Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11]([CH3:25])[NH:10]1.[N+:26]([O-])([OH:28])=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11]([CH3:25])[NH:10]1
Reactant: Cc1[nH]n(Cc2ccccc2Cl)c2nc(-c3ccncc3)nc(=O)c1-2
Reactant: O=[N+]([O-])O
Product: Cc1[nH]n(Cc2cc([N+](=O)[O-])ccc2Cl)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 90% nitric acid (30 ml) at -10° C. was added in portions over 4 hours 1-(2-chlorophenylmethyl)-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one (4.9 g, 0.014 mol). The mixture was stirred at -10° C. for 30 minutes and poured into ice-water. The product was collected by filtration and washed with water. The solid residue was dissolved in methanol/DMF (3/1), treated with charcoal and the solvent was concentrated in vacuo. Ether was added to the residue and the product was collected by filtration and washed with ether to afford 5.5 g (99%) of 1-(2-chloro-5-nitrophenylmethyl)-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white powder, m.p. 290°-1° C. when dried at 80° C. in high vacuum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:6][CH2:7][CH3:8].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:19][N:18]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8]
Reactant: CSc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Reactant: CCCN(CCCN)c1ccccn1
Product: CCCN(CCCNc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-propylamino]pyridine (1.16 g) and 2-methylthio-5-(4-fluorobenzyl)pyrimid-4-one (1.25 g) were fused together on an oil bath at 160° C. for 5 hr. On cooling the residue was crystallised twice from ethanol and finally from ethanol/water to give 2-[3-(N-propyl-N-pyrid-2-ylamino) propylamino]-5-(4-fluorobenzyl)pyrimid-4-one 1.2H2O, 0.75 g (36%) mp 107°-9° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[C:4]([Cl:12])[C:3]=1[OH:13]>C(O)C.[Pt]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:11])=[C:4]([Cl:12])[C:3]=1[OH:13]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1O
Agent: [Pt]
Solvent: CCO
Product: Cc1cc(N)c(C)c(Cl)c1O
Reaction time: 0.75 h
Yield: 96.1 %

Procedure:
Into a Parr bottle containing 5.0 grams (24.8 mmol) of 2,5-dimethyl-6-chloro-4-nitrophenol in 40 milliliters of ethyl alcohol was added 0.5 grams of 5 percent platinum on carbon. This mixture was hydrogenated for 45 minutes in a Parr apparatus. The resulting solution was filtered over charcoal and Celite and the solvent was evaporated to afford 4.09 grams of 2,5-dimethyl-6-chloro-4-aminophenol having a melting point of 127° C.-128° C. Recrystallization from ethyl acetate and hexane afforded a product having a melting point of 129° C.-130° C. Elemental analysis of the product indicated the following:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:33])[NH:15][C:16]2[S:17][C:18]3[C:24]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:23][CH:22]=[C:21]([O:31][CH3:32])[C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH3:32][O:31][C:21]1[C:19]2[N:20]=[C:16]([NH:15][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:33])[S:17][C:18]=2[C:24]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)nc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C3CCNCC3)nc12
Reaction time: 1 h
Yield: 77 %

Procedure:
4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (95 mg, 0.2 mmol) were dissolved in trifluoroacetic acid (0.8 ml). After 1 h at room temperature, the mixture was evaporated to dryness. Purification as described for tetrahydro-pyran-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide afforded the title compound as a white solid (77%), MS: m/e=377(M+H+).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.Cl[CH2:21][C:22]1[N:23]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:24]2[C:29]([CH3:30])=[C:28]([CH3:31])[N:27]3[N:32]=[N:33][N:34]=[C:26]3[C:25]=2[N:35]=1>CN(C=O)C>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:21][C:22]1[N:23]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:24]2[C:29]([CH3:30])=[C:28]([CH3:31])[N:27]3[N:32]=[N:33][N:34]=[C:26]3[C:25]=2[N:35]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNC(=O)c3ccccc3)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)c3ccccc3)c12
Reaction time: 72 h
Yield: 92.8 %

Procedure:
N-Hydroxyphthalimide (2.60 g, 16.0 mmol) and triethylamine (2.20 mL, 16.0 mmol) were added to a suspension of N-{4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}benzamide (4.70 g, 11.4 mmol) in DMF (285 mL). The reaction mixture was allowed to stir for 3 days, then was concentrated under reduced pressure to a white slurry. Methanol was added and a white solid was isolated by filtration, washed with methanol, and dried under vacuum to afford 5.70 g of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]benzamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:28]([O:27][C:26]([NH:25][C@H:22]1[CH2:23][CH2:24][N:20]([C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])[CH2:21]1)=[O:32])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A mixture of 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid (5 g, 20 mmol), tert-butyl (3S)-pyrrolidin-3-ylcarbamate (3.9 g, 21 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (9.2 g, 21 mmol), and triethylamine (3.8 g, 38 mmol) in dichloromethane (100 mL) was stirred at room temperature overnight. The reaction solution was washed with water, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel to give 7.5 g of product. MS (M+H) 432.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([N:8]([CH3:26])[CH:9]2[CH2:10][CH2:11][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH2:13]3)[CH2:24][CH2:25]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Yield: 93 %

Procedure:
To a suspension of tert-butyl 8-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (3.8 A: 0.14 g, 0.34 mmol) in n-BuOH (2.0 mL) was added 1-methyl-1H-pyrazol-4-amine hydrochloride (89 mg, 0.67 mmol) and DIPEA (0.17 g, 1.35 mmol). The mixture was stirred in a sealed tube and heated to 150° C. for 12 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EA/PE (v/v)=4/1) to afford 3.9A as a light yellow solid (0.15 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].BrBr>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]2[N:8]=[C:9]([NH2:11])[S:10][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccccc1F
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(F)cccc2s1
Yield: 71.3 %

Procedure:
To a suspension of (2-fluorophenyl)thiourea (1.7 g, 10.0 mmol) in chloroform (25ml) was added a solution of bromine (0.51 mL; 10.0 mmol) dropwise at room temperature. The resulting mixture was heated under reflux for 3 hrs. The solvent was evaporated, water was added and the mixture was neutralized with ammonium hydroxide. The resulting white precipitation was collected by filtration and dried to yield 1.2 g (72%) of the title compound which was used in the subsequent step without further purification.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[BH4-].[Na+].O.N>FC(F)(F)C(O)=O>[C:2]1(=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(O)N1CSc1ccncc1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1c2ccccc2CN1CSc1ccncc1
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
To a solution of 681 mg (2.5 mmol) of 4-[(3-hydroxyisoindolin-1-on-2-yl)methylthio]pyridine in 6 ml of trifluoroacetic acid, 0.30 g (7.93 mmol) of sodium borohydride was added in small portions, and the mixture was stirred for 15 minutes. The reaction mixture was poured into cold water and aqueous ammonia was added to make the mixture basic, followed by extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by recrystallization (solvent: ethyl acetate) to give 350 mg of the desired product (54.6% yield, colorless columns), mp. 131°-132° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[C:9]=2[CH:10]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].Cl.C(OCC)(=O)C>CN(C)C=O>[CH2:17]([O:13][C:12](=[O:14])[CH2:11][C:8]1[C:9]2[CH:10]=[C:2]([CH3:1])[NH:3][C:4]=2[CH:5]=[CH:6][CH:7]=1)[CH:16]=[CH2:15]
Reactant: Cc1cc2c(CC(=O)O)cccc2[nH]1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Cc1cccc2[nH]c(C)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methylindole-4-acetic acid (53 g) in N,N-dimethylformamide (500 ml) was added dropwise allyl bromide (31 ml), and added anhydrous potassium carbonate (59 g). The mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into a mixture of 2N hydrochloric acid—ethyl acetate and then extracted with ethyl acetate. The extraction was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane—ethyl acetate) to give the title compound (43.5 g) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=12.[Cu][C:12]#[N:13].O>CN1CCCC1=O>[C:12]([C:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=12)#[N:13]
Reactant: N#C[Cu]
Reactant: Brc1ccn2ccncc12
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccn2ccncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
2 g of 8-bromopyrrolo[1,2-a]pyrazine prepared in Preparation Example 7 was added to a mixture of 2 g of copper(I) cyanide dissolved in 20 ml of N-methylpyrrolidone at 160° C. The reaction mixture was stirred for 10 minutes and cooled to room temperature. The reaction mixture was poured into 100 ml of distilled water, extracted with ethyl acetate (50ml×3), and then concentrated to dryness to obtain 1.2 g of yellowish brown title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:11][C@H:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:25]([CH3:26])[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:16]3[CH2:15][CH2:14][N:13]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:12]([CH3:11])[CH2:17]3)=[CH:24][CH:23]=2)=[O:9])=[N:6][CH:7]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=C(Cl)c1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
The acid chloride from step 2 (0.801 g, 3.633 mmol) in DCM (10 mL) was added to a solution of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.928 g, 2.906 mmol) in DCM (20 mL). Triethylamine (1.009 mL, 7.266 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was re-extracted with DCM (×2) and the combined organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with a 0-50% ethyl acetate/petroleum ether gradient yielded the title compound as a yellow oil (1.432 g). δH (CDCl3, 400 MHz) 8.34 (1H, br.s), 7.72 (1H, br.d), 7.38 (1H, br.d), 7.18 (2H, br.m), 6.98 (2H, br.s), 4.17 (1H, br.s), 3.79 (1H, d), 3.51 (3H, s), 3.46 (1H, d), 3.32 (1H, d), 3.07 (1H, td), 2.68 (1H, d), 2.47 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.45 (9H, s), 1.19 (3H, d). MS (ES): MH+ 503/505.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1
Reactant: N#Cc1cn[nH]c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1cnn(C2CCCCO2)c1
Temperature: 3 °C
Reaction time: 8 h

Procedure:
The reaction was carried out in a 3 liter three-necked flask with internal thermometer under argon. 50 g (537 mmol) of 1H-pyrazole-4-carbonitrile were suspended in 1.66 liter of methylene chloride and, after 3 h, cooled to 3° C. using an ice bath. At this temperature, 10.2 g (53.7 mmol) of 4-toluenesulphonic acid monohydrate were added. At 3° to 6° C., 58.8 ml (54.2 g, 644 mmol) of 3,4 dihydro-2H-pyran were then added dropwise over a period of 30 min. The reaction was then stirred at RT overnight. The clear reaction solution was then washed with 2 M aqueous sodium carbonate solution and with water, dried over magnesium sulphate, filtered and concentrated. The residue was triturated with cyclohexane and the solid obtained was filtered off with suction and dried in a vacuum drying cabinet at 30° C. for 4 h. This gave 91.8 g (96% of theory) of the title compound as a light-yellow powder.
Reaction SMILES: [NH2:1]C1C(I)=C(C(O)=O)C(I)=C(C(O)=O)C=1I.CCC[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[N:1]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Reactant: CCCCCCCCCCCC
Product: c1ccc2ncccc2c1
Yield: 95.6 %

Procedure:
According to the procedure described in Example 1, the reaction is carried out with the same amounts of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid using n-dodecane instead of meta-xylene, with quinoline, giving a yield of 95.6%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:15]=1[NH:16][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)ccc1O
Yield: 24 %

Procedure:
Using 5-bromosalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:26](=[O:42])([O:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:30][NH2:31])[NH2:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[C:26](=[O:42])([O:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:30][NH:31][C:23](=[O:24])[CH2:22][N:10]1[C:11](=[O:21])[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[NH2:27]
Reactant: NCC(OC(N)=O)c1ccccc1C(F)(F)F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)OC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 40 mg (111 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [for the preparation see Example 156A in WO 2007/134862], 33 mg (133 μmol) of the compound of Example 37A, 25 mg (133 μmol) of EDC and 21 mg (133 μmol) of HOBt in 2.4 ml of DMF was stirred at RT overnight, 1 ml of 1 M hydrochloric acid was then added and the mixture was separated directly by preparative HPLC [Method 20] into its components. This gave 53 mg (81% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=3)[O:10][C:3]=12.[CH3:20][C:21]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][NH:25]2>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:30][C:29]3[C:21]([CH3:20])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)[CH:8]=2)=[CH:12][C:13]=1[CH3:19]
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: COc1ccc(-c2cc3nccc(Cl)c3o2)cc1C
Product: COc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1C

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(4-methoxy-3-methylphenyl)furo[3,2-b]pyridine (29.40 mg; 0.11 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (16.49 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (30 mg, 73%). (HPLC (method F): 97%, RT: 4.34 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.14 (s, 1H), 8.49 (s, 1H), 7.92 (d, J=5.5, 1H), 7.77 (d, J=8.6, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 7.30 (d, J=8.4, 1H), 7.22 (s, 1H), 7.02 (dd, J=17.9, 8.5, 2H), 6.52 (s, 1H), 6.09 (d, J=5.5, 1H), 3.85 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H); MS (m/z) 384 [M+H]+, RT: 4.2 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:13])[CH2:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][C:23](=[O:25])[CH3:24])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(N)CC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CC(NC(C)=O)CC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 7-methoxy-1,2,3,4-tetrahydronapthalen-2-ylamine (2.54 g; 14.3 mmol) in CH2Cl2 (20 mL) was added DIEA (3.4 mL) and the reaction mixture was cooled to 0° C. Acetyl chloride (1.22 mL; 17.1 mmol) was added dropwise at 0° C. and the reaction was allowed to warm to room temperature, then stirred for 18 h. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude solid. Purification by flash chromatography (SiO2) eluting with hexanes-EtOAc yielded N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide as a white solid.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:12]=2[CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:12]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc2cc(Br)ccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Brc1ccc2oc(Cc3ccccc3)cc2c1

Procedure:
A mixture of 42.2 g. (0.14 mol.) of 2-benzoyl-5-bromobenzofuran and 35 ml. of 98% hydrazine in 70 ml. of diethylene glycol is warmed for a few minutes on a steam bath. Then 23.3 g. of potassium hydroxide is added and the reaction mixture is refluxed for 2 hours. After cooling, water is added to the mixture and the resulting aqueous solution is extracted with benzene. The extract is washed with water, 10% aqueous hydrochloric acid and water, dried (MgSO4) and concentrated to yield 2-benzyl-5-bromobenzofuran.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[C:15]([C:16](=[O:18])[CH3:17])=[CH:14][N:13]=[C:12]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:11]=23)[CH2:5][CH2:4]1.[CH3:30]OC(OC)N(C)C>>[CH3:1][O:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([N:9]2[C:10]3[C:15](=[CH:14][N:13]=[C:12]4[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[CH:20]=[CH:21][C:11]4=3)[C:16](=[O:18])[CH:17]=[CH:30]2)[CH2:7][CH2:8]1
Reactant: CO[C@H]1CC[C@H](Nc2c(C(C)=O)cnc3c2ccn3COCC[Si](C)(C)C)CC1
Reactant: COC(OC)N(C)C
Product: CO[C@H]1CC[C@H](n2ccc(=O)c3cnc4c(ccn4COCC[Si](C)(C)C)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-[(trans-4-Methoxycyclohexyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone (179 mg, 0.428 mmol) in N,N-dimethylformamide dimethyl acetal (3 mL) was stirred at 170° C. for 6 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (3 mL) and stirred with 1 M hydrochloric acid (3 mL) at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous sodium hydrogen carbonate, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1 (v/v)) to give the title compound (141 mg, yield 77%).