Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)(=O)=O)=CC=1.Cl>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Nc1cc(O)c(Cl)cc1F)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1cc(OC2CCCC2)c(Cl)cc1F)OCc1ccccc1

Procedure:
Then, benzyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (12.2 g, 41.3 mmol), potassium carbonate (5.97 g, 432.1 mmol), cyclopentyl p-toluenesulfonate (11.2 g, 46.4 mmol) and acetone (150 ml) as a solvent were charged into a 500 cc round-bottom Flask and heated for 9 hours while refluxing. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid. After thoroughly stirring, the precipitated benzyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate as a pale yellow solid (14.9 g, 40.9 mmol, 994 yield) was isolated by filtration and well dried. 1H-NMR Spectrum (CDCl3, TMS, ppm): δ1.48-2.07 (8H, m), 4.83 (1H, m), 5.26 (2H, s), 6 92 (1H, br, s) 7.14 (1H, d, JHF =11.5 Hz), 7.47 (5H, s), 7.93 (1H, d, JHF =8.3 Hz).
Reaction SMILES: C(O[C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[CH:11][C:10]=1[F:33])C1C=CC=CC=1.[F:34][C:35]1([F:40])[CH2:37][CH:36]1[CH2:38][OH:39]>>[F:34][C:35]1([F:40])[CH2:37][CH:36]1[CH2:38][O:39][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[CH:11][C:10]=1[F:33]
Reactant: OCC1CC1(F)F
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCc4ccccc4)c(F)c3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4CC4(F)F)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (2,2-difluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1)([CH3:10])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21](N=C=NCCCN(C)C)C.CO>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:21][O:18][C:17]([C:15]1[N:16]=[C:12]([S:11][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:10])[CH3:9])[S:13][CH:14]=1)=[O:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)O)cs1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-tert-Butoxycarbonyl-1-methyl-ethylsulfanyl)-thiazole-4-carboxylic acid was dissolved in methylene chloride (1200 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191.70 g), 4-dimethylaminopyridine (5.86 g) and methanol (19.47 mL) were added and the mixture was stirred at room temperature overnight. The mixture was washed with dilute hydrochloric acid (about 0.5 mol/L), saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution (each 500 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved again in ethyl acetate (700 mL), washed successively with dilute hydrochloric acid (about 0.2 mol/L), saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution (each 300 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained solid was washed with a mixed solvent (10:1, about 500 mL) of hexane and ethyl acetate, and the solid was collected by filtration. The solvent was evaporated from the filtrate and the residue was purified by silica gel column chromatography (using 500 g of Fuji Silysia BW-300, elution solvent: hexane/ethyl acetate=3/1). The obtained solid was washed with hexane and combined with the solid obtained earlier to give 2-(1-tert-butoxycarbonyl-1-methyl-ethylsulfanyl)-thiazole-4-carboxylic acid methyl ester (94.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.227 ml 2-(3,4-dichloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at RT, and after stirring for 30 min at RT, were refluxed for 2 h. After cooling down to RT, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at RT, the reaction mixture was then refluxed for 2 h. After cooling down to RT, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 515 mg colorless viscous oil (97%). MS (ISP) 336.2 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1N(N)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(C)cccc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2-methylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[S:2].[Na+].[Na+].[N+]([O-])([O-])=O.[Pb+2:12].[N+]([O-])([O-])=O>>[S:1]([S:2][S:2][S:1]([O-:5])(=[O:4])=[O:3])([O-:5])(=[O:4])=[O:3].[Pb+2:12]
Reactant: O=S([O-])([O-])=S
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [Pb+2]
Product: O=S(=O)([O-])SSS(=O)(=O)[O-]

Procedure:
Sodium thiosulfate solution was slowly added to a solution of blue capricnitrate trihydrate until the blue colour just disappeared. A solution of lead nitrate was then added to give an off-white precipitate of lead tetrathionate. The precipitate was allowed to settle, the liquor poured off and distilled water added with stirring. The precipitate was filtered, washed again with distilled water, methylated spirits and finally with ether and thereafter dried.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19]C)=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([NH:2][NH2:3])=[O:19])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: NN
Reactant: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccsc1C(=O)NN

Procedure:
0.4 g of hydrazine hydrate is added to a solution of 1.3 g of methyl 3-(tert-butoxycarbonylamino)thiophene-2-carboxylate in 10 ml of ethanol and the mixture is heated to reflux for 5 hours. After the volatile fractions had been removed under reduced pressure at 40° C., the remaining oil was purified by column chromatography (silica gel, eluent: methylene chloride:methanol=95:5).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:26])[C:16]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:9])=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:26])[C:16]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)O)ccc3OCC)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)N4CCN(C)CC4)ccc3OCC)nc12
Yield: 25.3 %

Procedure:
A solution of 4-ethoxy-3-(1-methyl-7-oxo-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-5-yl)benzoic acid (0.095 g, 0.00027 mol), 1-methylpiperazine (0.265 g, 0.00265 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.077 g, 0.0004 mol) and 1-hydroxybenzotriazole (0.054 g, 0.0004 mol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. The reaction solution was washed with water (25 ml), dried (MgSO4) and evaporated under vacuum, and then the resulting residue crystallised from ethyl acetate-hexane to give the title compound as colourless crystals (0.03 g, 25%), m.p. 196°-197° C. Found: C,63.12; H,6.81; H,18.96. C23H30N6O3 requires C,62.99; H,6.90; N,19.16%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Product: COC(=O)c1ccc(C(=O)N2CCCC2)nc1
Yield: 36 %

Procedure:
The title compound was synthesized as described for Intermediate example I-97 in 36% yield starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and pyrrolidine. Purification by column chromatography using a gradient of ethyl acetate in heptane; 1H NMR (400 MHz, CD3OD) δ ppm 9.15 (d, 1 H), 8.47 (dd, 1 H), 7.84 (d, 1 H), 3.97 (s, 3 H), 3.61-3.68 (m, 4 H), 1.90-2.03 (m, 4 H); MS (ESI) m/z 235[M+H]+.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=1)([O-:3])=[O:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
4-Nitroimidazole (0.29 moles, 32.9 g in 30 ml DMF was treated portionwise with sodium hydride (0.29 moles, 11.6 g. 60% in mineral oil) and stirred for 45 minutes. Ethyl 2-bromooctanoate (0.29 moles, 73.1 g) was added dropwise over 1 hour. The reaction was stirred overnight at room temperature, poured onto ice water, and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to yield 91 g of ethyl 2-(4-nitro-1H-imidazol-1-yl)octanoate. (MS)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:27][C:24]1[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: Nc1ccncc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Nc3ccncc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and pyridin-4-ylamine to give 6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-N1-pyridin-4-yl-isoquinoline-1,3-diamine. LC-MS m/e 347(MH+).
Reaction SMILES: [H-].[Li+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1.[CH2:18]([O:20][P:21]([CH2:26][O:27][CH2:28][CH2:29][CH2:30]Br)([O:23][CH2:24][CH3:25])=[O:22])[CH3:19].O>CN(C)C=O>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26][P:21]([O:23][CH2:24][CH3:25])([O:20][CH2:18][CH3:19])=[O:22])=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1
Reactant: COCCOc1nc(N)nc2nc[nH]c12
Reactant: CCOP(=O)(COCCCBr)OCC
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(COCCCn1cnc2c(OCCOC)nc(N)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium hydride (560 mg, 60 mmol) in dry dimethylformamide (DMF, 200 ml) was added 2-amino-6-methoxyethoxy purine (8.0 g, 40 mmol) (prepared according to the literature procedure: J. Kjellberg, M. Liljenberg and N. G. Johansson, Tetrahedron Lett. 877, 1986]and stirred for 60 min at 25° C. To this solution was added over 3 min a solution of 3-(diethylphosphonomethoxy)-1-bromopropane (12.0 g, 41.5 mmol) in DMF (5 mL) and the solution was heated at 55° C. for 4 h. The reaction mixture was then cooled to room temperature and water (50 mL) was added dropwise. Insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give a viscous oil which was purified by column chromatography on silica gel (5% methanol in CH2Cl2) to afford 2-amino-9-(3-(diethylphosphonomethoxy)propyl]-6-methoxyethoxy purine as a white crystalline solid: yield 3.45 g (21%); mp 78°-79° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCOCC1.O>[CH2:18]([O:25][C:26]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H](CO)Cc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a mixture of L-phenylalaninol (20.2 g, 0.134 mol), sodium carbonate (21.1 g, 0.200 mol) and 1,4-dioxane (150 mL) was added a solution of benzyloxycarbonyl chloride (19.1 mL, 0.134 mol) in 1,4-dioxane (50 mL) and the mixture was stirred at room temperature for 3 hours. Water (300 mL) was added to the reaction mixture and the obtained mixture was added to ice-cooled 0.5 N hydrochloric acid (500 mL). The precipitated crystals were collected by filtration and washed with hexane and dried to give N-benzyloxycarbonyl-L-phenylalaninol as white crystals (28.8 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[N:10]([CH3:18])[N:9]=2)=[C:4]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:29][CH2:28][N:27]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:33]=[N:32][N:31]=4)[CH2:26][CH2:25]3)[C:3]=12.[CH2:43]([CH2:45][NH2:46])[OH:44]>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:46][CH2:45][CH2:43][OH:44])=[O:14])[N:10]([CH3:18])[N:9]=2)=[C:4]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:25][CH2:26][N:27]([C:30]4[N:34]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:33]=[N:32][N:31]=4)[CH2:28][CH2:29]3)[C:3]=12
Reactant: NCCO
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)nn1C
Solvent: CN(C)C=O
Product: Cn1nc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)cc1C(=O)NCCO
Temperature: 50 °C

Procedure:
To a sealable flask containing ethyl 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.047 g, 0.08 mmol) was added ethanolamine (0.7 mL). The mixture was sealed and heated to 50° C. for 20.5 h. The mixture was cooled to rt, and was diluted with DMF and was passed through a plug of celite to remove any solids. The DMF solution was purified by prep HPLC to give 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide.TFA (0.014g) as an off-white solid. LCMS: m/e 588.7 (M+H)+, ret time 2.03 min (method 2) 1H NMR (500 MHz, CDCl3) δ ppm 8.35 (s, 1 H) 8.23 (s, 1 H) 7.50-7.61 (m, 6 H) 4.29 (s, 3 H) 3.78-3.85 (m, 4 H) 3.54-3.64 (m, 4 H) 3.40 (s, 2 H) 3.29-3.34 (m, 2 H) 2.79 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[C:7]([C:14]([OH:16])=O)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH:22][C:23]([C:25]1[C:33]2[NH:32][C:31]([NH2:34])=[N:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:19]1[CH:20]=[CH:21][N:17]=[C:18]1[NH:22][C:23]([C:25]1[C:33]2[N:32]=[C:31]([NH:34][C:14]([C:7]3[N:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[CH:4][CH:3]=[C:2]([Cl:1])[C:11]=4[O:12][CH3:13])=[O:16])[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: COc1c(Cl)ccc2cc(C(=O)O)ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(Cl)ccc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ncc12
Yield: 13 %

Procedure:
10 mg (13%) of 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was synthesized according to the general procedure A using 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid (from previous step), 36.3 mg (0.15 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 69 mg (0.18 mmol) of HBTU, 0.106 mL (0.6 mmol) of DIEA in 2 mL of DMF stirring at 80° C. for 2 h. LCMS: 462 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:6][CH:7]=1.O1CCOCCOCCOCCOCC1.[H-].[Na+].[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:51]2[CH2:52][CH2:53][N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[CH2:49][CH2:50]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2ncc(Br)cn2)c1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ncc(Br)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
Diethyl 3-(5-bromopyrimidin-2-yloxy)benzylphosphonate (0.700 g, 1.74 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.017 mL, 0.087 mmol) were suspended in THF (2 mL). The mixture was cooled to 0° C. and sodium hydride (84 mg, 60% dispersion in mineral oil, 2.1 mmol) was added. The reaction was warmed to room temperature, stirred for 30 min and then cooled back to 0° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.452 g, 2.27 mmol) in THF (1.5 mL) was added and the reaction was warmed to room temperature. After 40 h, water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to an orange oil (about 1 g). This material was purified by flash chromatography on silica (10-40% EtOAc:heptane) to afford the title compound (0.285 g, 37% yield). MS (APCI) M−100=346; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 2.30-2.37 (m, 2H) 2.43-2.52 (m, 2H) 3.37-3.45 (m, 2H) 3.48-3.55 (m, 2H) 6.36 (s, 1H) 6.99-7.07 (m, 2H) 7.11 (d, J=7.80 Hz, 1H) 7.39 (t, J=7.90 Hz, 1H) 8.58 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>ClCCl>[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)C)cc12)C(=O)OCC
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A mixture of diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate (2.5 g), pyridine (1.2 g) and dichloromethane (55 ml) was stirred under ice-cooling. To the reaction mixture was added dropwise isobutyryl chloride (1.06 g). The reaction mixture was stirred under ice-cooling for 30 minutes and at ambient temperature for 20 minutes. After ice-water was added to the reaction mixture, the resultant mixture was stirred and extracted with chloroform. Insoluble materials were removed by filtration from the extracts. The extracts were washed three times with water and with aqueous solution saturated with sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by a column chromatography using silica gel (developing solvent: chloroform) and crystallized from a mixture of chloroform and hexane to give crystalline diethyl [(6-isobutyramido-4-quinazolinylamino)methylene]propanedioate (1.28 g). Crystals (0.67 g) of the same compound were recovered from the mother liquor by substantially the same crystallization as mentioned above.
Reaction SMILES: [N:1]([CH:4]([C:8]1[N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10](=[O:18])[C:11]2[C:16]([CH3:17])=[N:15][S:14][C:12]=2[N:13]=1)[CH:5]([CH3:7])[CH3:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]([C:8]1[N:9]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10](=[O:18])[C:11]2[C:16]([CH3:17])=[N:15][S:14][C:12]=2[N:13]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: Cc1nsc2nc(C(N=[N+]=[N-])C(C)C)n(Cc3ccccc3)c(=O)c12
Agent: [Pd]
Solvent: CO
Product: Cc1nsc2nc(C(N)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 6-(1-azido-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 29) (6.8 g, 19.2 mmol) in methanol (400 ml) was added 5% Pd/C (1 g, 20% by wt.) and the resulting mixture was stirred at r.t. in an atmosphere of H2 and the progress of the reaction was monitored by MS. After the disappearance of the starting material the reaction mixture was filtered through celite and washed with EtOAc. Concentration of the filtrate provided 6-(1-amino-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (5.42 g, 86%).
Reaction SMILES: [OH-].[K+].C(OC(=O)[NH:7][CH:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:9]1)C>C(O)C.O>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][C:10]3([CH2:9][CH:8]([NH2:7])[CH2:11]3)[CH2:16][CH2:15]2)=[N:18][CH:19]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CCOC(=O)NC1CC2(CCN(c3ccc(CC(C)C)cn3)CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Cc1ccc(N2CCC3(CC2)CC(N)C3)nc1
Temperature: 110 °C
Yield: 91.4 %

Procedure:
1.21 g (21.65 mmol) of potassium hydroxide are added, at room temperature, to a solution of 0.37 g (1.08 mmol) of ethyl[7-(5-isobutylpyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate in 5 mL of ethanol/water (1/1). The mixture is then heated at 110° C. for 15 hours. The resulting mixture is allowed to cool to room temperature and is then concentrated under reduced pressure. The reaction medium is taken up in saturated sodium chloride solution and dichloromethane, the aqueous phase is separated out and extracted with dichloromethane, and the combined organic phases are dried over sodium sulfate. After evaporating under reduced pressure and purifying on a column of silica gel, eluting with a 100/0/0 to 96/4/0.4 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.27 g of expected product is obtained in the form of a wax.