Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](O[C:17]3[C:26](=[O:27])[C:25]4[C:24]([OH:28])=[CH:23][C:22]([OH:29])=[CH:21][C:20]=4[O:19][C:18]=3[C:30]3[CH:31]=[CH:32][C:33]([OH:37])=[C:34]([OH:36])[CH:35]=3)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>>[CH:31]1[C:30]([C:18]2[O:19][C:20]3[CH:21]=[C:22]([OH:29])[CH:23]=[C:24]([OH:28])[C:25]=3[C:26](=[O:27])[CH:17]=2)=[CH:35][C:34]([OH:36])=[C:33]([OH:37])[CH:32]=1
Reactant: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: O=c1cc(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12
Temperature: 5 °C
Yield: 82.8 %

Procedure:
60 g of rutin are suspended in 6 l of demineralized wazer and, at 100° C., firstly 210 ml of 32% strength aqueous sodium hydroxide solution and then 600 g of sodium dithionite are added thereto. The mixture is then refluxed for a further 12 h with stirring, and the suspension is cooled to 5° C., slowly neutralized with 195 ml of fuming hydrochloric acid and stirred for 1 h at 0° C. Customary work-up gives 23.3 g of crude luteolin with a purity of 96.5%. Further purification and drying produces 20.9 g of luteolin with a purity of 99.6%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:24]C(=O)C2C=CC=CC=2)=[N:9]3)[S:6][CH:7]=1)#[N:2].N1C=CC=CC=1.Cl.CON>C(O)C>[NH2:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:5]2[S:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]=1
Reactant: N#Cc1csc(C23CN(c4ncc(F)cn4)CC2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#Cc1csc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(N)=N3)c1
Temperature: 25 °C

Procedure:
Racemic N-[7a-(4-cyano-2-thienyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (1.01 g, 2.17 mmol), pyridine (2.64 mL, 32.6 mmol), and O-methylhydroxylamine hydrochloride (1.82 g, 21.7 mmol) in ethanol (250 mL) are stirred at 60° C. for 24 hours. The mixture is cooled to ambient temperature and concentrated. The mixture is diluted with water and extracted with DCM followed by 3:1 chloroform:isopropyl alcohol. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated. The crude product is purified over silica gel using a gradient of hexane:ethyl acetate (1:0 to 0:1, over 30 min). The product is chirally separated by SFC (Column: Chiralpak AS-H 2.1×15 cm; 5μ; eluent: 30% methyl alcohol with 0.2% isopropylamine) in CO2; flow: 70 mL/minute at 225 nm). The first eluting isomer is the title compound (99% ee). Analysis column: Chiralpak AS-H 4.6×150 mm; eluent: 30% methyl alcohol with 0.2% isopropylamine) in CO2; flow: 5.0 mL/min at UV 225 nm, RT=1.08 minutes). ES/MS (m/e): 361(M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18](Cl)=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCO)cccc2c1=O
Reaction time: 2.5 h

Procedure:
A solution of 1.6 ml of 2-methylamino-ethanol in 10 ml of water was added dropwise over a period of 5 minutes to a suspension of 6 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and 1.52 g of potassium carbonate in 60 ml of acetone. After stirring for 2.5 hours at 20°-25° C., the solvent was removed in vacuo and the residue was taken up in 150 ml of acetone. The mixture was refluxed for 15 minutes, and was then filtered. The solvent was evaporated from the filtrate and the residue was dissolved in 20 ml of dimethylformamide, treated with 14 ml of 1.4% aqueous sodium carbonate solution, stirred for 30 minutes at 20°-25° C. and diluted by addition of 150 ml of water. The mixture was extracted with chloroform and the organic layer was washed with 0.5N aqueous hydrochloric acid solution and then with water. The solution was dried over anhydrous sodium sulfate and the chloroform was evaporated off. The resulting oil was taken up in 200 ml of diethyl ether and stirred for 2 hours at 20°-25° C. The solids were collected by filtration and crystallized from ethyl acetate to give 4.97 g of the title compound, m.p. 128°-130° C.
Reaction SMILES: N1(O[C:11]([CH:13]=[CH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:12])C2C=CC=CC=2N=N1.CCN(CC)CC.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[NH2:37]>C(Cl)Cl>[CH3:44][O:43][C:39]1[CH:38]=[C:36]([NH:37][C:11]([CH:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[O:12])[CH:35]=[C:34]([O:33][CH3:32])[C:40]=1[O:41][CH3:42]
Reactant: COC(=O)c1ccc(C=CC(=O)On2nnc3ccccc32)cc1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=CC(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
To a stirred suspension at room temperature of VIII (150 mg, 0.46 mmol) in anhydrous CH2Cl2 (10 ml) under nitrogen were added Et3N (194 μl, 1.39 mmol) and 3,4,5-trimethoxyaniline (94 mg, 0.51 mmol) or ArNH2(1.1–1.2 equiv.), respectively. The reaction mixture was heated to 60° C. After 20 h, the reaction mixture was concentrated, diluted with AcOEt, and successively washed with a saturated aqueous solution of NH4Cl, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (AcOEt/CH2Cl2:15/85→20/80) to give the title product IXa (130 mg, 0.35 mmol, 75% yield) as a yellow solid. 1H NMR (300 MHz, acetone-d6) δ(ppm): 9.42 (bs, 1H), AB system (δA=8.09, δB=7.78, J=8.1 Hz, 4H), 7.75 (d, J=15.6 Hz, 1H), 7.21 (s, 2H), 7.00 (d, J=15.8 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 6H), 3.73 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH:8]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[NH:6][C:5]=2[N:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH:8]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)[NH:6][C:5]=2[N:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc(=O)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(N4CCNCC4)cc3)cc(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)piperazine-1-carboxylate (300 mg, 0.62 mmol, 1.00 equiv) in dichloromethane (6 mL), trifluoroacetic acid (3 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was then concentrated under vacuum. The pH value of the solution was adjusted to about 9-10 with sodium bicarbonate. The resulting solution was extracted with of ethyl acetate (2×10 mL), the organic layers combined and dried over anhydrous magnesium sulfate. The residue was applied onto a silica gel column with MeOH:DCM (1:40) to yield 3-methyl-1-phenyl-6-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4(7H)-one as a yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[C:16]#[N:17])(=O)=O.[B-](F)(F)(F)[C:21]([CH3:23])=[CH2:22].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.CCOC(C)=O.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:21]([CH3:23])=[CH2:22])[C:8]=1[C:16]#[N:17])([O-:15])=[O:14]
Reactant: C=C(C)[B-](F)(F)F
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cccc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)c1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A suspension of 2-cyano-3-nitrophenyl trifluoromethanesulfonate (Example 129d) (0.93 g, 3.15 mmol), potassium trifluoro(prop-1-en-2-yl)borate (0.70 g, 4.73 mmol), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) (0.26 g, 0.32 mmol), cesium carbonate (3.08 g, 9.45 mmol) and water (5.6 mL) in THF (56 mL) was heated at reflux for 25 min, under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (100 mL) and EtOAc (100 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×100 mL). The combined extract was washed with diluted HCl (1.5M), brine and dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hexanes/EtOAc (7:3), to give 0.30 g (49%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.24-8.29 (m, 1H), 7.86-7.95 (m, 2H), 5.47-5.52 (m, 1H), 5.20-5.23 (m, 1H), 2.12-2.15 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][S:9]2(=[O:14])=[O:13])[CH:5]=[CH:4][C:3]=1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].O>ClCCl>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([C:15]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH2:10][S:9]3(=[O:14])=[O:13])=[CH:7][C:2]=2[NH:1][C:38](=[O:40])[CH3:39])=[O:16])[CH2:18][CH2:19]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N)CC2)c(C)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-Amino-4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (100 mg) described in Example 103 was dissolved in dichloromethane (2 mL), triethylamine (0.07 mL) and acetyl chloride (0.03 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (24 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Cl[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Clc1cccnc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(Nc2cccnc2)c1
Temperature: 110 °C
Yield: 81.8 %

Procedure:
3-nitroaniline (1.82 g, 13.2 mmol, 1.5 eq), 3-chloropyridine (1 g, 8.8 mmol, 1 eq), Cs2CO3 (4.02 g, 12.3 mmol, 1.4 eq), Pd2(dba)3 (403 mg, 0.44 mmol, 0.05 eq) and Xantphos (511 mg, 0.88 mmol, 0.1 eq) were dissolved in toluene (10 mL) in a flame-dried sealed tube and heated at 110° C. for 18 h. The reaction was cooled to rt, diluted with CH2Cl2 and filtered through a plug of celite. Purification by flash chromatography on silica gel afforded 1.55 g (82%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.42 (d, J=2.7 Hz, 1H), 8.17 (d, J=4.5, 1H), 7.79 (t, J=2.1 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.52-7.45 (m, 2H), 7.33 (dd, J=8.2, 4.6 Hz, 1H); ES-MS [M+1]+: 216.1.
Reaction SMILES: B(Cl)(Cl)Cl.[Br:5][C:6]1[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:34])[C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=1)=[CH:11]2.C(=O)=O.CC(C)=O.O>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:5][C:6]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:34])[C:20](=[O:33])[C:21]1[CH:22]=[CH:23][C:24]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:25][CH:26]=1)=[CH:11]2
Reactant: COc1ccc2cc(CN(C)C(=O)c3ccc(C4CCCCC4)cc3)ccc2c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Boron trichloride (5.5 mL of a 1 M solution in methylene chloride; 5.5 mmol) was added under argon to a solution of N-(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-4-cyclohexyl-N-methyl-benzamide (860 mg, 1.8 mmol), prepared by the general acylation procedure described above, and tetrabutylammonium iodide (2.04 g, 5.5 mmol) in 10 mL of methylene chloride at dry ice-acetone temperature. After the addition the reaction was allowed to warm to room temperature. The reaction was considered finished after HPLC/TLC analysis indicated the formation of a single product and the disappearance of the starting amide. The reaction was cooled to ice bath temperature followed by the addition of water. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (20-30% ethyl acetate in hexanes) to give N-(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-4-cyclohexyl-N-methyl-benzamide (799 mg, 97%), LCMS (Calc'd: 451.13; Found: 451.65).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:6]=[N:5][C:4]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16].[P:43](OCC)([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.C(OCC)(=O)C>[CH2:46]([O:45][P:43]([CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:6]=[N:5][C:4]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16])([O:48][CH2:49][CH3:50])=[O:44])[CH3:47]
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CBr)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: CCOP(=O)(OCC)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F)OCC
Temperature: 110 °C
Reaction time: 12 h

Procedure:
tert-Butyl (3S,5R)-3-[{[5-(bromomethyl)-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (440 mg) was dissolved in DMF (4 ml), triethyl phosphate (295 μl) was added and the mixture was stirred at 110° C. for 12 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (473 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][OH:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Br)cc1)C(C)C
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Step 1B [Intermediate 2: 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester (3.4 g, 9.71 mmol), 4-hydroxymethyl phenyl boronic acid (1.48 g, 9.71 mmol, 1 equiv.), Pd(PPh3)4 (561 mg, 0.48 mmol, 0.05 equiv.) were dissolved in ethylene glycol dimethyl ether (90 mL) under N2 atmosphere and stirred at room temperature for 30 min. Then K2CO3 (2.68 g, 19.4 mmol, 2 equiv.) in H2O (30 mL) was introduced to the reaction mixture and heat to reflux overnight. After TLC confirmation of reaction completion, solvent was removed by rotovap, residue partitioned between EtOAc and brine, organic layer dried over MgSO4, solvent removed, crude residue was triturated with EtOAc to give 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester in 67% yield (2.46 g).
Reaction SMILES: [Na].Br[CH2:3][C:4]1[C:5]([CH2:10]Br)=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:12](#[N:17])[CH2:13][C:14]([CH3:16])=[O:15].O>C(O)C.CCOCC>[C:14]([C:13]1([C:12]#[N:17])[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3]1)(=[O:15])[CH3:16]
Reactant: CC(=O)CC#N
Reactant: BrCc1ccccc1CBr
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(=O)C1(C#N)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (13.2 g) was dissolved in dry ethanol (220 ml). Dry diethyl ether (270 ml) was added. To the solution were simultaneously added α,α'-dibromo-o-xylene (85.2 g), dry ether (250 ml) and acetoacetonitrile (45.6 g) in dry ether (160 ml) over a period of one hour. (Acetoacetonitrile had been prepared by the method described in U.S. Pat. No. 4,152,336.) After the addition, the mixture was stirred for 1 hour at room temperature and then refluxed for 2 hours. The cooled reaction mixture wa poured into water. The ether layer was separated and the water layer was extracted once more with ether. The combined ether solutions were washed with water, dried (MgSO4) and evaporated. The yield of crude product was 73.8 g.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][C@H:17]4[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[C:12]4[CH:30]=[CH:31][N:32]=[CH:33][C:11]=4[C:10]=3[C:9](=[O:34])[NH:8][CH:7]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][C@H:17]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]4)[C:12]4[CH:30]=[CH:31][N:32]=[CH:33][C:11]=4[C:10]=3[C:9](=[O:34])[NH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc3c(C#CC4CC4)c[nH]c(=O)c3c3cnccc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cc(C#CC2CC2)c2nc(N[C@H]3CCCNC3)c3ccncc3c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (3S)-3-{[4-(cyclopropylethynyl)-1-oxo-1,2-dihydropyrido[4,3-c]-1,6-naphthyridin-6-yl]amino}piperidine-1-carboxylate (100 mg, 0.218 mmol) in dichloromethane (2 mL), trifluoroacetic acid (2000 26.0 mmol) was added. After stirring at room temperature for 10 min, the mixture was quenched with aqueous sodium hydrogen carbonate (saturated). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford 4-(cyclopropylethynyl)-6-[(3S)-piperidin-3-ylamino]pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one as a yellow solid. 1H NMR (500 MHz, C2D6SO) δ 10.97 (s, 1H), 8.74 (d, 1H), 8.29 (d, 1H), 8.06 (d, 1H), 7.61 (s, 1H), 4.42 (m, 1H), 3.03 (m, 2H), 2.74 (m, 1H), 2.16 (t, 2H), 1.66 (m, 2H), 0.84 (m, 6H). LRMS (APCI) calc'd for (C21H22N5O) [M+H]+, 360.2; found 360.1.
Reaction SMILES: [I:1][C:2]1[C:3](C)=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:13]C1C=CC(C(O)=O)=C(C)C=1>>[F:13][C:3]1[C:2]([I:1])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:11])[CH:4]=1
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Product: Cc1cc(F)c(I)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.3, except 4-fluoro-2-methylbenzoic acid was used in place of 2,4-dimethylbenzoic acid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([C:18]3[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=3)=[O:17])[C@H:11]([O:26][CH3:27])[CH2:10]2)=[N:6][C:5]=1[C:28]([O:30]CC)=[O:29])(=[O:3])[CH3:2].[OH-].[Li+]>CO.C1COCC1>[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([C:18]3[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=3)=[O:17])[C@H:11]([O:26][CH3:27])[CH2:10]2)=[N:6][C:5]=1[C:28]([OH:30])=[O:29])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)sc1C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)c(C(C)=O)s3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl cis(±)-5-acetyl-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-4-carboxylate obtained in Example (190b) (54 mg, 0.11 mmol) was dissolved in methanol (2 ml) and THF (2 ml). A 2 N aqueous lithium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid. The resulting solid was collected by filtration and washed with distilled water, to obtain the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CN1C=CN=C1.CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2)C(=O)O)cs1
Yield: 52.2 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetate (syn isomer, 21.15 g.), 1N sodium hydroxide aqueous solution (94 ml.), 1-methylimidazole (1.02 g.), methanol (220 ml.) and tetrahydrofuran (150 ml.) were treated in a similar manner to that of Example P-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetic acid (syn isomer, 10.13 g.).