Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:38]1([NH:41][C:42](=[O:51])[CH:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH3:44])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:47][CH2:46][N:45]([CH:43]([CH3:44])[C:42]([NH:41][CH:38]4[CH2:39][CH2:40]4)=[O:51])[CH2:50][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NC1CC1)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)C(=O)NC2CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with N-cyclopropyl-2-piperazin-1-yl-propionamide (Enamine) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C39H49Cl2N6O3 [(M+H)+] 719.3238, observed 719.3244.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.I[CH2:17][C:18]([NH2:20])=[O:19]>C(C(C)=O)C>[NH:1]=[C:2]1[N:6]([CH2:17][C:18]([NH2:20])=[O:19])[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3]1
Reactant: NC(=O)CI
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: CCC(C)=O
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CC(N)=O
Temperature: 20 °C
Yield: 53 %

Procedure:
The procedure is as in Example 15, starting with 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and iodoacetamide (14.8 g) in methyl ethyl ketone (50 cc). The mixture is heated for 18 hours to boiling and then cooled to a temperature in the region of 20° C. The precipitate formed is filtered off, then added to distilled water (100 cc) and treated with 1N sodium hydroxide (37 cc). The insoluble matter is filtered off, washed with distilled water (100 cc) and recrystallized in boiling methanol (100 cc). (2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)acetamide (6.2 g), m.p. 228° C., is obtained.
Reaction SMILES: [CH2:1]([CH:4]1[CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:18])[CH2:2][CH3:3].C=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([O:30][C:31](=O)C)(=[O:29])[CH3:28]>O1CCCC1.N1C=CC=CC=1>[C:27]([O:30][CH2:31][N:6]1[CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:18])(=[O:29])[CH3:28]
Reactant: CCCC1C(=O)NC1Sc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCC1C(=O)N(COC(C)=O)C1Sc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 273 mg (0.94 mmol) azetidinone from Step A, 26.3 mg paraformaldehyd and 178 mg (0.56 mmole) cesium carbonate was stirred in 20 ml dry tetrahydrofuran at ambient temperature 16.5 hours under nitrogen. A mixture of 430 μl pyridine and 2.56 ml acetic anhydride was added to the reaction mixture and the stirring continued 5 more hours. The solvents were evaporated in vacuo to give 604 mg crude product which was chromatographed on a silica gel flash column in hexane-ethyl acetate 3/1. This gave 102 mg (30%) of 1-acetoxymethyl-4-p-nitrophenylthio-3-n-propylazetidin-2-one.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23]O)[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(F)c(Cl)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)c(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C16H10ClFN4O, 329; Found, 329.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C(O[I:20](C1C=CC=CC=1)OC(=O)C)(=O)C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[I:20][C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:2][CH:3]=1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: O=C(O)CCCCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCCCc1ccc(I)cc1
Reaction time: 2 h
Yield: 129.1 %

Procedure:
5-Phenylpentanoic acid (50.0 g, 0.28 mol), iodine (37.77 g, 0.149 mol) and (diacetoxyiodo)benzene (48.0 g, 0.149 mol) are suspended in a mixture of glacial acetic acid (500 mL) and acetic anhydride (500 mL). Concentrated sulfuric acid (2 mL) is added and the suspension stirred for 2 h in the dark, during which the red colour fades. The solvent is removed under reduced pressure until approximately 80 ml remained, and the residue poured into ice-water (1 L) containing sodium metabisulfite (8 g). the resulting precipitate is stirred for 30 min, and then filtered. The crude product is recrystallised from ethanol/water, and then from acetic acid/water to afford the product (58.5 g). NMR showed the expected signals.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH:17]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:17]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:18]1[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: O=C(OCc1ccccc1)C1CCCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 115 %

Procedure:
Boc-L-Ile-OH ½ H2O (3.92 g, 16.8 mmol), H-D,L-Pip-OBzl HCl (3.57 g, 12 mmol) and HATU (7.75 g, 18 mmol) were dissolved in DMF (15 ml), mixed with Et3N (4.76 ml, 30 mmol) under ice cooling, and then stirred overnight. The reaction mixture was concentrated, extracted with ethyl acetate (120 ml), and washed twice with 10% citric acid, 4% NaHCO3 and then brine, respectively. After drying over magnesium sulfate, ethyl acetate was distilled off. The residue was vacuum dried and purified by flash chromatography (3.5×20 cm) with CHCl3/MeOH (99:1) to yield Boc-L-Ile-D,L-Pip-OBzl (5.90 g, 13.8 mmol; yield 97%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].C([Mg]Br)C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21](=[O:26])[C:22]([Cl:25])([F:24])[F:23]>CCOCC.C1COCC1>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21]([OH:26])([C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:22]([Cl:25])([F:23])[F:24]
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)Cl
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(O)(C#Cc1ccccc1)C(F)(F)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a 100 mL, 3 necked, oven dried round bottomed flask, with a stirring bar, argon inlet, reflux condenser, and a septum was added ethynyl benzene (2.13 g, 20.83 mmol), dry THF (50 mL) and ethyl magnesium bromide (6.94 mL of a 3.0M solution in ether). This mixture was aged 2 h at ambient temperature then a solution of 1-(2-amino-5-chlorophenyl)-2-chloro-2,2-difluoroethanone (1.00 g, 4.17 mmol) in THF (6 mL) was added with a syringe. The resulting orange-red solution was stirred at ambient temperature for 21.5 h. The reaction was quenched by addition of 1N HCl (50 mL) then diluted with EtOAc. The solution was then made basic with concentrated NH4OH and the layers were separated. The organic phase was washed with water and brine. Drying (MgSO4), filtration, removal of the solvent in vacuo, and chromatography on silica gel using 20% EtOAc in hexane as eluant gave 1.02 g of (+/-) 2-(2-amino-5-chlorophenyl)-4-phenyl-1-chloro-1,1-difluoro-3-butyn-2-ol as an off white solid. 1H NMR (CDCl3): δ4.42 (br s, 2H), 5.10 (br s, 1H), 6.65 (d, 1H, J=8.5 Hz), 7.15 (dd, 1H, J=2.4, 8.5 Hz), 7.38 (m, 3H), 7.55 (m, 2H), 7.70 (d, J=2.4 Hz).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[CH:6]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([Si](C)(C)C)([F:21])[F:20]>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:9]([CH:10]([OH:11])[C:19]([F:21])([F:20])[F:18])=[CH:8][N:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: O=Cc1cncn1CC1CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cncn1CC1CC1)C(F)(F)F
Yield: 66.4 %

Procedure:
According to Reference Example 8-2, by use of 1-(cyclopropylmethyl)-1H-imidazole-5-carbaldehyde (212 mg, 1.41 mmol) dissolved in N,N-dimethylformamide (4.2 mL), potassium carbonate (39 mg, 0.28 mmol) and (trifluoromethyl)trimethylsilane (0.626 mL, 4.23 mmol), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=12/1) was performed to give 1-[1-(cyclopropylmethyl)-1H-imidazol-5-yl]-2,2,2-trifluoroethanol (Compound DW) (206 mg, yield: 66%).
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].Br[CH2:15][CH:16]([CH3:18])[CH3:17]>CN(C)C=O.C(OCC)(=O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][N:9]([CH2:17][C:16]([CH3:18])=[CH2:15])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CC(C)CBr
Reactant: CS(=O)(=O)NCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)CN(Cc1ccco1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94.9 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.284 g, 7.1 mmol) was added in portions to a stirring solution of N-(furan-2-ylmethyl)methanesulfonamide (1.0 g, 5.7 mmol) in anhydrous N,N-dimethylformamide (12 mL), which was kept at 0° C. by an external ice bath. The ice bath was removed and the mixture was stirred for 50 mins at ambient temperature. 3-bromo-2-methylpropane (1.15 g, 8.6 mmol) was added in one portion, and the resulting mixture was stirred overnight at 65° C. before being diluted with ethyl acetate. The organic layer was successively washed with water and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to give a clear liquid (1.24 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 7.41-7.40 (m, 1H), 6.38-6.34 (m, 1H), 6.29-6.28 (m, 1H), 5.03-5.00 (m, 2H), 4.37 (s, 2H), 3.73 (s, 2H), 2.76 (s, 3H), 1.77 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[C:27]([NH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([NH:30][C:31]1[CH:36]=[C:35]([C:6]2[CH:7]=[C:8]3[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)[NH:11][N:10]=[C:9]3[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:34]=[CH:33][CH:32]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(C(=O)OC(C)(C)C)CC4)c3c2)c1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), [3-(acetylamino)phenyl]boronic acid (38 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[N:9]([N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[C:10](=O)[CH:11]=1)=[O:5])[CH3:2].C(OC(C1C=C([Cl:33])N2N=CC=C2N=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:33])[N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)n2nc(-c3ccccc3)cc2[nH]1
Reactant: CCOC(=O)c1cc(Cl)n2nccc2n1
Product: CCOC(=O)c1cc(Cl)n2nc(-c3ccccc3)cc2n1

Procedure:
This compound was synthesized from 7-oxo-2-phenyl-4,7-dihydro-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester, according to the process for synthesizing 7-chloropyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester. mp: 135-137° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[S:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[N:16]1[CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C2CCN(CC3CN(c4nc5ccccc5s4)CC3c3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 22 %

Procedure:
A mixture of 54 mg (0.16 mmol) of 3-(SR)-((4-phenyl)piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 30, Step A), 53 mg (0.31 mmol) of (2-chloro)benzothiazole and 65 mg (0.47 mmol) of K2CO3 in 3 mL of DMF was heated at 80° C. for 1 h. The reaction mixture was cooled, partitioned between 25 mL of ether and 15 mL of H2O and the layers were separated. The organic layer was dried over MgSO4 and concentrated in vacuo. Flash chromatography on 15 g of silica gel using 1:1 v/v hexnaes/EtOAc as the eluant afforded 16 mg (23%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ1.79-3.04 (12H), 3.29 (q, J=8.9, 1H), 3.55 (t, J=9.0, 1H), 3.69 (t, J=9.6, 1H), 4.03-4.11 (m, 2H), 7.07-7.64 (14H). Mass Spectrum (NH3 -CI): 454 (M+.1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=CC3C(=[N:54][N:55]([CH3:57])[CH:56]=3)C=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[C:22](=[N:54][N:55]([CH3:57])[CH:56]=5)[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cn1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 92 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-2-methyl-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a gummy solid (24 mg, 92%). LCMS (Method B): RT=4.69 min, [M+H]+=522.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][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)[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][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)[C:13]([C:24](=[O:26])[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:27])=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: CNCc1ccccc1
Product: COc1cc2c(C(=O)N(C)Cc3ccccc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Yield: 8 %

Procedure:
As described in example 1E, 80 mgs of 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid was coupled with N-methylbenzylamine to give 82 mgs (8%) of [4-(benzyl-methyl-carbamoyl)-6,7-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester: 1H NMR (CDCl3) δ 1.50 (s, 9H), 3.77 (s, 3H), 4.02 and 4.03 (2s, 6H), 4.87-4.90 (m, 4H), 6.10-6.22 (m, 1H), 6.93 (s, 0.6H), 7.06-7.12 (m, 1H), 7.16 (s, 0.4H), 7.27-7.42 (m, 4H), 7.50 (d, 1H, J=7.60 Hz), 8.32 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C:15](=[O:20])[C:16](=[N:18]O)[CH3:17].O.[ClH:22]>C(O)C.[Pd]>[ClH:22].[NH2:18][CH:16]([CH3:17])[C:15]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1])=[O:20]
Reactant: COc1cc(C(=O)C(C)=NO)c(OC)c2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)C(C)N)c(OC)c2ccccc12
Reaction time: 12 h

Procedure:
To a solution of 1-(1,4-dimethoxynaphthalen-2-yl)-propane-1,2-dione 2-oxime (1 g, 3.66 mmol, Example 2, Step B) in 1 M hydrogen chloride in ethanol (50 mL) was added Pd/C 10% (100 mg), The mixture was hydrogenated on a Parr hydrogenator apparatus under 40–50 psi pressure for 12 h. The catalyst was separated by filtration and the solvent removed in vacuo to give a white solid: 1H NMR (DMSO-d) δ 1.14 (d, 3H, CH3), 3.96 (s, 3H, OH3), 4.01 (s, 3H, OCH3), 5.03 (m, 1H, CH), 7.08 (s, 1H, Ar—H), 7.73 (m, 2H, Ar—H), 8.19 (m, 2H, Ar), 8.50 (bs, 3H, NH3+); Analysis calcd. for C15H17NO3.HCl.0.2 H2O: C, 53.62; H, 5.88; N, 4.81. Found: C, 53.53; H, 5.56; N, 4.77.
Reaction SMILES: [CH:1]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6]O[C:3](=[O:4])[CH:2]=1.[NH3:11]>>[OH:4][C:3]1[CH:2]=[CH:1][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:11]=1
Reactant: N
Reactant: O=C(O)c1ccc(=O)oc1
Product: O=C(O)c1ccc(O)nc1

Procedure:
2-Hydroxypyridine or quinoline carboxylic acids and esters are useful as herbicide and pharmaceutical intermediates. One method for their preparation involves oxidizing quinolinic acid to obtain 2 3-bis(methoxycarbonyl)pyridine N-oxide, treating the N-oxide with acetic anhydride to give the 2-acetoxy compound, and hydrolyzing to give 6-hydroxy-2,3-dimethoxycarboxylpyridine in 27.5% overall yield; see E. Spinner et al., J. Chem. Soc. (B), 289 (1971). Another method involves reacting an ester of coumalic acid with ammonia to yield 2-hydroxy-5-pyridinecarboxylic acid; see W. T. Caldwell et al. J. Am. Chem. Soc. 66, 1479 (1944). Another method involves converting alpha-pyrone-6-carboxylic acid with ammonium acetate and glacial acetic acid into 2-pyridine-6-carboxylic acid; see J. Fried et al., J. Org. Chem. 6, 566 (1941).
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=[CH:20]2)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13]C)=[O:12])(=[O:5])=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:1][N:2]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=[CH:20]2)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=[O:12])(=[O:5])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1C(=O)O
Reaction time: 3 h
Yield: 81.3 %

Procedure:
To a solution of methyl 3-({methyl[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]amino}sulfonyl)thiophene-2-carboxylate (300 mg) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated, and 1N hydrochloric acid (5 mL) was added to the residue. The precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (236 mg, yield 80%) as yellow crystals. melting point 225° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH2:14][OH:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[C:16]([O:15][CH2:14][CH2:13][N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CCO)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN(CCOC(C)=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-(ethyl-4-nitroanilino)-1-ethanol (4.2 g) and 4-dimethylaminopyridine (0.12 g) in pyridine (20 mL) at 0° C. under a drying tube is added acetic anhydride (5.0 mL) dropwise. The reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is diluted with ethyl acetate and partioned against saturated aqueous sodium carbonate. The layers are separated and the aqueous phase extracted with two additional portions of ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is azeotroped three times with toluene to remove residual pyridine. The residue is adsorbed onto silica and chromatographed on silica eluting with 50% ethyl acetate in heptane. The product-containing fractions are evaporated to give 4.9 g of 2-(ethyl-4-nitroanilino)ethyl acetate as a yellow oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([OH:28])=O)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.C[N:36](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([NH2:36])=[O:28])[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of 2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-3-carboxylic acid (0.090 g) in N,N-dimethylformamide (9 mL) were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (71 mg) and 1-hydroxybenzotriazole ammonium salt (0.056 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate. The suspension was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=70:30-100:0, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.058 g, yield 65%) as colorless crystals. MS: 486 (MH+). melting point 241-243° C.