide (300 mL), and the reaction mixture was heated at a temperature of about 75° C. for about 8 hours. After completion of reaction, the reaction mixture was cooled to about 40° C. and water was added. The reaction mixture was further cooled to about 0° C. and stirred for about 1 hour. The solid thus obtained was filtered, washed with water and dried to give title compound. (Yield: 111g, 92.9%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:15]([O:17][C:18](=[O:25])[C@H:19]([CH2:21][CH2:22][S:23][CH3:24])[NH2:20])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:25])[C@H:19]([CH2:21][CH2:22][S:23][CH3:24])[NH:20][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:16]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)[C@@H](N)CCSC
Agent: Cl
Product: CCOC(=O)[C@H](CCSC)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure G′ above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([N:14]2[C:19]3=[N:20][CH:21]=[N:22][C:18]3=[CH:17][N:16]([OH:23])[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[N+](C1C=CC(N=C=O)=CC=1)([O-])=O.[O:36]([C:43]1[CH:48]=[CH:47][C:46]([N:49]=C=O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[O:36]([C:43]1[CH:44]=[CH:45][C:46]([NH:49][C:6]([N:8]2[CH2:9][CH2:10][N:11]([N:14]3[C:19]4=[N:20][CH:21]=[N:22][C:18]4=[CH:17][N:16]([OH:23])[CH2:15]3)[CH2:12][CH2:13]2)=[O:7])=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(N2CN(O)C=C3N=CN=C32)CC1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Agent: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)N1CCN(N2CN(O)C=C3N=CN=C32)CC1

Procedure:
The target compound was produced in the same manner as in Example 2, except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl ester was replaced with 4-(6-hydroxy-4-imidazo[4, 5-d]pyrimidinyl )-1-piperazinecarboxylic acid tert-butyl ester produced in Reference Example 11, and that 4-nitrophenyl isocyanate was replaced with 4-phenoxyphenyl isocyanate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH:21]=2)[N:17]=[C:16]2[N:33]([CH:36]([CH3:38])[CH3:37])[N:34]=[CH:35][C:15]=12)=[O:13]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.8 g, 5.4 mmol) in DCM (15 mL), TFA (13 mL) was added at 0° C. and stirred it at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and residue neutralized with saturated NaHCO3 solution Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure, finally the residue was washed with diethyl ether to provide the desired intermediate (1.5 g, 66.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:25]=[CH:26][C:27]=1[CH3:28].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:24]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:22]([Cl:21])[CH:23]=2)[N:30]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: Cc1ccc(NNC(=O)OC(C)(C)C)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1Cl
Yield: 26.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-(3-chloro-4-methylphenyl)hydrazinecarboxylate (Intermediate-87, 0.450 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.180 g of the desired product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].I[CH2:10][CH2:11][CH3:12].CC1(C)CCCCC1=O>>[CH3:1][C:2]1([CH2:10][CH2:11][CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CC1CCCCC1=O
Reactant: CCCI
Agent: CC1(C)CCCCC1=O
Product: CCCC1(C)CCCCC1=O

Procedure:
The alkylation of 2-methylcyclohexanone with 1-iodopropane takes place in a manner similar to that described above for the preparation of 2,2-dimethyl-cyclohexanone.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([NH:10][C@@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].[N:42]1([C:47](N)=[NH:48])C=CC=N1>CN(C=O)C>[ClH:41].[C:35]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([NH:10][C@@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:26]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH:15][C:47](=[NH:42])[NH2:48])=[O:9])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N=C(N)n1cccn1
Reactant: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 73.4 %

Procedure:
Prepared according to the method described in Example 6(e) above from (R)-N2 -(diphenylacetyl)-(R)-N-[1-(4-benzyloxyphenyl)ethyl]ornithine amide (0.38 g; 0.71 mmol; from step (d) above), 1H-pyrazole-1-carboxamidine monohydrochloride (0.10 g; 0.71 mmol), TEA (0.14 g, 1.42 mmol) and DMF (5 mL), 18 hours reaction time. The resulting solution was concentrated and chromatographed on silica eluting with MeOH:CHCl3 :conc. NH4OH (3:6:1) and converted to the hydrochloride salt to afford the title compound as a white solid (0.32 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15])=[O:11])=[CH:8][CH:7]=1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[O:34][C:33](SC)=[N:32][C:31]=2[CH:37]=1>[Hg](OC(C)=O)OC(C)=O>[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[O:34][C:33]([NH:15][C@H:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13][NH:12][C:10](=[O:11])[C:9]3[CH:23]=[CH:24][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:25])=[CH:7][CH:8]=3)=[N:32][C:31]=2[CH:37]=1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: CSc1nc2cc(Br)ccc2o1
Agent: CC(=O)O[Hg]OC(C)=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](Nc2nc3cc(Br)ccc3o2)C(=O)OC(C)(C)C)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
A mixture constituted by 890 mg of 10-5, 620 mg of 5-bromo-2-methylthiobenzoxazole (prepared according to P1 but starting from 4-bromo-2-nitrophenol) and 350 mg of Hg(OAc)2 is heated for 2 hours at 75° C. then for 2 hours at 95° C. The cooled down medium is chromatographed eluting with a CH2Cl2/AcOEt mixture 82/18. 159 mg of expected product is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]([CH3:19])[C:8]([CH2:9][CH:10](C(O)=O)[C:11]([OH:13])=[O:12])=[C:7]([CH3:20])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].C(=O)=O.C(=O)(O)[O-].[Na+]>O.CCCCCC>[C:1]([C:5]1[CH:18]=[C:17]([CH3:19])[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:7]([CH3:20])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(C(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CCC(=O)O

Procedure:
17.9 grams of the compound of Example 16 was stirred together with white oil at 165° to 180° for two hours until little CO2 evolution could be detected. The reaction mixture was cooled to 50° and stirred thoroughly together with 5.2 grams of sodium bicarbonate dissolved in 100 ml of water until no foaming took place and all solids had dissolved. The reaction mixture was diluted with 50 ml of n-hexane and the upper organic phase separated from the lower aqueous phase. The organic phase was washed with water, the wash water being combined with the aqueous phase. The combined aqueous phase was then washed with n-hexane, clarified by filtration through filtercel, and added dropwise to about 150 ml of cold 6 N aqueous hydrochloric acid so that a granular off-white precipitate was obtained. The product was used as such after drying in the vacuum oven at 60° and 3 mm Hg. overnight.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[CH:17]=2)=[CH:12][CH:11]=1)[CH2:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:2]3[S:3][CH:4]=[CH:5][CH:6]=3)=[C:18]([F:25])[CH:17]=2)=[CH:12][CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Reactant: Brc1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(-c2ccc(-c3cccs3)c(F)c2)cc1

Procedure:
A mixture of 25.3 g (0.16 mol) of 2-bromothiophene, 40.0 g (0.16 mol) of 4′-propyl-3-fluoro-4-biphenylboronic acid, 8.5 g (7.4 mmol) of tetrakis(triphenylphosphine)palladium(0) and 170 ml of 2 N sodium carbonate solution in 420 ml of toluene/ethanol (1:2) is refluxed for 18 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with toluene. The combined organic phases are washed with water and sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-(4′-propyl-3-fluorobiphenyl-4-yl)thiophene as a colourless solid (m.p. 88° C.).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(OCC)[C@H](C)N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (S)-1,1-diethoxypropan-2-amine (Compound XIV-1) 682 mg (3.55 mmol) in tetrahydrofuran 2 ml, benzaldehyde 337 mg (3.55 mmol) was added and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with tetrahydrofuran 3 ml and sodium triacetoxyborohydride 829 mg (3.91 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate aq. 50 ml twice, water 50 ml twice and brine 50 ml twice. The organic phase was dried over magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 826 mg (98%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@H:13]([C:26]([N:28]([CH2:38][C:39]1[C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[S:42][CH:43]=1)[C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[S:42]1[CH:43]=[C:39]([CH2:38][N:28]([C@@H:29]([CH3:37])[CH:30]([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])[C:26]([C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4](=[O:11])[NH:3][CH2:1][CH3:2])=[O:27])[C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]1=2
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCNC(=O)NOCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 47 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-6-oxohexylcarbamate (Compound IV-15) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: CN1C=CC(C(O)=O)=C1.[CH3:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][NH:16][CH:15]=1)=[O:13].C1(N2CCC(OC3C=CC(I)=CC=3)CC2)CCC1.[C:37]([N:41]1[CH2:46][CH2:45][CH:44]([O:47][C:48]2[CH:53]=[CH:52][C:51](I)=[CH:50][CH:49]=2)[CH2:43][CH2:42]1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([N:41]1[CH2:42][CH2:43][CH:44]([O:47][C:48]2[CH:53]=[CH:52][C:51]([N:16]3[CH:17]=[CH:18][C:14]([C:12]([NH:11][CH3:10])=[O:13])=[CH:15]3)=[CH:50][CH:49]=2)[CH2:45][CH2:46]1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CNC(=O)c1cc[nH]c1
Reactant: CC(C)(C)N1CCC(Oc2ccc(I)cc2)CC1
Agent: Cn1ccc(C(=O)O)c1
Agent: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Product: CNC(=O)c1ccn(-c2ccc(OC3CCN(C(C)(C)C)CC3)cc2)c1

Procedure:
The titled compound was prepared as a colorless crystal by repeating the procedure of Example 1, except that the methyl 1H-pyrrole-3-carboxylic acid was replaced by N-methyl-1H-pyrrole-3-carboxamide and the 1-cyclobutyl-4-(4-iodophenoxy)piperidine by 1-tert-butyl-4-(4-iodophenoxy)piperidine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH:10][CH:11]([CH2:22][N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][NH:27][CH2:28]2)[CH2:24]1)[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(Cl)Cl.CC#N>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:27]2[CH2:28][CH:29]3[O:31][CH:25]([CH2:24][N:23]([CH2:22][CH:11]([OH:10])[CH2:12][O:13][C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:30]3)[CH2:26]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(OCC(O)CN2CC3CNCC(C2)O3)cc1
Reactant: Fc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(OCC(O)CN2CC3CN(Cc4ccc(F)cc4)CC(C2)O3)cc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A solution of 4-fluorobenzyl bromide (14.17 mg, 0.075 mmol) in DCM (0.5 mL) of was added, together with TEA (20 mg, 0.2 mmol) to a solution of 4-{[2-hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-propyl]oxy}benzonitrile (Preparation K; 15.2 mg, 0.05 mmol) in MeCN (0.5 mL). The mixture was stirred at 50° C. for 4 days before being concentrated in vacuo. The resulting residue was dissolved in CHCl3 and added to a solid-phase extraction plug (CBA, 0.4 g). The plug was washed with CHCl3 (4×0.3 mL), and the product was finally eluted with CHCl3:MeOH:TEA (5×0.3 mL of 8:1:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.O.[NH2:33][NH2:34]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:34][N:33]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]4)=[CH:14][CH:13]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(C(=O)CC(=O)c3ccc(Cl)cc3)cc2)C1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(-c3cc(-c4ccc(Cl)cc4)[nH]n3)cc2)C1
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-(4-(3-(4-chlorophenyl)-3-oxopropanoyl)phenyl)morpholine-4-carboxylate (210 mg, 0.473 mmol) and hydrazine hydrate (35.5 mg, 0.70 mmol) in ethanol (3.5 ml) was heated to reflux with stirring overnight. The clear yellow solution was evaporated under reduced pressure, water was added and ethyl acetate. The organic layer was separated, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (10 g silica gel, 10 to 50% ethyl acetate in heptane) to yield a white solid (208 mg, 89%). MS (ISP neg): 438.3 ([{35Cl}M−H]+), 440.4 ([{37Cl}M−H]+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].O.[C:23]1(C)[CH:28]=[CH:27]C=[CH:25][CH:24]=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[N:12][CH:23]([CH2:28][CH3:27])[CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: NCc1cccc(Oc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)N=Cc1cccc(Oc2ccccc2)c1
Yield: 92.5 %

Procedure:
60.5 g (0.226 mol) of N-3-pentylidene-(3-phenoxybenzylamine is dissolved in 50 ml of toluene; to the solution is then added 2 g (0.0179 mol) of potassium tert-butylate, and the mixture is refluxed for 4 hours. After cooling of the reaction mixture, extraction is effected by shaking with 50 ml of water, and the organic phase is separated in a separating funnel. The toluene is distilled off in a slight water-jet vacuum to leave 56 g (0.21 mol) of 3-phenoxybenzylidene-3-pentylamine, corresponding to a yield of 92.5% of theory; b.p. 125° C./Pa.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1>>[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH:26][C:10]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9]3)=[O:12])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)C2(c3ccccc3)CC2)cn1
Yield: 6 %

Procedure:
Prepared as in Example 4-8 from 1-phenylcyclopropanecarboxylic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 6%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.O.NN>[Ni].C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1CCc2cc(N)ccc21

Procedure:
Approximately 400 mg of Raney nickel is added to a mixture of 2.84 g (15.9 mmole) of −1-methyl-5-nitroindoline and 4 ml (80 mmole) of hydrazine hydrate in 60 ml of absolute ethanol. The reaction mixture is heated to reflux for 5 hours. After returning to 23° C., a little silica is added to the flask and the solvent is evaporated off under vacuum. The evaporation residue is placed directly at the top of a chromatography column. The expected product is eluted using a Heptane/AcOEt mixture (3/7). A violet powder is obtained (65%) which is used directly in the following stage.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH:7]=1.[Sn](Cl)[Cl:25]>C(O)C.Cl>[ClH:25].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:21]=[C:11]([NH2:12])[C:10]3[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NC1=Nc2ccc(F)cc2Nc2ccc(C(F)(F)F)cc21
Yield: 87.1 %

Procedure:
Heat a solution of 2-(5-fluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (1.62 g, 4.98 mmol) in ethanol (24 ml) to 60° C. Add to this a solution of tin (II) chloride (2.83 g, 14.94 mmol) in 5.0 N hydrochloric acid (24 ml). Heat the resulting mixture to reflux for 20 hours. Cool the reaction to room temperature, add 30 ml of 5.0 N hydrochloric acid and place the mixture in a freezer for 16 hours. The product precipitates from the solution and is collected by filtration. Wash solid with 5.0 N hydrochloric acid to obtain 1.44 g of the title compound (4.34 mmol, 87% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 295(M+1).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[S:30](Cl)([CH3:33])(=[O:32])=[O:31].OS(O)(=O)=O>N1C=CC=CC=1.O>[OH:27][CH:17]1[CH:16]2[CH:15]([CH2:14][CH:13]([OH:28])[C:12]3([CH3:29])[CH:11]2[CH2:10][CH2:9][CH:8]3[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([O:25][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:22][CH2:21]2)[CH2:18]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccncc1
Product: CC(CCC(=O)O)C1CCC2C3C(O)CC4CC(OS(C)(=O)=O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 g of cholic acid are dissolved in 500 ml of pyridine and 23.1 ml of mesyl chloride are added dropwise over a period of 30 minutes at 0° C. The mixture is stirred at RT for 3 hours, then poured into a solution of 400 ml of H2SO4 in 3 l of water at 0° C. and extracted 4 times using 750 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. The residue is crystallized using diisopropyl ether and 117.1 g are obtained; m.p. 121° C. (with decomposition).