Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].C[O:16][C:17]1[C:21](OC)=[N:20][S:19](=[O:24])[N:18]=1.[OH-].[Na+].Cl>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:21]2[C:17]([OH:16])=[N:18][S:19](=[O:24])[N:20]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)N=C1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)N=C2O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (4.15 g; 17.9 mmoles) in 50 ml of methanol was added dropwioe over a 30 minute period to a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.91 g; 17.9 mmoles) in 350 ml of methanol that had been cooled in an ice-water bath. The reaction mixture was treated with a solution of sodium hydroxide pellets (3.58 g; 89.5 mmoles) in methanol. After stirring overnight at ambient temperature, the mixture was neutralized with 14.9 ml (89.5 mmoles) of aqueous 6.0N HCl and after 10 minutes was evaporated under reduced pressure. The solid residue was triturated for 2 hours with 70 ml of water at ambient temperature and filtered to give product. Recrystallization from water yielded the title compound, mp 148°-151°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1.Cl>CN(C=O)C.C(O)(C)C>[ClH:1].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:25]([F:30])[CH:24]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCn1cncn1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCn1cncn1
Temperature: 150 °C
Yield: 20.2 %

Procedure:
A solution 2 4-chloro-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline (203 mg, 0.66 mmol), (prepared as described for the starting material in Example 38), and 4-chloro-2-fluoroaniline (74 μl, 0.66 mmol) in DMF (10 ml) containing 5M hydrogen chloride in isopropanol (0.4 ml) was heated at 150° C. for 8 hours. The volatiles were removed by evaporation and the residue was partitioned between water and methylene chloride. The aqueous layer was adjusted to pH9 with I M sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride/methanol and 2M ethereal hydrogen chloride (1 ml) was added. After removal of the volatiles by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline hydrochloride (60 mg, 17%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([NH2:31])[CH2:27][CH2:26]3)=[O:24])[C:17]=2[CH:32]=1.C(N(CC)CC)C.O>O1CCOCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:26][CH2:27][N:28]([NH:31][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:10])[CH2:29][CH2:30]3)=[O:24])[C:17]=2[CH:32]=1
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of 4-fluorophenyl isocyanate (273 mg) in dioxane (5 ml) was added dropwise to a mixture of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (981 mg), triethylamine (273 mg), dioxane (40 ml) and water (2 ml) at room temperature. The resulting mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was filtered, washed with water and ethyl acetate, and recrystallized from N,N-dimethylformamide to give 5-chloro-3-{[4-[N'-(4-fluorophenyl)ureido]-1-piperazinyl]carbonylmethyl}-2-benzothiazolinone (0.82 g).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][CH2:14][O:15][CH2:16][Sn](CCCC)(CCCC)CCCC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:30]/[C:31](/[CH2:35][CH2:36]/[CH:37]=[C:38](\[CH3:45])/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:32]\[CH2:33]Br.O>C1COCC1>[CH3:30]/[C:31](/[CH2:35][CH2:36]/[CH:37]=[C:38](\[CH3:45])/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:32]\[CH2:33][CH2:16][O:15][CH2:14][O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCOCc1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCOCOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
n-Butyl lithium (1.6M in hexane, 8.6 mL, 13.8 mmol) was added under nitrogen to a stirred solution of (benzyloxymethoxy)methyl-tri-(n-butyl) tin (6.1 g, 13.8 mmol) in THF (56 mL) at -78° C. The resulting mixture was stirred at -78° C. for 10 min, then added a solution of (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienylbromide (3.5 g, 12.3 mmol) in THF (4 mL) via a dropping funnel. The resulting mixture was stirred at -78° C. for 0.5 hours, then poured into cold water and extracted with ether. The ethereal extract was dried, filtered and evaporated to afford a residue, which was purified by flash chromatography on a silica gel column. Elution of the column with hexane:ether (25:1, v:v) provided the title compound as a colorless oil (2.39 g, 6.7 mmol, 54.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([OH:30])[C:24]=4[N:23]=[C:22]3[CH2:31][OH:32])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].[CH2:34](O)[CH3:35]>>[CH2:34]([O:30][C:29]1[C:24]2[N:23]=[C:22]([CH2:31][OH:32])[N:21]([CH2:20][C:18]3[CH:17]=[CH:16][C:10]4/[C:11](=[C:12](/[CH3:15])\[C:13]#[N:14])/[C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:33][C:6]=5[O:7][CH2:8][C:9]=4[CH:19]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1)[CH3:35]
Reactant: C/C(C#N)=C1/c2ccc(Cn3c(CO)nc4c(O)cccc43)cc2COc2cc(F)ccc21
Reactant: CCO
Product: CCOc1cccc2c1nc(CO)n2Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 49.5 %

Procedure:
[step 1] Using (E)-2-(3-fluoro-8-{[4-hydroxy-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (201 mg, 0.46 mmol) obtained in Reference Example 2A, step 4, and ethanol (0.27 mL, 4.55 mmol) instead of deuterated methanol, and in the same manner as in Reference Example 2A, step 5, (E)-2-(8-{[4-ethoxy-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (107 mg, 50%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1N.N([O-])=O.[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: c1ccncc1
Reactant: Nc1ccccc1Br
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccccc1-c1ccccn1
Temperature: 80 °C

Procedure:
2-Bromobenzenamine (18.77 g) in 50 ml of conc HCl and 50 ml of water, was cooled in an ice bath and treated dropwise with stirring with a solution of sodium nitrite (8.28 g) in water (35 ml). After the addition was complete, the mixture was stirred in the ice bath for a further 30 minutes and then added portionwise (over 5 minutes) to pyridine (275 ml) stirred in an oil bath at 80° C. The mixture was heated (at 80° C.) for a further 1 hour, when the excess of pyridine was distilled off under reduced pressure. The residue was basified (aqueous sodium hydrogen carbonate) and extracted with ethyl acetate (3×). The extracts were washed with water (2×), dried (sodium sulphate) and evaporated to give a dark oil, which was flash chromatographed on silica using methylene chloride/ethyl acetate (20/1) as eluant. Pure sub-title compound (6.56 g) was obtained as a dark brown oil. m/z 235/233 (MW), 154 (Base Peak).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NS(C)(=O)=O)CC1
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (87 mg, 0.139 mmole, example 204) in dichloromethane (5 mL) was treated with methanesulfonyl chloride (31.8 mg, 0.277 mmole, Aldrich) at 0° C. and allowed to stir for 1 h before diluted with dichloromethane (60 mL), washed with aqueous sodium carbonate (15 mL), water (15 mL) and concentrated. The residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1% to 10% methanol in dichloromethane) to give the title compound (83.8 mg). HR-MS (ES, m/z) calculated for C35H44Cl2N5O4S [(M+H)+] 700.2486, observed 700.2482.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:29][NH2:30].C(O)C>>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)=[N:30][NH:29][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(OC)c1)OCO2
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(3-methoxy-4-nitrobenzoyl)phenylacetate (1.2 g, 3.2 mmol) and hydrazine hydrate (0.6 mL, 11 mmol) in ethanol (15 mL) as a yellow solid (0.53 g, 1.5 mmol, 47%), mp: 267°-269° C. 1H NMR (CDCl3) 8.60 (s, 1H), 7.86 (d, J=8.5, 1H), 7.49 (d, J=1.5, 1H), 7.13 (dd, J=8.5, 1.5, 1H), 6.85 (s, 1H), 6.59 (s, 1H), 6.06 (s, 2H), 4.01 (s, 3H), 3.48 (s, 2H). Anal. Calcd. for C17H13N3O6 : C, 57.47; H, 3.69; N, 11.83. Found: C, 57.07; H, 3.42; N, 12.01.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.[N:11]([O-])=O.[Na+].CC([O-])=O.[Na+].[CH2:20]([O:22][C:23](=[O:27])[CH2:24][N+:25]#[C-:26])[CH3:21]>O.CCO.O>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH:26]=[N:25][C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:27])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=N[O-]
Reactant: Nc1ccc(F)c(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ncn(-c2ccc(F)c(F)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a solution of 3,4-difluoroaniline (1 mL, 10 mmol) in 5.4 mL of H2O at 0° C. was added 2.8 mL of conc. HCl followed by NaNO2 (1.0 g, 15 mmol, 1.5 eq). The mixture was stirred at 0° C. for 30 min. An additional amount of NaNO2 (0.35 g, 5 mmol, 0.5 eq) was added and the mixture was stirred for 1 h at 0° C. To a separate solution of NaOAc (8.9 g, 108 mmol, 11 eq) in 13 mL EtOH/H2O (12:1) was added ethyl-2-isocyanoacetate (1.1 mL, 10 mmol, 1 eq). The mixture was cooled to 0° C. and the diazonium salt mixture was added dropwise. After stirring for 1 h, the reaction was quenched with H2O and extracted with EtOAc. The organic layer was dried with Na2SO4 and concentrated in vacuo. Purification by silica gel flash chromatography (hex:EtoAc 1:1) afforded ethyl 1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylate (0.30 g, 1.3 mmol, 13%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Nc1cccnc1
Yield: 27 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-aminopyridine (20 mg, 0.21 mmol) as the coupling partner. Concentration (no chromatography) yielded 17 mg (27%) of the titled compound. ESI-MS m/z 368 (MH+), 366 (M−H−).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Br-:1].[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:9])=[O:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCCCBr
Solvent: CC#N
Product: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 98 %

Procedure:
A solution of 6-bromohexanoic acid (10.00 g, 51.27 mmol) and triphenyl phosphine (14.12 g, 53.83 mmol) in freshly distilled acetonitrile (50 mL) was vigorously stirred and refluxed for 48 hours. The solution was allowed to come to ambient temperature and the Wittig salt was precipitated upon scratching the inside wall of the glass reaction vessel with a spatula. The white solid product was collected, washed with ether and filtered to provide the title compound in 98% yield (22.87 g): 1H NMR (400 MHz, CD3OD) δ 1.62-1.72 (m, 6H), 2.29 (t, 2H), 3.40-3.47 (m, 2H), 7.76-7.91 (m, 15H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(C)cc1C
Reactant: SCc1ccc(Cl)cc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2C)c2ccc(Cl)cc2)c2ccc(Cl)cc2)c(C)c1

Procedure:
A solution of 2,4-dimethylphenylacetylene (0.02 mol), 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dimethylstyryl-4-chlorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:9][O:10][CH2:11][C:12]1[S:16][CH:15]=[N:14][C:13]=1[CH3:17]>>[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]([C:1]([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)([OH:3])[CH3:2])=[N:14][C:13]=1[CH3:17]
Reactant: CC(=O)c1ccsc1
Reactant: COCc1scnc1C
Product: COCc1sc(C(C)(O)c2ccsc2)nc1C

Procedure:
The title compound was prepared by following the general method of Example 36 but using 3-acetylthiophene and 5-methoxymethyl-4-methylthiazole.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[O-])[N:7]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:39][C:38]2[CH:40]=[CH:41][CH:42]=[C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][N:27]=3)[CH:37]=2)=[O:13])[N:7]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cc1ccncc1-n1nc(C(C)(C)C)cc1NC(=O)[O-]
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnccc4C)c3)c2cc1OC
Yield: 86.7 %

Procedure:
3-tert-Butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (105 mg, 0.30 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.30 mmol) (prepared as described in Example 113A) using the procedure in Example 115C to give 1-(3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (145 mg, 0.26 mmol, 87%). 1H NMR (300 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.58-8.51 (m, 3H), 8.38 (s, 1H), 7.54-7.47 (m, 3H), 7.38-7.32 (m, 2H), 7.12 (d, 1H), 6.91 (d, 1H), 6.36 (s, 1H), 3.98 (s, 6H), 2.06 (s, 3H), 1.24 (s, 9H); LC-MS (ESI) m/z 554 (M+H)+.
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[NH2:32][C@@H:33]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[C:39]=1[O:48][CH3:49])C(O)=O.[C:50]1([CH2:56][CH2:57][C:58](O)=[O:59])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH3:16][CH:14]([CH3:15])[CH2:13][C@H:12]([NH:11][C:10]([C@@H:8]([NH:7][C:6](=[O:31])[C@@H:33]([NH:32][C:58](=[O:59])[CH2:57][CH2:56][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[C:39]=1[O:48][CH3:49])[CH3:9])=[O:30])[B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: O=C(O)CCc1ccccc1
Reactant: COc1ccc(C[C@H](N)C(=O)O)c(OC)c1OC
Product: COc1ccc(C[C@H](NC(=O)CCc2ccccc2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)c(OC)c1OC

Procedure:
The title compound is prepared from {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester by reiteration of the 2-step (deprotection/coupling) procedure described in example 1 but using (S)-2-Amino-3-(2,3,4-trimethoxy-phenyl)-propionic acid and 3-Phenyl-propionic acid (Fluka) as the partners in each coupling reaction (step B, example 1), respectively.
Reaction SMILES: O1CCCC1.CS(O)(=O)=O.[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([C:16](=[O:35])[C:17]([C:30]([O:32]CC)=[O:31])=[CH:18][N:19]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[CH:14][C:13]=1[F:36]>O>[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([C:16](=[O:35])[C:17]([C:30]([OH:32])=[O:31])=[CH:18][N:19]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[CH:14][C:13]=1[F:36]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: CS(=O)(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of tetrahydrofuran (450 cm3), water (50 cm3), methanesulfonic acid (127 cm3) and ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (United Kingdom Patent Publication No. GB 2,191,776) was heated at reflux for 1 hour, and then cooled to 25° C. The resulting crystals were isolated, washed with tetrahydrofuran, and dried under vacuum to afford 41.3 g (89%) of the above-titled compound: m.p.=250° C.; (Found: C, 50.4; H, 1.7; Cl, 9.9; F, 16.0; N, 8.0. C15H6ClF3N2O3 requires C, 50.8; H, 1.7; Cl, 10.0; F, 16.1; N, 7.9%); 1H NMR (300 MHz, d6 -DMSO) δ 13.9 (s, 1H), 9.09 (s, 1H), 8.77 (d, J=7.5 Hz, 1H), 7.86 (td, J=5.9 and 8.8 Hz, 1H), 7.66 (ddd, J=2.7, 9.0 and 11.8 Hz, 1H), 7.39 (tm, J=8.6 Hz, 1H), 7.39 (tm, J=8.6 Hz, 1H); νmax (DRIFTS) cm-1 3130, 3060, 2947, 2885, 2821, 2723, 2637, 2594, 1734, 1641, 1623, 1579, 1544, 1516.
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[ClH:21]>>[Cl:21][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cl
Reactant: Nc1cc2ccccc2cn1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
3-Aminoisoquinoline (1.44 g, 10 mmol) was suspended in 10M HCl (5 mL) and cooled to 0° C. Sodium nitrite (689 mg, 10 mmol) was added in portions over 5 minutes. The reaction mixture was stirred at 0° C. for 2 hours and allowed to warm to room temperature over 1 hour. The reaction mixture was added carefully to saturated NaHCO3 solution (200 mL) and extracted into ethyl acetate. The insoluble byproduct was removed by filtration and the aqueous layer was re-extracted into ethyl acetate. The combined organics were washed with water and brine, dried (Na2SO4) and concentrated to a brown oil which solidified on standing. Flash chromatography on silica, eluting with dichloromethane, gave the title compound as a white solid (827 mg, 5.05 mmol, 51%). 1H NMR (d6-DMSO, 400 MHz) δ 9.12 (s, 1H), 8.41 (s, 1H), 8.12 (dd, 1H, J=7.5, 1.0 Hz), 7.93-7.90 (m, 1H), 7.84-7.80 (m, 1H), 7.74-7.70 (m, 1H). LCMS (1) Rt=1.79 min; m/z (ESI+) 164 (MH+).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].I.CS[C:9]1[NH:10][CH2:11][CH2:12][N:13]=1.[Na].[C:15]([CH2:17][C:18](OCC)=[O:19])#[N:16]>CCO>[NH2:16][C:15]1[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:9]2[N:10]([CH2:11][CH2:12][N:13]=2)[C:18](=[O:19])[CH:17]=1
Reactant: CC(C)CN
Reactant: CCOC(=O)CC#N
Reactant: CSC1=NCCN1
Agent: I
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(N)=CC(=O)N2CCN=C21

Procedure:
A mixture of 29.25 g. (0.40 mole) isobutylamine and 48.82 g. (0.20 mole) 2-(methylthio)-2-imidazoline hydroiodide in 250 ml. abs. EtOH were refluxed for 2 hr. The mixture was concentrated in vacuo to a viscous oil, which was dissolved in 100 ml. abs. EtOH and added to a solution of 8.40 g. (0.80 mole) sodium and 22.62 g. (0.20 mole) ethyl cyanoacetate in 1200 ml. abs. EtOH. The mixture was refluxed for 3 hr., then concentrated in vacuo to a viscous oil. Water (400 ml.) was added and a white solid slowly crystallized. The solid was filtered and air-dried to yield 35.43 g. (86%), mp 235°-238° (two crops). Recrystallization from CH3CN gave white crystals, mp 230.5°-232.5° (corr.).
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([CH2:20][O:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1COC(=O)c1ccccc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(COC(=O)c3ccccc3)cccc2c1=O
Yield: 46 %

Procedure:
Diphenyl ether (500 ml) was heated to boiling, ethyl 2-butyryl-3-(2-(benzoyloxymethyl)phenylamino)acrylate (60.5 g, 0.15 mol) added, and heating continued at reflux for 25 minutes. Most of the diphenyl ether was removed by vacuum distillation. Chromatography (silica gel, 0%-3% methanol in dichloromethane) and recrystallization from methanol gave 3-butyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (24.1 g, 45%), m.p. 115°-117°.