Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH:17]1[C:30]2[C:29](=[O:31])[CH2:28][C:27]([CH3:33])([CH3:32])[CH2:26][C:25]=2[O:24][C:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[CH2:20][C:19](=[O:36])[C:18]1=2.[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:15]3[NH:39][N:38]=[N:37][N:16]=3)[N:14]=2)=[CH:5][C:4]=1[CH:17]1[C:30]2[C:29](=[O:31])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26][C:25]=2[O:24][C:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[CH2:20][C:19](=[O:36])[C:18]1=2
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2cccc(C#N)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(-c3nnn[nH]3)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Temperature: 80 °C
Reaction time: 4 h
Yield: 9.3 %

Procedure:
A suspension of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carbonitrile produced in Example 6 (500 mg, 1.04 mmol), sodium azide (76.4 mg, 1.14 mmol), and ammonium chloride (61.0 mg, 1.14 mmol) in DMF (10 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 80° C. for 4 hours. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=66:34, v/v, methanol:dichloromethane=3:97 to 5:95, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (51 mg, yield: 9.4%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4](C)[CH:5]=O.[CH:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])OCC.C([O-])([O-])=O.[Na+].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:16]([O:15][CH:8]([O:12][CH2:13][CH3:14])[CH:4]([CH3:5])[CH2:3][CH2:2][Cl:1])[CH3:17]
Reactant: CCOC(OCC)OCC
Reactant: CC(C=O)CCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)C(C)CCCl
Temperature: 45 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 4-chloro-2-methylbutyraldehyde (4.8 g, 0.040 moles), triethyl orthoformate (6.48 g, 0.044 moles), ethyl alcohol (3.0 g), and p-toluenesulfonic acid monohydrate (0.0144 g, 0.000757 moles) was stirred at 45° C. overnight under an argon atmosphere. Next, after cooling to room temperature, Na2CO3 (0.40 g) was added and the mixture was stirred for 15 min. The reaction mixture was filtered and ethyl alcohol and residual triethyl orthoformate were distilled off under reduced pressure. The residue was subjected to fractional vacuum distillation giving 3.2 g of pure 4-chloro-2-methylbutyraldehyde diethyl acetal.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:9]=2[CH2:17][C:18](OC)=[O:19])=O)=[CH:4][CH:3]=1.O.[NH2:25][NH2:26].C(O)(=O)C.O>C(O)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[C:8]3[CH:13]=[C:12]4[O:14][CH2:15][O:16][C:11]4=[CH:10][C:9]=3[CH2:17][C:18](=[O:19])[NH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(F)cc1)OCO2
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C1Cc2cc3c(cc2C(c2ccc(F)cc2)=NN1)OCO3

Procedure:
The title compound was prepared from methyl 2-(4-fluorobenzoyl)-4,5-methylenedioxyphenylacetate (350 mg, 1.11 mmol), hydrazine hydrate (180 μL, 3.18 mmol), and acetic acid (50 μL) in ethanol (10 mL), mp: 205°-207° C. 1H NMR (CDCl3) 8.45 (s, 1H), 7.59 (dd, 2H, J=8.5, J=5.5), 7.11 (dd, 2H, J=8.5, J=8.5), 6.83 (s, 1H), 6.61 (s, 1H), 6.04 (s, 2H), 3.45 (s, 2H). Anal. calcd. for C16H11FN2O3.0.125 H2O: C, 63.94; H, 3.77; N, 9.32. Found: C, 63.83; H, 3.58; N, 9.03.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>CC#N.CN(C=O)C.CCOC(C)=O>[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH:37][C:8](=[O:10])[CH2:7][C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:35][CH:34]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(CC(=O)O)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(CC(=O)Nc2ccc(F)cc2)o1
Reaction time: 3 h
Yield: 94.9 %

Procedure:
5-Methyl-2-furanacetic acid (1.00 g, 7.14 mmol, synthesized as described WO 9507893, Example 19) was dissolved in CH3CN/DMF (4:1, 25 mL), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.37 g, 7.14 mmol) and 1-hydroxy-7-azabenzotriazole (0.972 g, 7.14 mmol) were then added followed by 4-fluoroaniline (0.676 mL, 7.14 mmol). After 3 h, the reaction was diluted with EtOAc (150 mL) and washed with 1 N HCl (1×30 mL), sat. aq. NaHCO3 (1×30 mL), brine (1×40 mL) and dried over sodium sulfate. Compound 216A (1.58 g, 95%)) was isolated as a yellow foam after concentration in vacuo. No further purification was necessary. HPLC: 78% at 2.647 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[CH:10]([N:25]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1.C(#N)C>O>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[CH2:1]([O:8][C:9](=[O:39])[CH:10]([NH2:25])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CC(N)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A solution of rac.-2-[(diphenylmethylene)amino]-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester (11.5 g, 22 mmol) and p-toluenesulfonic acid monohydrate (4.18 g, 22 mmol) in a 10/1 mixture of acetonitrile and water (640 ml) was stirred for 2 h at room temperature. Concentration provided a crude solid product which was recrystallized from ethanol-ether to give rac.-2-amino-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester p-toluenesulfonic acid salt, (8.1 g, 15 mmol) in 67% yield, mp. 154°-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](Br)[CH:9](OC)OC)[N:3]=1.[Cl:15][C:16]1[C:17]([NH2:22])=[N:18][CH:19]=[CH:20][N:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC#N.O>[Br:1][C:2]1[N:3]=[C:4]([C:8]2[N:18]3[CH:19]=[CH:20][N:21]=[C:16]([Cl:15])[C:17]3=[N:22][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(Br)c1cccc(Br)n1
Reactant: Nc1nccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: Clc1nccn2c(-c3cccc(Br)n3)cnc12
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-6-(1-bromo-2,2-dimethoxy-ethyl)-pyridine (from Example 37 supra) (5.267 g, 16.2 mmol), 3-chloropyrazin-2-amine (2.1 g, 16.2 mmol), and pTsOH.H2O (2.1 g, 11 mmol) in CH3CN (900 mL) and water (90 mL) was stirred and heated at reflux overnight. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure. The crude product was purified by chromatography (CH2Cl2:CH3OH, 100:1) to give 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine. (Yield 4.86 g, 52%). LC-MS: [M+H]+ 309.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH:9]3[CH2:15][CH2:14][CH2:13][CH:10]32)=[C:5]([CH2:24]O)[CH:4]=1.B(Br)(Br)[Br:27].C(Cl)Cl.Cl>C(OCC)(=O)C.O>[Br:27][CH2:24][C:5]1[CH:4]=[C:3]([OH:2])[CH:12]=[C:11]2[C:6]=1[CH2:7][CH:8]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH:9]1[CH2:15][CH2:14][CH2:13][CH:10]12
Reactant: COc1ccc(C2Cc3c(CO)cc(OC)cc3C3CCCC23)cc1
Reactant: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(C2Cc3c(CBr)cc(O)cc3C3CCCC23)cc1
Yield: 83.3 %

Procedure:
Combine [8-Methoxy-4-(4-methoxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-6-yl]-methanol (0.025 g, 0.074 mmol), boron tribromide (0.11 g, 0.44 mmol), and methylene chloride (1.5 ml) and stir 3 hours. Add water, ethyl acetate and 1N HCl. Rinse organic layer with water, dry over anhydrous sodium sulfate and remove solvent to yield the titled compound (0.023 g, 84%). 1H NMR (DMSO-d6) 9.18(s, 1H), 9.14 (s, 1H), 7.1 (d, J=7.9 Hz, 2H), 6.7 (d, J=7.9 Hz, 2H), 6.62 (s, 1H), 6.56 (s, 1H), 4.68 (d, J=10.1 Hz, 1H), 4.58 (d, J=9.6 Hz, 1H), 3.4 (m, 1H presumed), 2.95 (m, 1H), 2.8 (m, 2H), 2.45(m, 1H) 2.1 (m, 1H), 1.6-1.1 (m, 5H). MS m/z 371 (M−2).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH3:31].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.C(=O)(O)[O-].[Na+].C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH3:31])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([O:9][CH3:8])[C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]=2[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCN(OC)C(=O)c1ccccc1
Temperature: -8 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
Triethylamine (0.32 mL, 2.29 mmol, 1.2 eq) was added to a solution of 1-[4-(methoxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]-1,5-naphthyridin-4-amine (0.626 g, 1.91 mmol, 1.0 eq), prepared as described in Parts A-H of Example 1, in dichloromethane (10 mL) and cooled to −8° C. Benzoyl chloride (0.22 mL, 1.91 mmol, 1.0 eq) was added dropwise and the reaction mixture was stirred for 2 hours. The reaction was then diluted with dichloromethane (80 mL) and saturated aqueous sodium bicarbonate (40 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (30 mL). The combined organics were dried over magnesium sulfate, filtered, concentrated, and purified by HPFC (silica gel eluting with 0-25% CMA in chloroform) to afford 0.47 g of a pale yellow substance. The material was dissolved in acetonitrile, sonicated, filtered, and dried under vacuum at 100° C. for 24 hours to afford 0.225 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N-methoxybenzamide as off-white needles, mp 125-127° C. Anal. calcd for C24H28N6O2: C, 66.65; H, 6.53; N, 19.43. Found: C, 66.43; H, 6.47; N, 19.60.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:15])=[C:11]([CH3:13])[N:12]=1)=[O:6].C(NC(C1SC(NC(=O)CCCBr)=NC=1C)=O)C1C=CC=CC=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]([C:10]2[S:9][C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[N:12][C:11]=2[CH3:13])=[O:15])=[CH:19][CH:20]=1
Reactant: Cc1nc(NC(=O)CCCBr)sc1C(=O)NCc1ccc(F)cc1
Agent: Cc1nc(NC(=O)CCCBr)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 85 %

Procedure:
Following the procedure as described in Example 1, making variations as required to use 2-(4-bromobutanamido)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide in replace of N-benzyl-2-(4-bromobutanamido)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 85% yield: 1H NMR (300 MHz, CD3OD) δ 7.39-7.33 (m, 2H), 7.09-7.02 (m, 2H), 4.48 (s, 2H), 4.15-4.09 (m, 2H), 2.68 (t, J=8.1 Hz, 2H), 2.55 (s, 3H), 2.25 (m, 2H); MS (ES+) m/z 334.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a stirred solution of 2-bromo-5-chlorobenzoic acid (8 g, 34.0 mmole) in dichloromethane (35 mL) was added DMF (1 mL) and oxalyl chloride (3.54 mL, 37.4 mmol) drop wise at 0° C. After complete addition, the reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure to furnish 2-bromo-5-chloro-benzoyl chloride (8.5 g). The crude product was used without further purification.
Reaction SMILES: Cl[C:2]1[N:25]=[C:5]2[C:6]([N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[CH3:11])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:24][N:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:10]([CH3:11])[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:38][CH:37]=3)[N:25]=2)[CH:9]=[CH:8][CH:7]=1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CN(Cc1ccccc1N(C)S(C)(=O)=O)c1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(N(C)Cc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
185 a) To a solution of N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (250.0 mg, 0.6834 mmol) in acetonitrile (1 mL, 20 mmol) at room temperature was added sodium hydride, 60% disp. in mineral oil (33.0 mg, 0.825 mmol) followed by iodomethane (46.80 uL, 0.7517 mmol). The mixture was stirred at room temperature for 2 hours then additional iodomethane (10 uL) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a tan resin. The recovered material was purified via chromatography using an ISCO automated purification apparatus (silica gel column 24 g 20%→80% ethyl acetate:hexane solvent gradient). N-(2-{[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino}-methyl]-phenyl)-N-methyl-methanesulfonamide was isolated as tan foam (0.207 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.6 Hz, 1H), 7.35-7.27 (m, 4H), 6.89-6.84 (m, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.54-5.40 (br m, 1H), 5.06-4.90 (br m, 1H), 3.32 (s, 3H), 3.24 (s, 3H), 3.01 (s, 3H). MS=380, 382 (MH)+. 185 b) N-Methyl-N-{2-[(methyl-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-amino)-methyl]-phenyl}-methanesulfonamide was prepared from N-(2-{[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino]-methyl}-phenyl)-N-methyl-methanesulfonamide (75.0 mg, 0.197 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (42.0 mg, 0.220 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (18.0 mg, 0.0329 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.023 g, 21%). 7.94 (d, J=6.6 Hz, 1H), 7.56-7.51 (m, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.35-7.28 (m, 3H), 6.88 (d, J=8.1 Hz, 2H), 6.70 (t, J=7.3 Hz, 1H), 6.57-6.50 (m, 2H), 5.35-5.23 (m, 1H), 5.12-5.00 (m, 1H), 3.23 (s, 3H), 3.15-3.10 (m, 4H), 3.07 (s, 3H), 2.99 (s, 3H), 2.63-2.58 (m, 4H), 2.36 (s, 3H). MS=535 (MH)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[N:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:13]1([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:12]2.C(N(CC)CC)C.[N:32]1([C:36](OC2C=CC=CC=2)=[O:37])[CH2:35][CH2:34][CH2:33]1>CS(C)=O>[N:32]1([C:36]([N:16]2[CH2:17][CH2:18][C:13]3([CH2:12][C:11]4[C:21](=[N:22][CH:23]=[C:9]([Br:8])[CH:10]=4)[NH:20][C:19]3=[O:24])[CH2:14][CH2:15]2)=[O:37])[CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Oc1ccccc1)N1CCC1
Reactant: O=C1Nc2ncc(Br)cc2CC12CCNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N1CCC1)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
To a stirred solution of 6-bromo-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Intermediate-14) (600 mg, 1.47 mmol) in DMSO (5 mL) was added triethylamine (0.60 mL, 4.40 mmol) at 0° C. and the mixture was stirred at the same temperature for 15 min. Then phenyl azetidine-1-carboxylate (J) (520 mg, 2.93 mmol) was added and the reaction mixture was allowed to stir at 100° C. for 24 h. The reaction mixture was cooled to 20-35° C., diluted with ice cold water (30 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue; which was purified by column chromatography using mixture of 3% MeOH/DCM as an eluent to get the desired compound as a brown solid (180 mg, 32%); 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.22 (d. J=1.5 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 3.86 (t, J=7.8 Hz, 4H), 3.43-3.36 (m, 2H), 3.21-3.13 (m, 2H), 2.96 (s, 2H), 2.18-2.10 (m, 2H), 1.73-1.67 (m, 2H), 1.34-1.23 (m, 2H).
Reaction SMILES: [P:1]([O-:40])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N+:36]([CH3:39])([CH3:38])[CH3:37])([O:3][CH2:4][CH:5]([OH:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[CH3:41][N:42]=[C:43]=[O:44]>>[P:1]([O-:40])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N+:36]([CH3:39])([CH3:38])[CH3:37])([O:3][CH2:4][CH:5]([O:26][C:43](=[O:44])[NH:42][CH3:41])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OCCCCCCCC[N+](C)(C)C
Reactant: CN=C=O
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCC[N+](C)(C)C)OC(=O)NC
Yield: 41 %

Procedure:
By following the procedure of 8, 720 mg of the alcohol derivative obtained in Example 28 was reacted with 2 ml of methyl isocyanate to give 320 mg (yield: 41%) of the desired product.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)=[O:24])[N:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CCOC(=O)N1CCNC[C@H]1C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NCC3CC3)n(-c3ccccc3)n2)C[C@H]1C
Reaction time: 16 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 6 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 16 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 560 μl TFA. After stirring for 16 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 65 mg MS (ES+): m/e=696.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CO.C(Cl)(Cl)Cl.[I-]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: C[Sn](C)(C)c1ccncc1
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccncc3)c(F)c2)C(=O)O1

Procedure:
A slurry of (±)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (PREPARATION 18, 0.063 g, 0.165 mmol) and trimethyl(4-pyridyl)tin (0.060 g, 0.248 mmol) in 1,4-dioxane (5 ml) is degasseal by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium (II) chloride (0.012 g, 0.0165 mmol) is added, the reaction again alegassed, and then the mixture is brought to reflux under nitrogen. After 4 hr TLC (silica gel, 10% methanol/chloroform) reveals some of the iodide still remains. The mixture is refluxed a further 20 hr, cooled to 20°-25°, and concentrated under reduced pressure. The residue is chromatographed over silica gel, eluting with a litfie chloroform and then methanol/chloroform (1%, 2%, and then 5%). The appropriate fractions are pooled and concentrated to give the enantiomerically enriched title compound, mp 190.5°-191.0°; [ct]25 -16.4 ° (c 0.5, CHCl3). The following characteristics are noted for a racemic sample, mp 179°-180°; IR (internal reflectance) 3279, 3063, 1756, 1752, 1657, 1626, 1600, 1542, 1522, 1485, 1412, 1407, 1377, 1222, 1198 cm-1 ; NMR (CDCl3, 300 MHz) 8.67, 7.59, 7.50, 7.47, 7.33, 6.15, 4.84, 4.11, 3.85, 3.78-3.62, 2.04 δ; MS (m/z) 329 (39.8, M+), 285, 257, 201,172, 73 and 42. ##STR3## .
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:10]1[C:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:35]([O:34][C@@H:9]([C:10]1[C:11]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 50 °C
Yield: 79 %

Procedure:
To the solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate (15 mg) in THF/MeOH (1 mL/1 mL) was added sodium hydroxide solution (1.0 N, 1 mL). The mixture was heated at 50° C. for 16 hours and was diluted with water. The aqueous was extracted with ethyl acetate, and the organic phase was washed with brine, and dried over sodium sulfate. Concentration under reduced pressure gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol (10 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H32ClN2O3: 454.2. Found: 455.3.