Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:7]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.[ClH:19].N([O-])=O.[Na+]>O>[Cl:19][C:2]1[N:7]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1
Reactant: Cl
Reactant: Cc1cccc(C)c1Nn1c(N)cc(=O)[nH]c1=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1Nn1c(Cl)cc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1 mole of 6-amino-1-(2,6-dimethylanilino)-2,4-pyrimidinedione dissolved in 3 moles of dilute aqueous hydrochloric acid cooled to 0°-5° in an ice bath is slowly added 1.1 mole of sodium nitrite (dissolved in water at 5°) with rapid stirring. After addition is complete, add dropwise but rapidly 1.1 mole cuprous chloride dissolved in water. Stir for 30 minutes, then heat to 50° for 1 hour. The mixture is cooled to RT and filtered to obtain 6-chloro-1-(2,6-dimethylanilino)-2,4-pyrimidinedione.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[CH2:11][CH2:10][CH2:9]2.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:19])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:27](=[O:28])[C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=4)[CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCCc3ccc(N)cc32)C(F)(F)CO1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: NC1=N[C@@]2(CCCc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)C(F)(F)CO1
Yield: 42 %

Procedure:
The condensation of (R)-5′,5′-difluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazine]-2′,7-diamine (intermediate A7.1) and 5-chloropicolinic acid yielded the title compound (42% yield) as a white solid. MS (ISP): m/z=407.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([S:8]([C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.C[Si](C)(C)[O-].[K+]>C1COCC1>[Cl:17][C:14]1[N:13]=[CH:12][C:11]([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:18])=[O:3])(=[O:9])=[O:10])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc(Cl)nc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of 834 mg (2.86 mmol) of 2-(6-chloro-pyridine-3-sulfonyl)-2-methyl-propionic acid ethyl ester in THF (30 mL) were added 552 mg (4.3 mmol) of potassium trimethylsilanolate. The reaction was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was partitioned between DCM (50 mL) and water (50 mL). The aqueous layer was acidified with 1 M aqueous HCl solution and extracted with DCM (4×50 mL). The combined organic extracts were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford 661 mg of 2-(6-chloro-pyridine-3-sulfonyl)-2-methyl-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:29])[CH:3]=1.[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:31]#[C:30][CH:32]4[CH2:34][CH2:33]4)=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:29])[CH:3]=1
Reactant: C#CC1CC1
Reactant: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c(Cl)cc1F
Yield: 46.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 using N-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-90, 0.200 g, 0.370 mmol), ethynylcyclopropane (0.050 g, 0.75 mmol), TBAF (0.360 g, 1.13 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0 mL) at 80° C. to afford 0.080 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.77 (br s, 9H), 0.92 (br s, 2H), 1.10 (s, 3H), 1.57 (m, 1H), 4.30 (d, J=5.4 Hz, 2H), 7.43-7.50 (m, 3H), 7.65 (d, J=5.4 Hz, 2H), 7.77 (d, J=5.1 Hz, 2H), 12.57 br s, 1H); MS (m/z): 467.36 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:42][CH3:43])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:26]([F:29])([F:28])[F:27])[CH:11]=[C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH:13]=2)[C:8]([OH:40])([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[C:7]1=[O:41])[CH3:2].Cl>O1CCOCC1>[CH2:42]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:26]([F:28])([F:27])[F:29])[CH:11]=[C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:13]=2)[C:8]([OH:40])([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[C:7]1=[O:41])[CH3:43]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CCCC(=O)OC(C)(C)C)cc2C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CCCC(=O)O)cc2C(F)(F)F
Yield: 85.3 %

Procedure:
Treating 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-(4-t-butoxycarbonyl-1-butynyl)-3-hydroxy-3-(2-naphthyl)oxindole (25.5 mg, 0.0429 mmol) with 4 N HCl in dioxane (1 mL) at 50° C. for 2 h followed by evaporation of the solvent to dryness gave the title compound (19.7 mg, 80%).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)[O:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)[O:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:14]
Reactant: CC(C)CN
Reactant: O=C(Cl)c1cccnc1Oc1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: CC(C)CNC(=O)c1cccnc1Oc1cccc(Cl)c1

Procedure:
In the same manner as in Example 1(c) 1.4 grams (0.02 mole) isobutylamine and 2.7 grams (0.01 mole) of the acyl chloride produced in step (b) were combined in 50 milliliters toluene to yield 2.8 grams (92.1% of theoretical yield) of the desired product, m.p. 86°-87° C. The structure was confirmed by mass spectrometry.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:31])[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:23]([F:31])([F:22])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (426844-51-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=417.5 [MH+].
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[CH:25][C:26]=1[CH3:27].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(C(C)(C)C)n3)CC2)cc1C

Procedure:
62 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (50 mg, 0.195 mmol), 1-(3,4-dimethylphenyl)piperazine (35.4 mg, 0.186 mmol), DIPEA (49 mL, 0.279 mmol) and NaBH(OAc)3 (118 mg, 0.558 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][C:14]([O-])(C)[CH3:15].[K+].C(Br)(C)C>CN(C=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:14]([CH3:15])[CH3:13])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (750 mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate (804 mg, 6.64 mmol). After the mixture was stirred for 30 min at room temperature, a solution of isopropyl bromide (814 mg, 6.64 mmol) in 10 ml dry DMF was added and the mixture heated to 80° C. After stirring for additional 48 h, the mixture was cooled to room temperature and diluted with 150 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 4/1, Rf=0.21) gave 6-bromo-1-isopropyl-3,4-dihydro-1H-quinolin-2-one (347 mg, 1.29 mmol, 33%) as pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Reactant: ClCc1cccnc1SC1CCC1
Product: O=C(O)CCc1ccc(OCc2cccnc2SC2CCC2)c(Cl)c1
Yield: 60.7 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (34 mg, 0.17 mmol) obtained in Step C of Preparation Example 23 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (43 mg, 0.19 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (39 mg, 73%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.[C:20]([O:24][C:25]([NH:27][C:28](N1C=CC=N1)=[N:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25](=[O:26])[NH:27][CH:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1)[NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(=O)Nc1nc(CCc2ccc(CN)cc2)cs1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CNC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
A mixture of N-(4-{2-[4-(aminomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (20 mg) prepared in a similar manner according to Production Example 12, N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (23 mg) and tetrahydrofuran (0.5 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica-gel with chloroform as an eluent. The crystalline residue was collected and washed with diisopropyl ether to give di-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl)amino]methylidene}biscarbamate (22 mg).
Reaction SMILES: Cl.[C:2]([CH2:4][S:5]C(=N)N)#[N:3].C[O-].[Na+].[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35](/[C:37](=[N:43]/[O:44][CH2:45][CH2:46]I)/[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35](/[C:37](=[N:43]/[O:44][CH2:45][CH2:46][S:5][CH2:4][C:2]#[N:3])/[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)/C(=N\OCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#CCSC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCCSCC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -35 °C
Yield: 88.7 %

Procedure:
In 10 ml of dimethylformamide is suspended 0.976 g of S-cyanomethylisothiourea hydrochloride prepared according to the method described in Japanese Published Unexamined Patent Application No. 50-154279. Under cooling at -35° C. and stirring, 2.73 g of 28% (w/w) sodium methylate solution is added dropwise, after which the mixture is stirred at -40° C. to -35° C. for 10 minutes. Then, a solution of 3.94 g of ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-iodoethoxyimino)acetate in 10 ml of dimethylformamide is added at the same temperature. The mixture is stirred at or below -30° C. for 5 minutes and then under ice-cooling for 4 hours. The reaction mixture is poured into 400 ml of ice-water and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. To the solid residue is added a mixture of ether-petroleum ether (1:1) and the mixture is filtered to give 3.18 g of ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-cyanomethylthioethoxyimino)acetate as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[C:12]([O:13]COC)=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:17])=[O:6].S(=O)(=O)(O)O.CC(C)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:17])=[O:6]
Reactant: COCOc1ccc[n+]([O-])c1C(=O)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1cccc(Br)c1)c1c(O)ccc[n+]1[O-]
Yield: 80.8 %

Procedure:
A mixture of 2-(3-bromobenzoyl)-3-methoxymethoxy pyridine 1-oxide (4.00 g), 3.6N-sulfuric acid (11 mL) and acetone (50 mL) was refluxed for 5 hours. The reaction mixture was poured into water, neutralized with an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromobenzoyl)-3-hydroxypyridine 1-oxide (2.81 g). Physical properties and spectrum data of the product are shown below.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:11][CH:12]([CH3:14])[CH3:13].[N:15]([O-])=O.[Na+]>Cl.O>[CH:12]([N:11]1[C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=[N:15]1)([CH3:14])[CH3:13]
Reactant: O=N[O-]
Reactant: CC(C)Nc1cc(C(=O)O)ccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)n1nnc2ccc(C(=O)O)cc21
Yield: 77.4 %

Procedure:
To a stirred, cold (0° C.) mixture of 4-amino-3-isopropylamino-benzoic acid (11 g) in 120 mL of 6 N hydrochloric acid was added drop-wise a solution of 5.9 g of sodium nitrite in 40 mL of water. After 2 hours the solids were collected by filtration, washed with water, and dried to give 9 grams of 3-isopropyl-3H-benzotriazole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([O:6][C:7](=[O:24])[C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][C:9]=1[O:22][CH3:23])[CH2:2][CH2:3]C=C>ClCCl>[CH3:23][O:22][C:9]1[C:8]2[C:7](=[O:24])[O:6][CH2:1][CH2:2][CH2:3][CH:19]=[CH:18][CH2:17][CH2:16][CH2:15][O:14][C:13]=2[CH:12]=[C:11]([O:20][CH3:21])[CH:10]=1
Reactant: C=CCCCOC(=O)c1c(OC)cc(OC)cc1OCCCC=C
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1)OCCCC=CCCCOC2=O
Yield: 96.6 %

Procedure:
To a solution of bis(tricyclohexylphosphine)benzylidine ruthenium IV dichloride (39 mg, 0.045 mmol) in dichloromethane (100 ml) at reflux was transferred a solution of 2,4-dimethoxy-6-pent-4-enyloxy-benzoic acid pent-4-enyl ester (255 mg, 0.76 mmol) in dichloromethane (70 ml). After 5 hours at reflux, the solvent was removed and chromatography gave the 1,3-dimethoxy-6,7,8,11,12,13-hexahydro-5,14-dioxa-benzocyclotridecen-15-one (225 mg).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5]CCC1.[C:9]([O-:22])(=[O:21])[CH2:10][CH2:11]CCCCCCCCC.[C:23]([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>>[C:9]([O:22][CH2:5][CH2:6][N:7]=[C:1]=[O:8])(=[O:21])[C:10]([CH3:23])=[CH2:11]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: O=C1CCCCCN1
Agent: CCCC[Sn+2]CCCC
Product: C=C(C)C(=O)OCCN=C=O
Reaction time: 3 h

Procedure:
96.0 grams IEM was added to 77.0 grams (10% excess) caprolactam plus 0.17 grams dibutyltin dilaurate (DBTDL) under agitation at 75° C. over a period of 30 minutes, and held at 75° C. for a further 3 hours at which point the free NCO content had dropped to a trace by infrared spectroscopy. The product (IB) was a syrupy liquid.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[N:23]=[CH:22][C:21]3[C:16](=[N:17][C:18]([C:24]#[C:25][CH2:26][N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)=[CH:19][N:20]=3)[C:15]2=[O:32])=[CH:9][CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O>[O:32]=[C:15]1[C:16]2[C:21](=[N:20][CH:19]=[C:18]([C:24]#[C:25][CH2:26][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[N:17]=2)[CH:22]=[N:23][N:14]1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:33])=[O:5])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2ncc3ncc(C#CCn4cncn4)nc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2ncc3ncc(C#CCn4cncn4)nc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 4-[1-oxo-7-(3-[1,2,4]triazol-1-ylprop-1-ynyl)-1H-3,5,8-triazaisoquinolin-2-ylmethyl]benzoic acid tert-butyl ester (0.46 g, 1.04 mmol, Example 15A) is treated with trifluoroacetic acid (10 mL) and stirred at room temperature for 40 minutes. The reaction mixture is evaporated to dryness, triturated with ethyl acetate, the solid is collected by filtration, washed with water, washed with ethyl acetate, and dried under house vacuum. This will afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+].[Na]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]#[N:10])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: N#CCc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 45.3 g. (0.31 mol.) of p-chlorophenylacetonitrile and 107 g. (0.72 mol., 99 ml.) of diethyl oxalate in an alcoholic sodium ethoxide solution [prepared by dissolving 7.13 g. (0.31 g.-atom) of sodium in 120 ml. of absolute ethanol] was refluxed with stirring for 2 hours. The cooled reaction mixture was diluted with 700 ml. of water, acidified with acetic acid and cooled to ice bath temperature. The resulting solid was collected and recrystallized from aqueous methanol to give ethyl 3-(p-chlorophenyl)-3-cyanopyruvate, m.p. 134°-135°.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:27]>>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:27])[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: O=C(CBr)c1ccc(F)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(F)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was prepared from norfloxacin (0.5 g, 1.56 mmole) and 2-bromo-4′-fluoroaceto-phenone(0.40 g, 1.86 mmole) by a method similar to that described for Example 4 (61% yield). Mp: 208° C. (dec). 1H NMR (DMSO-d6) δ 1.41 (t, 3H, J=7.0), 2.73 and 3.3 (two m, 8H), 3.94 (s, 2H), 4.58 (q, 2 H. J=7.0), 7.18 (d, 1H, J=7.0), 7.36 (m, 2H), 7.90 (d, 1H, J=13.2), 8.11 (m, 2H), 8.94 (s, 1H), 15.30 (br s, 1H). Anal. Calcd. for C24H23F2N3O4: C, 63.29; H, 5.09; N, 9.23. Found: C, 62.96; H, 5.19; N, 9.16.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[I-].[CH3:13][S+](C)(C)=O.CC(C)([O-])C.[K+]>ClCCl>[O:10]1[C:7]2([CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)[CH2:13]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: C1COC2(CCC3(CC2)CO3)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 30.0 g (192 mmol) of 1,4-cyclohexanedione monoethlene acetal in 750 ml of dichloromethane was added to a homogeneous mixture of 50.7 g (231 mmol) of trimethylsulphoxonium iodide and 25.9 g (231 mmol) of potassium tert-butoxide, and the reaction mixture was stirred at room temperature for one hour. Ice-water was added, the phases were separated, the aqueous phase was extracted repeatedly with dichloromethane and the combined organic phases were washed repeatedly with water, dried over sodium sulphate, filtered and concentrated. This gave 28.3 g (87% of theory) of the title compound.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)[CH2:3]Br.[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>C(O)C.C1C=CC=CC=1>[OH:1][CH:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)[CH2:3][N:20]1[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]1
Reactant: OC1CCNCC1
Reactant: OC(CBr)c1cc(-c2ccccc2)on1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: OC1CCN(CC(O)c2cc(-c3ccccc3)on2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
A mixture of 3-(1-hydroxy-2-bromoethyl)-5-phenylisoxazole (268 mg) and 4-hydroxypiperidine (121 mg) is dissolved in a mixture (4 ml) of 99% ethanol and benzene (1:1). To the solution is added sodium hydrogen carbonate (168 mg) and stirred at 70°C for 5 hours. After removal of the solvent, the residue is subjected to a column chromatography (silica gel,) eluted with a mixture of methylene chloride and methanol, and the crude crystals collected are recrystallized from ethyl acetate to give 3-[1-hydroxy-2-(4-hydroxypiperidino)ethyl]-5-phenylisoxazole (180 mg) as colorless prisms melting at 117-119°C.
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:18])[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][C:4]21[CH2:6][CH2:5]2>C(O)C>[ClH:1].[F:2][C:3]1([F:18])[CH2:10][NH:9][CH2:8][CH2:7][C:4]21[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C(F)(F)C1
Agent: Cl
Solvent: CCO
Product: FC1(F)CNCCC12CC2
Yield: 92.1 %

Procedure:
Hydrogen chloride (4 M in dioxane, 3.29 ml, 13.2 mmol) was added to a solution of tert-butyl 4,4-difluoro-6-azaspiro[2.5]octane-6-carboxylate (592 mg, 2.39 mmol) in ethanol (0.5 ml). The solvents were evaporated to give a white solid. The solid residue was washed with tert-butylmethylether to afford the title compound (404 mg, 92%).White solid, MS: 148.2 (M+H)+.