Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]Br>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (65 mg), potassium carbonate (30 mg), and 1,2-dibromoethane (30 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 36 mg (yield 45%) of N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N′-propylurea as an intermediate. The intermediate (36 mg), potassium carbonate (30 mg), and N-methylethanolamine (30 μl) were dissolved in N,N-dimethylformamide (3 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under, the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 21 mg (yield 55%) of the title compound.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](F)=[C:6]([F:14])[C:5]=1[F:15]>C1COCC1>[F:14][C:6]1[C:5]([F:15])=[C:4]([F:3])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]=1[NH:2][CH3:1]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1F
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])cc(F)c(F)c1F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
A solution of MeNH2 in THF (50.7 mL, 2 M, 101 mmol) was added dropwise to a solution of 1,2,3,4-tetrafluoro-5-nitrobenzene (9.88 g, 50.7 mmol) in THF (200 mL) at −20° C. The mixture was stirred at −20° C. for 1.5 h, concentrated, washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from EtOAc/PE gave the sub-title compound. Yield: 8.5 g (81%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:12][C:13]1[N:14]([CH3:29])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[N:18]=[C:17]([Cl:28])[N:16]=2>>[C:1]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:18]=[C:17]([Cl:28])[N:16]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)C1CCNCC1
Product: Cn1c(CN2CCC(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Yield: 68.1 %

Procedure:
4-tert-butylpiperidine (0.45 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (1.0 g) via General Procedure C to yield 4-(8-((4-tert-butylpiperidin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.80 g) as a white solid.
Reaction SMILES: [O-2].[Ca+2:2].[O:3]=[C:4]([OH:15])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6].[B:16]([OH:19])([OH:18])[OH:17]>O>[B:16]1([OH:17])[O:10][CH:9]([CH:7]([OH:8])[CH:5]([OH:6])[C:4]([O-:15])=[O:3])[CH:11]([CH2:13][OH:14])[O:12]1.[B:16]1([OH:19])[O:18][CH:9]([CH:7]([OH:8])[CH:5]([OH:6])[C:4]([O-:15])=[O:3])[CH:11]([CH2:13][OH:14])[O:17]1.[Ca+2:2]
Reactant: OB(O)O
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: O=C([O-])C(O)C(O)C1OB(O)OC1CO
Yield: 40 %

Procedure:
28 grams of calcium oxide were added to water to form a thick slurry. This slurry was slowly added with stirring to 392 grams of a 50% aqueous solution of technical grade gluconic acid. After all of the slurry was added the resultant mixture was cooled and 61.8 grams of technical grade boric acid added. The mixture was stirred until a dark brown solution was obtained and then adjusted by water addition to provide a 40% solids solution.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4](Br)[CH3:5].[F:8][C:9]1[C:10]2[NH:17][CH:16]=[C:15]([I:18])[C:11]=2[CH:12]=[N:13][CH:14]=1>>[F:8][C:9]1[C:10]2[N:17]([CH:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])[CH:16]=[C:15]([I:18])[C:11]=2[CH:12]=[N:13][CH:14]=1
Reactant: Fc1cncc2c(I)c[nH]c12
Reactant: COC(=O)C(C)Br
Product: COC(=O)C(C)n1cc(I)c2cncc(F)c21

Procedure:
Prepared according to the method described for Preparation 45 using 2-bromo-propionic acid methyl ester and 7-fluoro-3-iodo-pyrrolo[3,2-c]pyridine (Preparation 61). Purified using silica gel column chromatography eluting with 0-5% MeOH in DCM.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:4](O)[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].BrC(Br)C.C[CH2:22][O:23][CH2:24]C>C(O)CO>[CH3:9][C:6]1[C:4]2[CH2:24][O:23][CH2:22][O:10][C:3]=2[C:2]([CH3:1])=[CH:8][CH:7]=1
Reactant: CCOCC
Reactant: Cc1ccc(C)c(O)c1O
Agent: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Product: Cc1ccc(C)c2c1COCO2
Temperature: 120 °C

Procedure:
To a stirred solution of 3.00 g of 3,6-dimethylcatechol and 6.15 g of potassium carbonate in 35 mL of ethylene glycol is added 3.74 mL of dibromoethane. A reflux condenser is attached and the mixture heated in an oil bath to 120° C. for 4 hours. The mixture is allowed to cool to room temperature and then is distributed between 100 mL of saturated potassium carbonate solution and 200 mL of ether. The ether layer is dried over magnesium sulfate and concentrated under reduced pressure to yield a red liquid, which is purified by chromatography on silica gel to afford 2.90 g of 5,8-dimethyl-1,3-benzodioxane as a light yellow liquid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:19][CH:18]([CH3:20])[C:17](=[O:21])[CH:16]([CH3:22])[CH2:15]1)C1C=CC=CC=1>C1C=CC=CC=1>[C:2]([N:14]1[CH2:19][CH:18]([CH3:20])[C:17](=[O:21])[CH:16]([CH3:22])[CH2:15]1)([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CC1CN(Cc2ccccc2)CC(C)C1=O
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CC(C)C(=O)C(C)C1
Reaction time: 6 h

Procedure:
Ethyl chloroformate (10.0 g, 90 mmol) was added to a stirred solution of 1-benzyl-3,5-dimethyl-4-piperidinone (5.0 g, 24 mmol) in benzene (20 ml), refluxed with stirring for 6 hr and concentrated to dryness to give 1-carbethoxy-3,5-dimethyl-4-piperidinone as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:11][C:12]([F:13])([F:14])[F:15])[CH:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1Cl
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCC(C(=O)OC(C)(C)C)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 1B using 2-chloro-4-[(2,2,2-trifluoroethyl)amino]benzonitrile and tert-butyl 2-bromobutanoate: MS (ES) m/z 377 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH:14]=3)[CH:9]=2)[CH:4]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH:9]=2)[CH:4]=1
Reactant: [H][H]
Reactant: CCCC1CC=C(c2ccc3cc(OC)ccc3c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H](c2ccc3cc(OC)ccc3c2)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
44.9 g of 2-methoxy-6-(4-propylcyclohexa-1-ene-1-yl)naphthalene was dissolved in 800 ml of ethyl acetate. To the solution was then added 10 g of 5% palladium carbon. The reaction mixture was then stirred at a hydrogen pressure of 4 kg/cm2 for 6 hours. The catalyst was then removed by filtration. The solvent was then distilled off. The residue was then dissolved in 180 ml of N,N-dimethylformamide. To the solution was then added 18 g of potassium t-butoxide. The reaction mixture was then heated to a temperature of 120° C. with stirring for 1 hour. The reaction solution was then allowed to cool to room temperature. To the reaction solution was then added 70 ml of a 10% hydrochloric acid to cause crystallization. The crystal thus precipitated wax filtered off, washed with water, and then dried under reduced pressure. The crystal was then recrystallized from ethanol to obtain 28.0 g of 2-methoxy-6-(trans-4-propylcyclohexyl)naphthalene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=2)[CH:36]=1.[B][B][B][B][B][B][B][B][B][B].C(O)(C(F)(F)F)=O>>[CH2:33]([N:30]([CH2:31][CH3:32])[C:28](=[O:29])[C:25]1[CH:24]=[CH:23][C:22]([C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:45][C:44]3[CH:43]=[CH:42][C:41]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)=[CH:48][CH:47]=3)[CH:3]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:27][CH:26]=1)[CH3:34]
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NCc3ccc(-c4cccnc4)cc3)c2)N2CCNCC2)cc1
Yield: 113.3 %

Procedure:
Using the same method as for COMPOUND 17 and using INTERMEDIATE 5a (205 mg, 0.44 mmol), 4-(3-pyridinyl)benzaldehyde (88.7 mg, 0.48 mmol), and decaborane (16.4 mg, 0.13 mmol) afforded COMPOUND 52 (266 mg, 61% yield) as its TFA salt. This material was lyophilized from CH3CN/H2O to produce a slightly yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH2:17][CH3:18])[C:6]=1[OH:20])=[S:4].[BH4-].[Na+]>CO>[CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH2:17][CH3:18])[CH:6]1[OH:20])=[S:4]
Reactant: CCC1(C)Oc2ccc(C#N)cc2C(C(=S)NC)=C1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(C)Oc2ccc(C#N)cc2C(C(=S)NC)C1O
Yield: 53.4 %

Procedure:
To a mixture of 0.8 g of N,2-dimethyl-6-cyano-2-ethyl-3-hydroxy-2H-1-benzopyran-4-carbothioamide and 20 ml of methanol was added 0.24 g of sodium borohydride (NaBH4) while stirring under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure, and water was added to the residue. The residue was extracted with diethyl ether, and the organic layer was washed with water and dried. The solvent was removed by distillation to obtain 0.43 g of N,2-dimethyl-6-cyano-3,4-dihydro-2-ethyl-3-hydroxy-2H-1-benzopyran-4-carbothioamide. The resulting product were added 0.1 g of p-toluenesulfonic acid monohydrate and 30 ml of toluene, followed by heating at reflux for 3 hours. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.2 g of N,2-dimethyl-6-cyano-2-ethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: [NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[CH:3]=[C:2]1[C:13]([O:15]C)=[O:14].C[Si](C)(C)[O-].[K+]>O1CCCC1>[NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[CH:3]=[C:2]1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cc2ccc3[nH]ccc3c2[nH]1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc3[nH]ccc3c2[nH]1
Yield: 44 %

Procedure:
A mixture of 0.53 g (2.5 mmol) of methyl 1,6-dihydro-1,6-diaza-as-indacene-2-carboxylate, 0.36 g (2.5 mmol) of potassium trimethylsilanolate (Aldrich) and 6.0 ml of tetrahydrofuran is refluxed for 1 h, further 0.18 g (1.25 mmol) of potassium trimethylsilanolate is added and after 5 h reflux the reaction mixture is concentrated. The residue is mixed with 20 ml of water, the undissolved material is filtered off, 0.32 ml of hydrochloric acid is added to the filtrate, the precipitated crude product is filtered off and purified by column chromatography using Kieselgel 60 (Merck) as adsorbent, and chloroform:methanol=9:1 as eluent. The product is crystallized with diethyl ether to yield 0.22 g (44%) of the title compound. Mp.: 248-250° C. (diethyl ether).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:9][CH2:8][C@@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]2)[CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:4][CH:3]([N:5]2[CH2:9][CH2:8][C@@H:7]([NH2:10])[CH2:6]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C2COC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(C2COC2)C1
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 455A (0.7 g) in dichloromethane (2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 4 hours and concentrated. The concentrate was loaded onto an ion exchange column (Bond Elut Plexa column from Varian) which had been previously washed with 1:1 methanol/CH2Cl2. The trifluoroacetic acid was washed through with 1:1 methanol/CH2Cl2. The column was then eluted with 7 N NH3 in methanol to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][N:23]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:24][CH2:25]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 18.6 g of p-methylbenzoyl chloride in 30 ml of methylene chloride is added dropwise, over a period of 15 minutes, to a solution, stirred at room temperature, of 22.4 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine and 12.1 g of triethylamine in 200 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature. The reaction solution is diluted with 100 ml of methylene chloride, washed with 2N NaOH and with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is recrystallised twice from alcohol. 1-[2-(4-chlorophenyl)-ethyl]-4-(4-methylbenzoyl)-piperazine having a melting point of 105°-106° is thus obtained.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]([Cl:26])[CH:8]=1)C.Cl.C(O)(=O)C>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:9]([Cl:26])=[CH:8][C:7]([O:6][CH2:5][CH:4]=[O:3])=[CH:12][C:11]=2[Cl:13])=[CH:20][CH:21]=1
Reactant: CCOC(COc1cc(Cl)c(OCCCOc2ccc(Cl)cc2)c(Cl)c1)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=CCOc1cc(Cl)c(OCCCOc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
4-(3-(4-Chlorophenoxy)propyloxy)-3,5-dichlorophenoxyacetaldehyde diethylacetal (manufactured in Production Example 1 of intermediate described hereinafter) (1.6 g) was added dropwise to a mixed solution of 1 ml of hydrochloric acid and 9 ml of acetic acid with stirring at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was poured into iced water and extracted twice with 100 ml of diethyl ether. The ether layers were combined. washed with water, washed twice with aqueous 5% sodium hydrogencarbonate, washed with water, dried over anhydrous magnesium sulfate and then concentrated to obtain 0.8 g of 4-(3-(4-chlorophenoxy)propyloxy)-3,5-dichlorophenoxyacetaldehyde as a crude product.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH3:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH2:14]>C1COCC1>[CH:5]([NH:14][C:13]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:12]=1[CH3:11])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: C1CCOC1
Solvent: O=CO
Product: Cc1cc([N+](=O)[O-])ccc1NC=O
Temperature: 55 °C
Yield: 77.2 %

Procedure:
25 g (0.26 mol) of acetic anhydride were cooled to 0° C. under nitrogen. 15 g (0.32 mol) of formic acid were added dropwise at this temperature. The resultant mixture was then allowed to melt, and was then warmed to from 50 to 60° C. over the course of two hours. The mixture was then cooled to room temperature, and 20 ml of dry tetrahydrofuran were added, and the resultant mixture was again cooled to 0° C. A suspension of 15.2 g (0.1 mol) of 2-methyl-4-nitroaniline in 100 ml of THF was then added dropwise to this mixture, and the resultant mixture was left at 0° C. for one hour and then warmed to room temperature. The resultant yellow precipitate was filtered off with suction, washed with water and dried at 50° C. under reduced pressure, to give 13.9 g of N-formyl-2-methyl-4-nitroaniline (yield: 77%). The product had the same physical/chemical properties as that prepared in the above-described manner (compare section 1.1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:25](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:25])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
32.94 g (100 mmol) of N-benzyloxycarbonyl-tyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 15.6 g (110 mmol) of iodomethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, distributed between ethyl acetate and water, and, after drying (Na2SO4), the organic phase is mixed with hexane. The title compound crystallizes out.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][C:9]([OH:11])=O.[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:9](=[O:11])[CH2:8][S:7][C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(O)CSc1ncccn1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)CSc1ncccn1

Procedure:
Using, the general method of Example 105 (2-pyrimidinylthio)acetic acid (0.11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.2 g, 0.64 mmol) to provide N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamide as a white solid, m.p. 156-160° C. (dec.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+].Cl.[C:17]([O:21][NH2:22])([CH3:20])([CH3:19])[CH3:18].Cl>O>[C:17]([O:21][N:22]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]([OH:9])=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: CC(C)(C)ON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)ON=C(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
A solution of thien-2-ylglyoxylic acid (6.2g.) and sodium bicarbonate (3.36g.) in water (100 ml.) was added dropwise to a stirred solution of t-butoxyamine hydrochloride (5.65 g.) and sodium bicarbonate (3.78g.) in water (100 ml.) at 0°-5° and the mixture was stirred at room temperature for 18 hr. The mixture was acidified with 2N hydrochloric acid to pH 2.0 and extracted with ethyl acetate. The combined extracts were washed with water, dried and concentrated to give a solid (9.75 g.). Recrystallisation from petroleum (b.p. 60°-80°) gave the title compound (4.0 g., 44%), m.p. 106°-107°, λmax. (EtOH) 290 nm (ε11,600), τ (CDCl3) values include 2.46, 2.66, 2.98 (d doublets, thienyl protons), 8.60 (C(CH3)3).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.OS(O)(=O)=O.CO.[C:34]([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]([O:16][CH3:34])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in example 12, 18.0 mg, 0.0514 mmol) in 1 mL of DCM was added conc H2SO4 (50 μL) followed by 50 μL of MeOH. The resulting mixture was stirred at RT for 0.5 h and then treated with 10 mL of saturated NaHCO3 aqueous solution. The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1% MeOH/DCM) gave 8.2 mg (44%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.31 (s, 1H), 9.65 (s, 1H), 8.30 (d, 1H, J=8.6 Hz), 7.76 (s, 1H), 7.35 (dd, 1H, J=8.6, 2.3 Hz), 7.25 (d, 1H, J=2.3 Hz), 5.88 (m, 1H), 3.11 (s, 3H), 2.23-2.37 (m, 4H), 1.75-1.90 (m, 4H), 1.55 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C2=CCCCC2)ccc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C2CCCCC2)ccc1C(=O)O
Yield: 86.2 %

Procedure:
To a solution of 4-cyclohexenyl-2-methylbenzoic acid (2.61 g) in ethanol (30 ml) and ethyl acetate (30 ml) is added 5% palladium-carbon (0.4 g), and the mixture is stirred at room temperature under atmospheric pressure of hydrogen gas for 30 minutes. The palladium-carbon is removed by filtration through celite, and the filtrate is evaporated to remove the solvent. The precipitated crystals are collected by filtration, crystallized from acetone/n-hexane, and washed to give 4-cyclohexyl-2-methylbenzoic acid (2.27 g) as white powder.