Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:1]/[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COC(OC)N(C)C
Reactant: Cc1cnccc1C#N
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cnccc1C#N
Temperature: 25 °C
Yield: 54.1 %

Procedure:
To a solution of 3-methylisonicotinonitrile (10 g, 85 mmol) in DMF (100 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (18.05 mL, 135 mmol). The mixture was heated to reflux overnight. The mixture was cooled to rt and an additional 3.0 mL of 1,1-dimethoxy-N,N-dimethylmethanamine was added to the mixture, and it was again heated to reflux. After heating the mixture overnight, it was cooled to rt and an additional 3.0 mL of 1,1-dimethoxy-N,N-dimethylmethanamine was added to the mixture. The mixture was heated overnight at reflux. The mixture was cooled to rt and an additional 3.0 mL of 1,1-dimethoxy-N,N-dimethylmethanamine were added. The mixture was again heated to reflux. After heating the mixture overnight, it was cooled to rt. To the mixture was added 3.0 mL of 1,1-dimethoxy-N,N-dimethylmethanamine. The mixture was heated to reflux overnight. The mixture was cooled to rt and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was loaded onto a BIOTAGE® 65+M cartridge and was purified using a 10-70% EtOAc in hexanes gradient. The expected product, (E)-3-(2-(dimethylamino)vinyl)isonicotinonitrile (7.97 g, 46.0 mmol, 54.4% yield), was isolated as a bright-yellow solid. LC/MS: m/z 174.11 (M+H)+, 1.690 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 1H NMR (500 MHz, chloroform-d) δ ppm 8.69 (s, 1H) 8.14 (d, J=5.19 Hz, 1H) 7.23 (d, J=4.88 Hz, 1H) 7.15 (d, J=13.43 Hz, 1H) 5.21 (d, J=13.73 Hz, 1H) 2.95 (s, 6H)
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:16])=[O:3])=[CH:8][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)COc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A mixture of ethyl-(4-isopropylphenoxy)acetate (1.61 g, 7.24 mmol) and 2N NaOH(aq) (10.9 mL) in 20 mL of methanol was stirred at ambient temperature for 3 h and concentrated under reduced pressure. The resulting residue was taken up in water (100 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×100 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 1.32 g (94%) of 4-isopropylphenoxyacetic acid as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[CH2:13][CH2:14]Br>>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[CH2:13][CH2:14][CH2:9][C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: Clc1ccccc1CCBr
Reactant: CCc1cnccc1C
Product: CCc1cnccc1CCCc1ccccc1Cl
Yield: 42.8 %

Procedure:
1.13 g (9.35 mmol) of 3-ethyl-4-methylpyridine and 2.05 g (9.35 mmol) of 2-chlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.04 g of the desired compound (yield: 42.8%).
Reaction SMILES: [CH3:1][O:2][P:3]([CH:7]([OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(=[O:6])[O:4][CH3:5].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][P:3]([CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[O:17][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1)(=[O:6])[O:4][CH3:5]
Reactant: C1=COCCC1
Reactant: COP(=O)(OC)C(O)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COP(=O)(OC)C(OC1CCCCO1)c1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
[Hydroxy-(3-nitro-phenyl)-methyl]-phosphonic acid dimethyl ester (26.7 g, 0.102 mol) was suspended in dry toluene (340 mL) under nitrogen atmosphere. 3,4-Dihydro-2H-pyrane (20.6 mL, 0.228 mol, 2.2 eq) was added, followed by p-toluensulfonic acid (590 mg, 0.003 mol, 0.03 eq) and the mixture was stirred at 60° C. for 1 h. the reaction mixture was then concentrated under reduced pressure, taken up with ethyl acetate (300 mL) and washed with saturated aqueous NaHCO3 and water. The organic layer was dried over Na2SO4 and concentrated to dryness. The desired product was obtained in quantitative yield as a yellow solid (mixture of 2 diastereoisomers).
Reaction SMILES: [Br:1][C:2]1[CH:35]=[C:34]([F:36])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:37])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:35]=[C:34]([F:36])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:37])[CH:3]=1
Reactant: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
A solution of 4-(4-bromo-2,6-difluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (578 mg, 1 mmol) in methylene chloride (10 ml) containing TFA (4 ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was suspended in water. The aqueous layer was adjusted to approximately pH10 and was extracted with methylene chloride. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with ether and dried under vacuum to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (110 mg, 23%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[O:22]=[C:20]1[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:27])[N:21]1[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(C=Cc1cccnc1)NCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)c2ccccc2C1=O

Procedure:
Batch size: 7.8 g (35.4 mmol) N-(4-hydroxybutyl)-3-pyridin-3-yl-acrylamide, 9.3 g (35.4 mmol) tripdhenylphosphine, 5.2 g (35.4 μmmol) phthalimide and 6.2 g (35.4 mmol) azodicarboxylic acid diethyl ester in 100 ml THF.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:27]1([CH2:33][CH2:34][CH:35]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl.[OH-].[Na+]>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH:25][CH2:35][CH2:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Reactant: O=CCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)c1cccc(C(=NOCc2cccc(NCCCc3ccccc3)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a stirred solution of 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine (125.0 mg, 0.35 mmol) in dry 1,2-dichloroethane (10 mL), under argon atmosphere, were added 3-phenylpropionaldehyde (66.6 mg, 0.49 mmol) and sodium triacetoxyborohydride (135 mg, 0.63 mmol) at room temperature. After stirring at room temperature for 18 h, the reaction mixture was diluted with dichloromethane (50 mL) and aq. NaOH (1 M, 30 mL) was added. After phase separation, the organic layer was washed with water (40 mL), dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}-N-(3-phenylpropyl)pyridin-2-amine as an oil [82 mg, yield 47%; HPLC/MS: m/z=471 (M+H); logP(HCOOH)=2.57].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[S:14][CH:15]=[CH:16][C:3]=12.[NH:17]1[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]1>>[C:8]1([C:6]2[N:5]=[C:4]3[S:14][CH:15]=[CH:16][C:3]3=[C:2]([N:17]3[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1cc(-c2ccccc2)nc2sccc12
Product: CCOC(=O)C1CCN(c2cc(-c3ccccc3)nc3sccc23)CC1
Temperature: 170 °C
Yield: 33 %

Procedure:
A mixture of 4-chloro-6-phenyl-thieno[2,3-b]pyridine (200 mg, 0.82 mmole) and ethyl isonipecotate (5 mL) is stirred and heated in an oil bath at 170° C. for 6 hours. The reaction mixture is cooled and purified on a preparative tlc plate to give ethyl 1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylate (100 mg, 33% yield) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:11]2[CH:10]=[CH:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-n2ccnc2-c2ccccc2)cc1
Yield: 25 %

Procedure:
A mixture of 28.8 parts of 2-phenyl-1H-imidazole, 37.4 parts of 1-bromo-4-methoxybenzene, 20 parts of potassium carbonate and 180 parts of N,N-dimethylacetamide is stirred for one week at reflux temperature. The reaction mixture is cooled, poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are dried, filtered and evaporated, yielding 10 parts (25%) of 1-(4-methoxyphenyl)-2-phenyl-1H-imidazole as a residue.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][S:34]([C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)(=[O:36])=[O:35])[CH:27]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][S:34]([C:37]2[S:38][C:39]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:40][CH:41]=2)(=[O:36])=[O:35])[CH:27]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCc1cccnc1)c1ccc(Br)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NCc1cccnc1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (pyridin-3-ylmethyl)-amide (example B.x) (example B.56) (167 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (132 mg, 43%). MS (ISN) 606.2 [(M−H)−]; mp 177° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8](Cl)=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)[CH3:2].[NH2:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([NH:20][C:21]2[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][CH:22]=2)=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(N)(=O)=O)c1
Reactant: Cc1cccc(N)n1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Nc2cccc(C)n2)c(S(N)(=O)=O)c1
Reaction time: 2 h

Procedure:
A mixture of ethyl-4-chloro-3-nitro-5-sulphamyl-benzoate (3.08 g) and 6-amino-2-methyl-pyridine (3.24 g) was melted on an oil bath at 140° C and kept at this temperature for 2 hours, while stirring. The still warm reaction mixture was triturated with ethanol (35 ml) and after cooling, the ethyl-4-(2-methyl-6-pyridylamino)-3-nitro-5-sulphamyl-benzoate was collected by suction and washed with ethanol. After recrystallization from acetonitrile, the compound had a melting point of 203°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][N:6]=1.[CH2:17]=[O:18]>CO>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:17][OH:18])[N:6]=1
Reactant: C=O
Reactant: COC(=O)Cc1n[nH]c(=O)c2ccccc12
Solvent: CO
Product: COC(=O)Cc1nn(CO)c(=O)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of methyl-4-oxo-3-H-phthalazin-1-ylacetate (2.18 g), methanol (50 ml) and aqueous formaldehyde (37% concentration, 10 ml) was refluxed for 40 hours. The reaction mixture was cooled to room temperature and then poured onto water (50 ml). The resulting solid was collected and crystallized from methanol (yield: 0.5 g; m.p. 154°-155° C.).
Reaction SMILES: C([O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17]([C:18](=[O:34])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:16]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([O:44]CC)=O)=[CH:37][CH:36]=3)[S:15][C:14]=2[CH:47]=1)(=O)C1C=CC=CC=1.C([O-])(=O)[C:49]1[C:50](=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:51]([O-])=O>>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17]([C:18](=[O:34])[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][CH:24]=3)=[C:16]([C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]([CH:49]4[CH2:57][CH2:56][CH2:55][CH2:54][CH2:50][CH2:51]4)=[O:44])=[CH:39][CH:40]=3)[S:15][C:14]=2[CH:47]=1
Reactant: CCOC(=O)Oc1ccc(-c2sc3cc(OC(=O)c4ccccc4)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: O=C([O-])c1ccccc1C(=O)[O-]
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(OC(=O)C3CCCCCC3)cc2)sc2cc(O)ccc12

Procedure:
6-benzoyloxy-2-(4-ethoxycarbonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, phthalate
Reaction SMILES: [O-]CC.[Na+:4].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1>C(O)C>[Na+:4].[C:5]1([CH3:15])[CH:6]=[CH:7][C:8]([S:11]([NH-:14])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S([NH-])(=O)=O)cc1
Temperature: 20 °C
Yield: 90.7 %

Procedure:
To a stirred solution of sodium ethoxide (23.8 g) in ethanol (anhydrous, 400 ml) is added toluene-4-sulfonamide (60 g) around 50 C. The formed slurry is heated up to reflux for 2 hours and then cooled to 20° C. The precipitated solid is collected by filtration, rinsed with anhydrous ethanol and dried under vacuum with nitrogen flow to give toluene-4-sulfonamide monosodium salt (61.3 g, yield: 90.6%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][C:24]1[O:25][CH:26]=[CH:27][C:28]=1[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]([C:28]4[CH:27]=[CH:26][O:25][C:24]=4[CH3:23])=[O:30])=[N:37][CH:36]=3)=[O:39])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1occc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1occc1C(=O)Nc1ccc(C(=O)N2Cc3cccnc3Nc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution of 0.296 g of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine and 624 μL of triethylamine in 3 ml of dichloromethane is added a solution of 6-[(2-methyl-3-furanylcarbonyl)amino]-3-pyridinecarbonyl chloride in 4 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and the solvent removed under vacuum. To the residue is added 1M NaHCO3 and the mixture extracted with ethyl acetate. The extract is washed with H2O, 1M NaHCO3 brine and dried (Na2SO4). The solvent is removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:22]1([CH2:25][N:26]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[N:27]2)[CH2:24][CH2:23]1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][N:26]([CH2:25][CH:22]3[CH2:24][CH2:23]3)[N:27]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: NCc1ccn(CC2CC2)n1
Product: O=C(NCc1ccn(CC2CC2)n1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and C-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-methylamine (51 mg, 0.33 mmol) as starting materials; off white solid (48 mg, 33.3%). MS (ESI): 437 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1cc[nH]n1
Product: O=C(NC(=S)NCCSCc1cc[nH]n1)c1ccccc1

Procedure:
By the procedure of Example 18, 3-[(2-aminoethyl)thiomethyl]pyrazole is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(3-pyrazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(3-pyrazolylmethylthio)ethyl]thiourea.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[NH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)=[O:13]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCCCCCCCCCBr
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)CCCCCCCCCCBr)cc1

Procedure:
A solution of 20 g. of 11-bromoundecanoyl chloride in 100 ml. of methylene chloride is slowly added with stirring to a solution of 20 g. of ethyl 4-aminobenzoate in 100 ml. of methylene chloride. The mixture is filtered and the filtrate is washed with dilute hydrochloric acid and water, dried, and evaporated. Crystallization from acetonitrile affords ethyl 4-(11-bromoundecanamido)benzoate as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=2)=[N:4][CH:5]=[C:6]([S:8](=[O:21])(=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=1.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([NH:9][S:8]([C:6]2[CH:7]=[CH:2][C:3]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=3)=[N:4][CH:5]=2)(=[O:21])=[O:20])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ncc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)cc2Br)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Oc2ccc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)cn2)cc1

Procedure:
To a solution of ethyl 3-(4-(3-bromo-5-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)pyridin-2-yloxy)phenyl)propionate (0.41 g, 0.7 mmol) in ethanol (10 mL) were added 10% palladium-carbon (0.041 g) and ammonium formate (0.226 g, 3.6 mmol), and the resulting solution was heated to reflux for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.28 g of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCC)[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2].[CH2:22](C(CCCC)C(Cl)=O)[CH3:23]>>[C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:20])[CH:12]([CH2:22][CH3:23])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: CCCCCCCCC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: CCCCC(CC)C(=O)Cl
Product: CCCCC(CC)C(=O)N1CC(=O)N(C(C)=O)CC1=O

Procedure:
##STR25## Synthesized as for 1-Acetyl-4-nonanoyl-2,5-piperazinedione in EXAMPLE I using 2-ethylhexanoyl chloride in place of nonanoyl chloride.
Reaction SMILES: C(NC1C=C(C=C(C2OC=CN=2)C=1)[C:13]([NH:15][C@@H:16]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:17]([C@H:26]1[CH2:30][C@@H:29]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH2:28][N:27]1C(OC(C)(C)C)=O)[O:18][Si](C(C)(C)C)(C)C)=[O:14])(=O)C1C=CC=CC=1.[CH2:59]([N:62]([CH2:79][CH2:80][CH3:81])[C:63]([C:65]1[CH:66]=[C:67]([CH:71]=[C:72]([C:74]2[O:75][CH:76]=[CH:77][N:78]=2)[CH:73]=1)C(O)=O)=[O:64])[CH2:60][CH3:61].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:18][C@H:17]([C@H:26]1[CH2:30][C@@H:29]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH2:28][NH:27]1)[C@@H:16]([NH:15][C:13](=[O:14])[C:67]1[CH:71]=[C:72]([C:74]2[O:75][CH:76]=[CH:77][N:78]=2)[CH:73]=[C:65]([C:63]([N:62]([CH2:59][CH2:60][CH3:61])[CH2:79][CH2:80][CH3:81])=[O:64])[CH:66]=1)[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCCS(=O)(=O)[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)[C@H]2C[C@@H](S(=O)(=O)CCC)CN2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
Step 17 (F): (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-(oxazol-2-yl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-phenylpropyl)-4-(propylsulfonyl)pyrrolidine-1-carboxylate. To a solution of 3-(dipropylcarbamoyl)-5-(oxazol-2-yl)benzoic acid (prepared as reported in WO 2002/02512, 20 mg, 0.062 mmol) in DCM is added HATU (28 mg, 0.073 mmol) and DIEA (33 mg, 0.26 mmol). After the solution is stirred at rt for 5 min, a 28 mg portion of the compounds of step 17 (E) (0.052 mmol) is added. The reaction solution was stirred 16 h at rt, and then the reaction solution was partitioned between ethyl acetate and water, the organic layer was concentrated, and the crude product was purified by chromatography eluting with a step gradient of 20% to 50% to 70% ethyl acetate in hexanes to provide 40 mg (98%) of the desired amide. MS (ESI) (M+H-Boc)+=739.34