Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:5]([O:4][CH2:3][CH2:2][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOCCBr
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOCCOc1ccc(-c2ccc(O)cc2)cc1
Yield: 15.9 %

Procedure:
One gram (5.5 millimoles) of 1-bromo-2-butoxyethane was combined with 5.5 grams (30 millimoles) of 4,4'-dihydroxybiphenyl in 75 mls. of acetonitrile. To the reaction mixture were added 8.3 grams (60 millimoles) of finely ground potassium carbonate. Stirring was begun and the reaction mixture was brought to reflux and maintained for 48 hours. The reaction product was filtered, washed with acetonitrile and evaporated for removal of solvent. The product was passed through a silica gel chromatographic column using dichloromethane eluent, for recovery of 0.25 gram (20% yield) of a biphenol ether compound having the following formula confirmed by TLC, IR and mass spectral analyses: ##STR26##
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCCC[C@@H]1c1ccnn1C
Yield: 99.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.17 g, 0.29 mmol) prepared in Example 64a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield the title compound (129 mg, 99%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([OH:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:31][CH:32]([CH3:39])[CH2:33][O:34][CH2:35][C:36](Cl)=[O:37].O>ClCCCl.CN(C)C1C=CN=CC=1>[CH3:31][CH:32]([CH3:39])[CH2:33][O:34][CH2:35][C:36]([O:23][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[N:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)=[O:37]
Reactant: CC(C)COCC(=O)Cl
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)COCC(C)C)nc2n1
Yield: 62.6 %

Procedure:
To a solution, maintained at a temperature in the region of 20° C., of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (9.2 g) and triethylamine (20 cc) in 1,2-dichloroethane (150 cc), there is added, in the course of 20 minutes, a solution of 2-methylpropoxyacetyl chloride (9 g) in 1,2-dichloroethane (20 cc) followed by 4-dimethylaminopyridine (50 mg), and the mixture is heated to reflux for 16 hours. The reaction mixture is poured into water (250 cc) and then extracted with methylene chloride (100 cc.) After the extract is washed with water, dried and concentrated to dryness under reduced pressure (3kPa), the residue obtained is purified by two successive recrystallizations in ethanol. 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 2-methylpropoxyacetate (7.9 g), m.p. 114° C., is thereby obtained.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]=[CH:6]1)(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([O:4][CH:5]1[CH2:9][C:8](=[O:10])[CH:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C=CC(O)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(=O)OC1C=CC(=O)C1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
144 milligrams of optically inactive 3-acetoxy-5-hydroxycyclopent-1-ene prepared as in Example 1 and 460 milligrams of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) were dissolved in 5 milliliters of dioxane, after which the resulting solution was heated with stirring for 48 hours at 60° C. The precipitate separating out after the reaction was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].[H-].[Na+].F[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1>CN(C)C=O.O>[NH2:2][CH2:3][C:4]([S:6][C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:13][CH:12]=1)([CH3:7])[CH3:5]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: CC(C)(S)CN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(SC(C)(C)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a suspension of 1-amino-2-methyl-2-propanethiol hydrochloride (75 mg) in N,N-dimethylformamide (2 mL) is added sodium hydride (60% dispersion in mineral oil, 50 mg) and the mixture is stirred at room temperature for 30 minutes. To the mixture is added tert-butyl 4-fluorobenzoate (50 mg) and the mixture is stirred at 70° C. for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is concentrated in vacuo and the resultant product is purified by flash column chromatography on NH-silica gel (solvent; ethyl acetate) to give tert-butyl 4-[(2-amino-1,1-dimethylethyl)thio]benzoate (54 mg, yield; 75%) as a colorless oil. MS (APCI) m/z: 282 [M+H]+
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15]([CH2:23][C:24]([O:26]CC)=[O:25])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:23]([C:24]([OH:26])=[O:25])[N:3]=[N:2]2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
4-Azido-N-ethylbenzamide (267 mg, 1.40 mmol) and ethyl benzoylacetate (0.316 ml, 1.75 mmol, 1.25 eq.) were dissolved in ethanol (8 ml), sodium ethoxide (122 mg, 1.75 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 13 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (3:1, 40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and stood still at 0° C. The precipitate was collected by filtration, washed with water and dried to give the title compound as a pale-yellow powder (465 mg, 1.38 mmol, 98.8%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])[C:12](O)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N(CC)C(C)C)(C)C.[O:44]1[C:48]2([CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[O:47][CH2:46][CH2:45]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(Cl)Cl>[O:44]1[C:48]2([CH2:53][CH2:52][N:51]([C:12](=[O:13])[CH:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])[CH2:10][C:6]3[CH:7]=[C:8]4[C:3](=[CH:4][CH:5]=3)[NH:2][N:1]=[CH:9]4)[CH2:50][CH2:49]2)[O:47][CH2:46][CH2:45]1
Reactant: O=C(O)C(Cc1ccc2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: C1CC2(CCN1)OCCO2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC(Cc1ccc2[nH]ncc2c1)C(=O)N1CCC2(CC1)OCCO2)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
To a solution of the 3-(1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (95 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.82 mmol) in dimethylformamide (5 mL) was added a solution of 1,4-dioxa-8-azaspiro[4,5]decane (32 mg, 0.23 mmol) and PyBOP® (107 mg, 0.21 mmol) in methylene chloride (5 mL). The reaction mixture was stirred for 16 h at room temperature. All solvent was removed using high vacuum. The residue was subjected to flash column chromatography using methylene chloride/methanol/triethylamine (93:5:2) to give the title compound as a white solid (67 mg, 56% yield). 1H-NMR (CDCl3, 500 MHz) δ 10.52 (s, 1H), 7.97 (s, 1H), 7.54 (s, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.20 (d, J=10.7 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 6.94 (t, J=8.6 Hz, 1 H, 6.67 (d, J=7.6 Hz, 1H), 5.64 (d, J=7.9 Hz, 1H), 5.16 (dd, J=15.0, 6.7 Hz, 1H), 4.56–4.49 (m, 1H), 4.25 (s, 2H), 4.11 (br t, J=15.6 Hz, 2H), 3.92–3.84 (m, 4H), 3.73–3.69 (m, 1H), 3.60–3.56 (m, 1H), 3.48–3.43 (m, 1H), 3.22–3.17 (m, 1H), 3.11 (d, J=6.7 Hz, 2 H), 2.90–2.85 (m, 2H), 2.68–2.60 (m, 4H), 1.67–1.61 (m, 2H), 1.54–1.49 (m, 2H). Mass spec.: 588 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.N#N.[Br-].[CH2:13]([Zn+])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.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>[CH2:13]([C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccnc(Cl)n1
Reactant: [Zn+]Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccnc(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of 2-chloro -4-methoxypyrimidine (0.500 g, 3.46 mmol) and PdCl2(PPh3)2 (0.121 g, 0.173 mmol) in THF (10 mL) was sparged with N2. Benzylzinc(II) bromide (8.30 mL, 4.15 mmol; 0.5 M solution in THF) was added and the reaction mixture was stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude dark brown oil. The crude product was purified by flash column chromatography, eluting with 20:1 dichloromethane/EtOAc. The desired product (0.676 g, 98%) was obtained as a dark yellow oil. 1H NMR (400 MHz, CDCl3) δ8.34 (d, J=5.9 Hz, 1H), 7.41-7.25 (m, 4H), 7.21 (m, 1H), 6.53 (d, J=5.5 Hz, 1H), 4.16 (s, 2H), 3.95 (s, 3H). LRMS (ESI pos) m/e 201 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:22]([OH:25])([CH3:24])[CH3:23]>>[CH:22]([O:25][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:24])[CH3:23]
Reactant: COc1cccc(O)c1Cc1cc2ccccc2nc1N
Reactant: CC(C)O
Product: COc1cccc(OC(C)C)c1Cc1cc2ccccc2nc1N

Procedure:
Synthesis was performed according to EXAMPLE 3 from 2-[(2-aminoquinolin-3-yl)methyl]-3-methoxyphenol and isopropanol.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[OH2:18]>CN(C=O)C>[O:9]=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([N:8]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:18])[CH3:16]
Reactant: O=C1CCCCN1
Reactant: BrCCCCCCBr
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CCCCN1CCCCC1=O)N1CCCCC1=O
Reaction time: 8 h
Yield: 41 %

Procedure:
To a 50% oil suspension of sodium hydride (3.16 grams, 65 mmol) in 60 mL dry DMF under nitrogen was added 6.53 grams (65 mmol) of delta-valerolactam. The mixture was stirred overnight. Then, 4.0 grams (16.3 mmol) of 1,6-dibromohexane was added, and the mixture was stirred for an additional six hours. Two hundred mL of water was added, and the aqueous phase was extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was removed in vacuo. Fractional distillation afforded 1.9 gram (41%) of pure material as an oil, boiling point 160° C. (0.1 torr).
Reaction SMILES: C(O[C:6]([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([CH3:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)C)=O)(C)(C)C.CC1C2C(S([Cl:43])(=O)=O)=CC=CC=2C=NC=1.C(OC(N(C1CCNC1)C)=O)(C)(C)C.BrC1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[CH3:28][C:20]1[C:19]2[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:6])[CH2:11]3)(=[O:17])=[O:16])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:23]=[N:22][CH:21]=1.[ClH:43]
Reactant: Cc1cncc2cccc(S(=O)(=O)N3CCC(N(C)C(=O)OC(C)(C)C)C3)c12
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Agent: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Product: CNC1CCN(S(=O)(=O)c2cccc3cncc(C)c23)C1
Product: Cl

Procedure:
3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(4-methyl-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 23) can be prepared by using 4-methyl-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 1-3, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in the method of Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([O:27][CH:28]([F:30])[F:29])[C:8]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[C:9]([F:14])[CH:10]=2)[N:5]([CH2:31][CH3:32])[CH:4]=1)#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.Cl>C1(C)C(C)=CC=CC=1>[CH2:31]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:14])=[C:8]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[N:22]=[CH:23][CH:24]=[CH:25][N:26]=4)[CH2:19][CH2:20]3)[C:7]=2[O:27][CH:28]([F:30])[F:29])[C:12](=[O:13])[C:3]([C:1]2[NH:35][N:34]=[N:33][N:2]=2)=[CH:4]1)[CH3:32]
Reactant: CCn1cc(C#N)c(=O)c2cc(F)c(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCn1cc(-c2nnn[nH]2)c(=O)c2cc(F)c(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21
Temperature: 25 °C
Yield: 69 %

Procedure:
To 25 ml of xylene were added 0.5 g (0.0011 mole) of 3-cyano-1-ethyl-6-fluoro-8-difluoromethoxy-7-[4-(2-pyrimidinyl)piperazin-1-yl]-1,4-dihydro-4-oxoquinoline obtained as described above, 0.21 g of (0.0033 mole) of sodium azide and 1.07 g (0.0033 mole) of tributyltin chloride, and the mixture was stirred under reflux by heating for 9 hours. After the mixture was cooled to room temperature, 7 ml of a 1N hydrochloric acid aqueous solution was added thereto, and the mixture was stirred. Then, crystals precipitated were collected by filtration, washed with ethanol and toluene, and applied to silica gel column chromatography (the eluent used was a mixture of chloroform:methanol=9:1) to obtain 0.37 g of the title compound as pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[CH2:22][C:23]([N:52]=[N+:53]=[N-:54])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(CC(=O)O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(CC(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.8 %

Procedure:
To 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoic acid (C41) (1.77 g, 4.52 mmol) in toluene (18 mL) was added triethylamine (0.82 mL, 5.88 mol) and diphenyl phosphorazidate (1.05 mL, 4.98 mmol) and the solution was stirred at room temperature for 3 hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was loaded onto a Celite® cartridge and purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent to afford the title compound as a clear oil (0.223 g, 12% yield): 1H NMR is consistent with a mixture of carbonyl azide and isocyanate. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.28-8.03 (m, 2H), 7.88-7.66 (m, 2H), 7.48-7.30 (m, 4H), 3.60-3.40 (m, 2H), 3.08 (q, J=6.9 Hz, 1H), 2.81-2.49 (m, 1H), 1.37 (dd, J=10.4, 7.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 417 ([M+H]+)
Reaction SMILES: O[C:2]1([C:13]([F:16])([F:15])[F:14])[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3]1.S(=O)(=O)(O)O>C(O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([C:13]([F:16])([F:14])[F:15])[NH:6][N:5]=1
Reactant: OC1(C(F)(F)F)CC(c2ccccn2)=NN1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: FC(F)(F)c1cc(-c2ccccn2)n[nH]1
Yield: 82.1 %

Procedure:
2-(2′,4′-difluorophenyl)pyrazole (3.6 g, 20 mmol) and K3IrBr6 (6.3 g, 8 mmol) were added to a flask containing 90 ml 2-ethoxyethanol and 30 ml water. The reaction mixture was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the pale yellow precipitate was vacuum filtered and washed first with ethanol followed by heptanes. The product [2-(4′,6′-diflouorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-diflouorophenyl)pyrazole]2 was dried in vacuum oven (4.2 g, 81%). Step 2 To a 60 ml THF suspension of potassium t-butoxide (7.9 g, 59 mmol) and 2-acetylpyridine(7.1 g, 59 mmol) was added dropwise ethyl trifluoroacetate (10 g, 70 mmol) at 10° C., and the mixture was stirred at room temperature for 15 h. After the PH value of the mixture had been adjusted to 6-7 with 10% H2SO4, the solution was extracted with Et2O. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel with CH2Cl2 followed by recrystallization from ethanol to give 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (10.2 g, 81%). Step 3 Hydrazine hydrate (1.44 g, 27.7 mmol) was added dropwise to 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (5 g, 23 mmol) in 250 ml diethyl ether, and the mixture was stirred at ambient temperature for 3.5 h. Most of the solvent was evaporated and the mixture was extracted with water. The organic layer was dried (MgSO4) and evaporated to give 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 78%). Step 4 Compound 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 24 mmol) was boiled under reflux in 300 ml ethanol in the presence of conc. sulfuric acid (1.85 ml) for 30 min. The reaction mixture was then extracted with water. Evaporation and chromatography (ethyl acetate/heptanes 1:5) gave 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (4.2 g, 85%). Step 5 [2-(4′,6′-difluorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-difluorophenyl)pyrazole]2 (0.15 g, 0.12 mmol), 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (70 mg, 0.3 mmol) and 0.2 g of K2CO3 were refluxed under an nitrogen atmosphere in 2-ethoxyethanol for 18 h. After cooling to room temperature, water was added and a white precipitate was filtered and washed with water. The crude product was chromatographed on a silicon column with dichloromethane/methanol (9:1 v/v) as the mobile phase (110 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[N:17]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>Cl.O>[C:11]1([C:3]2[C:2]3[N:1]=[N:17][NH:10][C:8](=[O:9])[C:7]=3[CH:6]=[CH:5][N:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC(=O)c1ccnc(-c2ccccc2)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]nnc2c(-c3ccccc3)nccc12
Yield: 62.5 %

Procedure:
639 mg of 3-amino-2-phenyl-4-pyridinecarboxamide in 7 ml of concentrated hydrochloric acid were stirred in an ice-bath during the addition of 240 mg of sodium nitrite in 2 ml of water. After 0.5 hour aqueous sodium bicarbonate solution was added until the mixture was basic and the produce was then extracted into ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated, and the residue was recrystallized from ethanol to yield 420 mg of 8-phenylpyrido[3,4-d]-1,2,3-triazin-4(3H)-one of melting point 211° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=2[CH3:32])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=4[CH3:32])[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CCCC2)CC1

Procedure:
Example 81 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H, J=2.0 Hz), 7.37–7.34 (m, 2H), 7.31–7.25 (m, 4H), 7.09 (d, 1H, J=8.0 Hz), 6.50 (brs, 1H), 3.29 (dd, 2H, J=6.4, 12.0 Hz), 2.92 (d, 2H, J=11.6 Hz), 2.66 (m, 1H), 2.54–2.48 (m, 3H), 2.33–2.29 (m, 5H), 2.03–1.94 (m, 4H), 1.83–1.59 (m, 10H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: [C:1]([NH:4][O:5][CH:6]([CH3:29])[C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([C:21]3([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:15]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH2:30](Br)[C:31]#[CH:32]>>[CH2:32]([N:4]([C:1](=[O:3])[CH3:2])[O:5][CH:6]([CH3:29])[C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([C:21]3([O:27][CH3:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:15]=2)=[CH:9][CH:8]=1)[C:31]#[CH:30]
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)ONC(C)=O)cc3)c2)CCOCC1
Reactant: C#CCBr
Product: C#CCN(OC(C)c1ccc(Sc2cc(F)cc(C3(OC)CCOCC3)c2)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Using an analogous procedure to that described in Example 7 except that the reaction mixture was stirred at ambient temperature for 2 hours, 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl acetohydroxamate was reacted with 2-propynyl bromide to give 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl N-(2-propynyl)acetohydroxamate as a gum (80%).