Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH3:17])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.O>CN(C)C=O>[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH3:17])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1csc(NCCc2ccccc2)n1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1csc(N(CCc2ccccc2)Cc2ccc(COc3ccc(CCC(=O)OC)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of N-(2-phenylethyl)-4-propyl-1,3-thiazole-2-amine (246 mg) in N,N-dimethylformamide (2 mL) was added sodium hydride (40 mg), and the mixture was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]-oxy}phenyl)propanoate (318 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give the title compound (380 mg) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:27][N:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:27][N:26]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Brc1ccc(OC2CCOCC2)cn1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)cn1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 2-bromo-5-(tetrahydro-pyran-4-yloxy)-pyridine (Intermediate 23) in analogy to Example 1a): MS (ISP): 481.2 and 483.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:8][CH2:9][OH:10].[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]#[N:19].O>C(Cl)Cl>[Cl:16][C:17]([Cl:21])([Cl:20])[C:18](=[NH:19])[O:10][CH2:9][CH2:8][C:7]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][CH3:3])[CH:6]=1
Reactant: COc1ccc(CCO)cc1OC
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCOC(=N)C(Cl)(Cl)Cl)cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 74.7 %

Procedure:
A 500 mL 2-necked round bottom flask equipped with an argon inlet, rubber septum and magnetic stir bar was charged with NaH (80% dispersion, 5.2 g, 173.3 mmol). NaH was washed with anhydrous hexanes (15 mL) prior to the addition of 50 mL of anhydrous CH2Cl2 and of 3,4-dimethoxyphenethyl alcohol (20.0 g, 109.8 mmol) in anhydrous CH2Cl2 (30 mL). The solution was allowed to stir at r.t. for 75 min. The solution was then cooled to 0° C. prior to the dropwise addition of trichloroacetonitrile (16.5 mL, 23.8 g, 164.7 mmol) at 0° C. The solution was stirred for 15 min at 0° C. and 2 hr at room temperature. Distilled water (150 mL) was slowly added dropwise to quench the reaction. The aqueous layer was then extracted with CH2Cl2 (4×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous MgSO4 and concentrated by rotary evaporation to afford a brown syrup (26.8 g, 95%). The product was allowed to solidify overnight at −20° C. Rf 0.74 (EtOAc-hexanes, 1:2, v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:39]([C:36]5[CH:35]=[N:34][C:33]([O:32][CH3:31])=[N:38][CH:37]=5)=[O:40])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)no1
Reactant: COc1ncc(C(=O)O)cn1
Product: COc1ncc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)cnc43)CC2)cn1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 37) has been coupled with 2-methoxy-pyrimidine-5-carboxylic acid to yield the title compound as off-white solid. MS: 564.2 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:34]([NH:37]O)([CH3:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:37][CH:34]([CH3:36])[CH3:35])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: CC(C)NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 46.5 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione (300 mg, 1.03 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (251 mg, 1.55 mmol) in N,N-dimethylformamide (12 mL) was stirred for 1 hour. In one portion N-isopropylhydroxylamine hydrochloride (345 mg, 3.09 mmol) was added and the solution was stirred for 55 minutes at room temperature. To the resulting solution was added water (40 mL) giving a precipitate which was separated by filtration. This Crude product was purified by flash chromatography eluting with chloroform:2-propanol (98:2-96.5:3.5) to give the title compound (167 mg, 47% yield, m.p. 224° C.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[Si](C)(C)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)Cl>[C:39]([NH:20][C:19]1[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:30])([F:31])[F:29])=[CH:22][N:15]([C@@H:13]2[O:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C@@H:11]([OH:33])[CH2:12]2)[C:16](=[O:17])[N:18]=1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(N)nc2=O)C[C@@H]1O
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
The starting material (8) (10 g, 20.43 mmol) was azeotroped in dry pyridine (2×100 ml) then dissolved in dry pyridine (160 ml) under N2 atmosphere. Chlorotrimethylsilane (10 ml, 79.07 mmol) added drop wise to the solution and stirred for 2 hours at room temperature. Benzoyl chloride (2.6 ml, 22.40 mmol) was then added to solution and stirred for one further hour. The reaction mixture was cooled to 0° C., distilled water (50 ml) added slowly to the solution and stirred for 30 minutes. Pyridine and water were evaporated from mixture under high vacuum to yield a brown gel that was portioned between 100 ml of sat. aq. NaHCO3 (100 ml) solution DCM. The organic phase was separated and the aqueous phase extracted with a further (2×100 ml) of DCM. The organic layers were combined, dried (MgSO4), filtered and the volatiles evaporated under reduced pressure. The resulting brown oil was purified by flash chromatography on silica gel (DCM:MeOH 99:1 to 95:5) to yield a light yellow crystalline solid (13) (8.92 g, 74%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.78 (s, 9H, tBu), 1.94 (m, 1H, H-2′), 2.27 (m, 1H, H-2′), 3.64 (d, 1H, J=11.6 Hz, H-5′), 3.75 (d, 1H, J=11.6 Hz, H-5′), 3.91 (m, 1H, H-4′), 4.09 (br m, 3H, CH2NH, H-3′), 5.24 (s, 1H, 3′-OH), 6.00 (m, 1H, H-1′), 7.39 (m, 2H, Ph), 7.52 (m, 2H, Ph), 7.86 (m, 1H, Ph), 8.0 (s, 1H, H-6), 9.79 (t, 1H, J=5.4 Hz, NHCH2), 12.67 (br s, 1H, NH). Mass (+ve electrospray) calcd for C27H33F3N4O6Si, 594.67. found 595.
Reaction SMILES: CSC1C=CC(N[N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])=CC=1.[CH3:16][S:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(#N)CC#N.O.[NH2:31][NH2:32]>>[CH3:16][S:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][N:10]=[C:11]2[C:12]([NH2:13])=[N:32][N:31]=[C:14]2[NH2:15])=[CH:20][CH:19]=1
Reactant: NN
Reactant: CSc1ccc(N)cc1
Reactant: CSc1ccc(NN=C(C#N)C#N)cc1
Solvent: O
Solvent: N#CCC#N
Product: CSc1ccc(NN=C2C(N)=NN=C2N)cc1

Procedure:
4-[(4-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 108 mg (0.5 mmol) of 2-[(4-methylsulfanylphenyl)hydrazono]malononitrile, which was derived from 4-methylthioaniline (117 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 95 mg (77%) of the compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].C(N(CC)CC)C.O>C(Cl)Cl>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cc([N+](=O)[O-])ccc1F
Yield: 100 %

Procedure:
A solution of methoxyacetyl chloride (5.85 ml) in methylene chloride (50 ml) was added dropwise to a solution of 2-fluoro-5-nitroaniline (5.06 g) and triethylamine (8.92 ml) in methylene chloride (150 ml) under an argon atmosphere. The resultant mixture was stirred at ambient temperature for 5 hours, then poured into water and extracted with methylene chloride. The organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to yield N-(2-fluoro-5-nitrophenyl)-2-methoxyacetamide as a solid (7.7 g, 100%); NMR: 3.26 (s, 2H), 4.5 (s, 3H), 7.57 (t, 1H), 8.03 (m, 1H), 8.82 (m, 1H), 9.83 (s, 1H); m/s: M+H+ 229.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([OH:15])=O)=[O:7])=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:41]1([CH2:47][C:48]2[CH:49]=[C:50]([CH:57]=[CH:58][CH:59]=2)[O:51][CH2:52]/[CH:53]=[CH:54]\[CH2:55][NH2:56])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>ClCCl>[N:41]1([CH2:47][C:48]2[CH:49]=[C:50]([CH:57]=[CH:58][CH:59]=2)[O:51][CH2:52]/[CH:53]=[CH:54]\[CH2:55][NH:56][C:13](=[O:15])[CH2:12][S:11][CH2:10][CH2:9][NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C(O)CSCCNC(=O)c1ccoc1
Reactant: NC/C=C\COc1cccc(CN2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CSCCNC(=O)c1ccoc1)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
There was suspended 3.52 g (0.0154 mol) of 2-[(3-furoylamino)ethylthio]acetic acid in 80 ml of dichloromethane and added 2.36 g (0.0154 mol) of HOBt and 3.17 g (0.0154 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 4.0 g (0.0138 mol) of 4-[3-(piperidinomethyl)phenoxy]-cis-2-butenylamine, and the mixture was stirred for 12 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 10% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 2.9 g of the titled compound as oily matter.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([CH2:10][NH2:11])O.C1C=CC=CC=1.[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21]>O>[Cl:18][CH:19]([Cl:23])[C:20]([N:11]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:8][CH2:10]1)=[O:21]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C1CCCCC1
Reactant: NCCO
Solvent: c1ccccc1
Solvent: O
Product: O=C(C(Cl)Cl)N1CCOC12CCCCC2
Temperature: 25 °C

Procedure:
From a boiling mixture of 64 g. (0.645 moles) of cyclohexanone and 30 g. (0.491 moles) of ethanolamine in 100 ml. of benzene the water formed is continuously distilled off. Boiling is continued until 8.8 ml. of water are separated. The reaction mixture is then cooled, 55 g. (0.55 moles) of a 40% aqueous sodium hydroxide solution are added followed by dropwise addition of 74 g. (0.5 moles) of dichloroacetyl chloride with external salt/ice cooling. The mixture is stirred for two additional hours at room temperature and thereafter washed with an aqueous hydrochloric acid solution and subsequently with water. From the neutral mixture obtained benzene is distilled off in vacuo. 10 g. (0.4 moles) of a greenish-white crystalline substance are obtained. Recrystallization from absolute ethanol affords a white crystalline product melting at 105.5° to 107° C. The structure of the named compound can be verified by IR spectrum analysis.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[CH3:13][N:14]1[C:22]2[CH:21]3[CH2:23][CH:18]([CH2:19][CH2:20]3)[C:17]=2[C:16]([CH2:24]O)=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:13][N:14]1[C:22]2[CH:21]3[CH2:23][CH:18]([CH2:19][CH2:20]3)[C:17]=2[C:16]([CH2:24][O:1][N:2]2[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[N:15]1
Reactant: Cn1nc(CO)c2c1C1CCC2C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nc(CON2C(=O)c3ccccc3C2=O)c2c1C1CCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (4.10 g, 252 mmol), (1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)methanol 147 (2.24 g, 12.6 mmol) and triphenylphosphine (6.59 g, 25.2 mmol) in THF (100 mL) was added DIAD (5.35 mL, 27.6 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue, which was subjected to chromatography to give 148 (1.80 g, 62%) as a yellow solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([N:22]([CH2:28][CH2:29][CH3:30])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:27][N:25]([CH3:26])[C:23]([N:22]([C:20]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[N:19]=1)=[O:21])[CH2:28][CH2:29][CH3:30])=[O:24]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCN(C(=O)c1cccc(C#N)n1)C(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(C(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1)C(=O)N(C)C
Yield: 73 %

Procedure:
A mixture of methyl thiosalicylate (1.6 g, 9.6 mmol), N-[(6-cyano-2-pyridyl)carbonyl]-N′,N′-dimethyl-N-propylurea (1.2 g, 4.7 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 9 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.36 g, 72%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:19])[CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: CCC(C)Br
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Sc1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
1-Bromo-4-(1-methylpropylthio)benzene is prepared by the following procedure. To a solution of 4-bromobenzenethiol (4.73 g, 5.0 mmol) in 25 ml of DMF at 70° under N2 is added potassium carbonate (4.15 g, 30.0 mmol). The mixture is allowed to stir for 15 min., after which 3-bromobutane (4.8 ml, 44.0 mmol) is added dropwise. The mixture is stirred at 70° for ca. 5 hours. Water is added to the cooled solution and the aqueous phase is extracted with ether (3×). The combined organic layers are washed with water and with brine and dried and the solvent is removed in vacuo to give, following purification by distillation under vacuum, 1-bromo-4-[1-methylpropylthio)benzene.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26](N)=[O:27])=[CH:3]1.S(=O)(=O)(O)[OH:30]>O1CCOCC1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]([OH:27])=[O:30])=[CH:3]1
Reactant: O=S(=O)(O)O
Reactant: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(N)=O)oc2c1
Solvent: C1COCCO1
Product: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1

Procedure:
A suspension of 1.0 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxamide in 10 parts of dioxane and 10 parts of 10% v /v sulphuric acid was heated on a steam can for eight hours. The solid obtained on cooling was collected, washed with water and crystallised from acetone to give 0.75 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxylic acid, m.pt. 164°-166°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[N:68]1([CH2:74][C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([N:71]3[CH2:72][CH2:73][N:68]([CH2:74][C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:69][CH2:70]3)=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)CN1CCNCC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCN(C(=O)c2c[nH]c(-c3cc(Oc4ccc(NC(=O)Nc5cc(C)ccc5F)c(F)c4)ccn3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.65 mmol), HATU (296 mg, 0.78 mmol) and N,N-diisopropylethylamine (185 mg, 1.43 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of ethyl piperazinoacetate (168 mg, 0.98 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give to the crude, which was purified by silica gel chromatography eluting with 5-8% of methanol in chloroform to afford ethyl {4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazin-1-yl}acetate as white solid. Yield: 250 mg, 63%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]#[N:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:22][OH:23].C(=O)([O-])O.[Na+]>CCO>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](=[NH:20])[NH:22][OH:23])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C#N)cnc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCn1ncc2c(NC3CCOCC3)c(C(=N)NO)cnc21
Reaction time: 2.5 h
Yield: 41.3 %

Procedure:
Intermediate 137 (3.50 g, 12.9 mmol), hydroxylamine hydrochloride (3.30 g, 47.8 mmol) and sodium hydrogencarbonate (4.01 g, 47.8 mmol) in EtOH (45 ml) were heated at 45° C. for 1.5 hours then at 50° C. for 2.5 hours. The suspension was concentrated in vacuo and the solid stirred in dichloromethane (80 ml) for 0.5 hours. The mixture was filtered and the solid stirred in EtOH, the resultant mixture was filtered and the filtrate evaporated. The solid was then washed with dichloromethane three time to afford Intermediate 138 as a white solid (1.62 g). LCMS showed MH+=305; TRET=1.85 min
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[C:11]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl.C(N(CC)CC)C>[Si:15]([O:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH:2]=[O:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cccc(C=O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxymethylbenzaldehyde (step 1) (3 g) in methylene chloride (15 mL) and triethylamine (4.1 mL) was slowly added t-butylchlorodiphenyl silane (8 mL). Finally, a few mgs of 4-pyrrolidinopyridine was added as a catalyst. The reaction mixture was stirred overnight at room temperature (R.T.). The solution was quenched with 25% ammonium acetate and extracted with ethyl acetate, which was washed with brine (2×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography, using 4% ethyl acetate in hexane afforded the title compound.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:17]=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:2])[C:7]=2[N:17]=1
Reactant: [NH4+]
Reactant: Cc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2c(N)nc3cccnc3c2n1CC(C)C
Temperature: 11 °C
Reaction time: 0.08 h

Procedure:
Aqueous ammonium hydroxide (5.07 kg of 30% w/w) was added over a period of ten minutes to a suspension of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-5-oxide (6.00 kg, 23.4 mol) in ethanol (23.2 kg) at 22° C. The reaction was stirred for five minutes. Benzenesulfonyl chloride (8.80 kg, 49.8 mol) was added over a period of 30 minutes. The reaction was stirred for one hour at 22° C. A solution of aqueous sodium hydroxide (15.0 kg of 25% w/w) and water (34.0 kg) was added to the reaction mixture over a period of 30 minutes at 22° C. to adjust the mixture to pH 13. The resulting mixture was cooled to 11° C. and stirred at that temperature for three hours and then separated by centrifugation. A solid was collected, washed with demineralized water (105.0 kg) at 22° C. until the filtrate was pH 7, and dried under vacuum (2×103 Pa, 0.02 bar) at 45° C. for 24 hours to provide 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.