Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH:2]([P+:5]1([CH:28]([CH3:30])[CH3:29])[CH2:11][C:10]2[CH:12]=[CH:13][C:14]3[C:19]([C:9]=2[C:8]2[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[CH:26]=[CH:27][C:7]=2[CH2:6]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1>[CH:28]([P:5]([CH2:6][C:7]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:8]=1[C:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:10]=1[CH3:11])[CH:2]([CH3:4])[CH3:3])([CH3:29])[CH3:30]
Reactant: CC(C)[P+]1(C(C)C)Cc2ccc3ccccc3c2-c2c(ccc3ccccc23)C1
Agent: [Al+3]
Agent: [Br-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1ccc2ccccc2c1-c1c(CP(C(C)C)C(C)C)ccc2ccccc12

Procedure:
4 g (8.4 mmol) of 4,4-diisopropyl-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]phosphepinium bromide are suspended in 70 ml of absolute toluene under protective gas and reacted with 400 mg (10.5 mmol) of lithium aluminum hydride using a method analogous to Example 5.
Reaction SMILES: ClC1C=C(OC)C=CC=1N1[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=[O:17])[N:12]=[N:11]1.[Cl:19][C:20]1[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[C:25]([O:27][C:28]([F:29])([F:30])[F:31])[CH:24]=[CH:23][C:21]=1[N:22]1[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=[O:17])[N:12]=[N:11]1
Reactant: COc1ccc(-n2nnc(C(=O)O)c2C)c(Cl)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Product: Cc1c(C(=O)O)nnn1-c1ccc(OC(F)(F)F)cc1Cl

Procedure:
The title compound was prepared analogously to 1-(2-chloro-4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Example step 2) by replacing 2-chloro-4-methoxyaniline (step 1) with 2-chloro-4-trifluoromethoxyaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C1(C)C=CC=CC=1.[CH2:31]([N:38]=[C:39]=[S:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C>[CH2:31]([NH:38][C:39]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[S:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: S=C=NCc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NCc4ccccc4)cc3Cl)c2cc1OC
Temperature: 80 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (2 ml) and ethanol (2 ml) to prepare a solution. Benzyl isothiocyanate (48 μl) was then added to the solution, and the mixture was stirred at 80° C. for 6 hr. The reaction solution was concentrated, and ether and hexane were added to the residue. The resultant crystal was collected by filtration to give the title compound (46 mg, yield 65%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[N:20]1([CH2:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][C:27]2[CH:34]=[CH:33][C:30]([C:31]3[NH:1][C:2]4=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]5[C@@H:15]6[CH2:16][C@@H:12]([CH:13]=[CH:14]6)[C@@H:11]5[C:17]([NH2:19])=[O:18])=[C:7]4[N:8]=3)=[CH:29][CH:28]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 31.5 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-morpholin-4-ylmethyl-benzaldehyde (43.5 mg, 0.212 mmol) were reacted to produce 27 mg (32%) of the title compound. mp: 240-244° C., 1H NMR (300 MHz, DMSO-d6): 13.06 (s, 1H), 8.09 (d, J=8 Hz, 2H), 7.91 (d, 1H), 7.67 (s, 1H), 7.45 (d, J=8 Hz, 1H), 7.16 (s, 1H), 6.88 (m, 1H), 6.41 (d, J=8 Hz, 1H), 6.33 (s, 1H), 3.88 (br s, 1H), 3.59 (br s, 4H), 3.52 (s, 2H), 2.88 (s, 1H), 2.76 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.38 (s, 4H), 2.23 (d, J=8 Hz, 1H), 1.43 (d, J=8 Hz, 1H). MS: 445 (M+H), HPLC: 1.51 min (G method).
Reaction SMILES: [OH-].[K+].[CH3:3]/[C:4](/[CH:11]=[CH:12]/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:5]\[C:6]([O:8]CC)=[O:7]>CC(O)C>[CH3:3]/[C:4](/[CH:11]=[CH:12]/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=C/C(C)=C/C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
Potassium hydroxide (3.0 g) was dissolved in 20 ml of 2-propanol at 100° C. The solution was added with 2-propanol (10 ml) solution of ethyl (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate obtained in Example 1, and stirred at the same temperature for 5 minutes. The reaction mixture was added to ice-water and washed with n-hexane. The solution was neutralized with 10% hydrochloric acid and extracted with n-hexane. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to obtain 3.5 g of the title compound (yield 51%) as a yellow crystal.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=O)[CH2:19][C:20](=O)[C:21]([O:23][CH3:24])=[O:22])=[N:16][CH:17]=1.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[Cl:2])[N:10]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=2)=[N:16][CH:17]=1
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(Br)cn2)n(-c2ccccc2Cl)n1
Temperature: 120 °C
Yield: 12.7 %

Procedure:
A mixture of (2-chlorophenyl)hydrazine hydrochloride (1.1 g, 6.1 mmol) and methyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate (1.7 g, 6.0 mmol) in MeOH (30 mL) was divided into two microwave reaction vessels. Each reaction vessel was then heated in the microwave at 120° C. for ten minutes. LC/MS analysis at this time showed the reaction to be essentially complete. The solutions were concentrated under reduced pressure to afford a dark brown semi-solid. This material was taken up in EtOAc and saturated aqueous NaHCO3. The layers were separated and the basic aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford a dark oil. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc in hexane to afford methyl 5-(5-bromopyridin-2-yl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate (300 mg, 13% yield) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13]([O-:15])=[O:14])=[O:9].[NH2+]1CCOCC1.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:9]
Reactant: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)[O-])cc1OC
Agent: C1COCC[NH2+]1
Agent: Cl
Solvent: O
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 98 %

Procedure:
A 20 g quantity of morpholinium N-(3,4-dimethoxycinnamoyl)anthranilate is dissolved in 40 ml of water and the resultant solution is added dropwise to 45 ml of diluted hydrochloric acid (5 ml of conc. hydrochloric acid and 40 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at 90°-100° C. under reduced pressure for 3 hours to yield 15.5 g of N-(3,4-dimethoxycinnamoyl)anthranilic acid (98% yield). The compound is confirmed as identical to that obtained in EXAMPLE VI.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:31](=[O:32])[CH2:30][N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1
Reactant: CN1CCN(CC(=O)O)CC1
Product: CN1CCN(CC(=O)Nc2ccc3nc(NC4CCc5ccc(F)cc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine and (4-methyl-piperazin-1-yl)-acetic acid; MS: m/e=434.5 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:48][CH2:49][C:50]1[N:51]=[CH:52][N:53]([C:55]2[CH:60]=[CH:59][C:58]([N:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]3=[O:67])=[CH:57][CH:56]=2)[CH:54]=1>CN(C=O)C>[O:67]=[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][N:61]1[C:58]1[CH:59]=[CH:60][C:55]([N:53]2[CH:54]=[C:50]([CH2:49][NH:48][C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[O:12])[N:51]=[CH:52]2)=[CH:56][CH:57]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1)c1ccc2[nH]ccc2c1
Reaction time: 0.08 h
Yield: 40.7 %

Procedure:
To a solution of indole-5-carboxylic acid (40 mg, 0.25 mmol) and triethylamine (0.150 mL, 1.08 mmol) in DMF (2 mL), BOP (135 mg, 0.30 mmol) was added. After 5 min of stirring, 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one hydrochloride (53 mg, 0.18 mmol) was added. The mixture was stirred at room temperature overnight. It was then purified by HPLC to give the titled compound (30 mg). MS 410.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[C:14]([O:18][C:19](=[O:39])[NH:20][CH2:21][CH2:22][N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][N:27](CC3C=CC=CC=3)[CH2:28]2)[CH2:24]1)([CH3:17])([CH3:16])[CH3:15].CC(C)CC(O)C.[H][H]>[Pd].CO>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[C:14]([O:18][C:19](=[O:39])[NH:20][CH2:21][CH2:22][N:23]1[CH2:24][CH:25]2[O:31][CH:29]([CH2:28][NH:27][CH2:26]2)[CH2:30]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Solvent: CC(C)CC(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Temperature: 55 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamic acid tert-butyl ester 2,4,6-trimethylbenzenesulfonic acid salt (150 g prepared as described below), 4-methyl-2-pentanol (MIBC) (300 mL) and methanol (300 mL) were combined in a metal hydrogenation vessel. Solid 5% Pd/C catalyst (4.5 g, 61% water wet, Johnson Matthey type 440L) was added. The mixture was then hydrogenated under 2.5 bar of hydrogen pressure and was simultaneously heated to 55° C. Gas uptake measurement showed the reaction to be complete after 2 hours. After cooling to 40° C. the catalyst was removed by filtration through a glass fibre filter paper. The catalyst was washed on the filter with MIBC (300 mL) and the washings added to the main filtrate. Solvent (185 mL) was removed by distillation at atmospheric pressure. More solvent (243 mL) was then removed by reduced pressure (<100 mmHg) distillation. Isopropyl ether (IPE) (1050 mL) was added quickly at 70° C., which caused the temperature to fall to 45° C. An unstirrable precipitate formed in the reaction vessel. The mixture was re-heated and solvent distilled and collected (268 mL). MIBC (150 mL) was added and at 80° C. all material dissolved. The ratio of MIBC:IPE was now approximately 4:5. The solution was allowed to cool and was seeded (86 mg) at 70° C. The reaction was left to cool overnight to ambient temperature. The mixture was cooled to 8° C. and then the solid product collected by filtration. The solid was washed on the filter with IPE (450 mL) and then sucked dry. Further drying in vacuo at 60° C. gave the title compound as a white solid (115.0 g, 91%).
Reaction SMILES: I[C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:6]=1.I[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25].CN(C=O)C>C(OCC)(=O)C.[Cu]>[CH3:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][N:5]1[CH:6]=[C:2]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4]1
Reactant: FC(F)(F)C(F)(F)I
Reactant: Cc1cc(Cn2cc(I)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(C(F)(F)C(F)(F)F)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrobenzyl)-3-trifluoromethyl-1H-pyrazole (2.06 g), copper powder (0.95 g), iodopentafluoroethane (4.92 g) and DMF (13 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 130-135° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and an insoluble matter was filtered with Celite and washed with ethyl acetate. The filtrate was concentrated under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-pentafluoroethyl-3-trifluoromethyl-1H-pyrazole (1.39 g)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[S:10][C:11]3[CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][C:16]=3[C:3]=12.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[NH2:28]>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[S:10][C:11]4[CH2:12][N:13]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:14][CH2:15][C:16]=4[C:3]=23)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Yield: 64 %

Procedure:
In analogy to Example 54A, the title compound was synthesized from tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 53A (190 mg, 0.54 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline from Example 6A (127 mg, 0.54 mmol) to yield 215 mg (88% purity, 64% yield), which were used without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1.C(=O)(O)[O-].[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:1])([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[O:3][CH2:4][CH2:5]2)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(c2cccnc2)OCCc2cc(O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Oc1ccc2c(c1)CCOC2(C)c1cccnc1
Reaction time: 1 h

Procedure:
A mixture of 1-methyl-1-(3-pyridyl)-6-isochromanol (5.0 g), described in Example 22, and acetic anhydride (50 ml) is heated on the steam bath for 4 hr. The mixture is poured upon ice, left at room temperature for 1 hr, rendered basic with sodium bicarbonate and then extracted with chloroform. The extracts are washed with brine, dried, evaporated, and the residue is crystallized from isopropanol to give the title compound, m.p. 113°-115° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.O>C1COCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33][N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCn1c(=O)c(NC(=O)Nc2cc(CBr)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(=O)c(NC(=O)Nc2cc(CN3CCCC3)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-(bromomethyl)phenyl]urea (330 mg, 0.56 mmol) in THF (tetrahydrofuran, 5 ml) is added pyrrolidine (362 mg, 5.09 mmol), and the mixture is stirred at room temperature for 3 hours. The mixture is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (5-10% methanol/chloroform) to give the title compound (234 mg, 0.42 mmol) as colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:6]=[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[N:12]=[C:11]([CH3:13])[NH:10][C:9]=2[CH:14]=1)=[O:4].[H-].[Na+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>CN(C)C=O>[CH3:23][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[N:12]=[C:11]([CH3:13])[N:10]([S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[C:9]=2[CH:14]=1)=[O:4]
Reactant: Cc1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OCc4ccccc4)cc(C(=O)N(C)C)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a suspension of N,N,2-trimethyl-4-[(phenylmethyl)oxy]-1H-benzimidazole-6-carboxamide (928 mg, 3.0 mmol, STEP 5) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% in mineral oil, 180 mg, 4.50 mmol) at 0° C. After stirring at room temperature for 30 minutes, the reaction mixture was cooled to 0° C. To the mixture was added 4-methylbenzenesulfonyl chloride (572 mg, 3.00 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from dichloromethane only to ethyl acetate only) to afford the title compound as a white solid (1.00 g, 72%).
Reaction SMILES: CI.[C:3](=O)([O-])O.[Na+].[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:33][S:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:17][NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]([O:31][CH3:32])=[O:30])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:33][S:34][C:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:17][N:18]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]([O:31][CH3:32])=[O:30])[CH3:3])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1cccc2c(NC[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)cccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c(N(C)C[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)cccc12
Temperature: 20 °C
Reaction time: 20 h

Procedure:
3.6 cm3 of methyl iodide and 7 g of solid sodium hydrogen carbonate are added, with stirring, to a solution of 1.5 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)-propylamino)-1-naphthoate in 25 cm3 of dimethyl-formamide. The reaction mixture is stirred for 20 hours at a temperature in the region of 20° C. and then poured onto 200 cm3 of ice. The aqueous phase is extracted 3 times with 150 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The red oil obtained is purified by chromatography on silica [eluent: cyclohexane/ethyl acetate (90/10 by volume)]. 0.56 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)propyl-N-methylamino)-1-naphthoate is obtained, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[C:14]([C:15]3[NH:19][C:18]4[CH:20]=[C:21]([CH3:25])[C:22](C)=[CH:23][C:17]=4[N:16]=3)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[Cl:28]C1C(C)=CC2NC(C3C4CNCCC=4NN=3)=NC=2C=1.C(N(CC)C(Cl)=O)C>>[CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[C:14]([C:15]3[NH:19][C:18]4[CH:20]=[C:21]([CH3:25])[C:22]([Cl:28])=[CH:23][C:17]=4[N:16]=3)[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)N1CCc2[nH]nc(-c3nc4cc(C)c(C)cc4[nH]3)c2C1
Reactant: Cc1cc2[nH]c(-c3n[nH]c4c3CNCC4)nc2cc1Cl
Agent: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)N1CCc2[nH]nc(-c3nc4cc(Cl)c(C)cc4[nH]3)c2C1

Procedure:
By proceeding in a manner similar to Example 258(a) above but (i) using 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [Example 251(b)] and diethylcarbamyl chloride, and (ii) subjecting the reaction product to flash column chromatography, eluting with ethyl acetate to ethyl acetate/methanol (47:3, v/v) followed by trituration with ethanol, there was prepared 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide (35.6 mg) as a pale yellow solid. MS: 387/389 (M+H)+. HPLC (METHOD E1): RT=11.07 minutes.