Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.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.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 39 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (76 mg, 0.14 mmol), 3-tributylstannanyl-pyridine (0.070 mL, 0.21 mmol) and PdCl2(PPh3)2 (20 mg, 0.029 mmol) in 4 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-95% EtOAc/hexanes+1% AcOH) to give 29 mg of the title compound. MS: (+) m/z 532.30 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([O:8]C(C)(C)C)=[O:7])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
102 mg (0.20 mMol) of tert.butyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate (melting point: 122°-123° C.; [α]D20 =+8.7°; c=1 in methanol) are refluxed in 5 ml of benzene together with a few crystals of p-toluenesulphonic acid hydrate, for half a day. The desired product is then obtained, according to thin layer chromatography, according to the RF value and mass spectrum.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[N:13]=[CH:12][CH:11]=[C:10]3[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ccnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ccnc23)c1F
Yield: 10.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine (Intermediate-25, 100 mg, 0.33 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 190 mg, 0.66 mmol), oxalyl chloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (128 mg, 0.99 mmol) in CH2Cl2 (6 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.35 (s, 1H), 8.73-8.71 (d, J=7.2 Hz, 1H), 8.52 (d, 1H), 8.17 (m, 2H), 7.71-7.62 (m, 4H), 7.48-7.36 (m, 3H), 7.14 (m, 1H), 4.31 (d, 2H), 1.14 (s, 9H); MS (m/z): 573.36 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].C(O)(C)(C)C.[H][H]>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: [H][H]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Yield: 37.3 %

Procedure:
An ambient temperature mixture of benzyl 2-azido-carbapen-2-em-3-carboxylate (7.7 mg, 27 micromol) and palladium on calcium carbonate poisoned with lead (2.8 mg) in dry dioxane (0.80 ml) containing t-butanol (50 microliter) was stirred while hydrogen was bubbled through for 20 min. The mixture was filtered and the solid washed with diethyl ether (3×0.5 ml). The combined filtrate and washes were concentrated to 0.5 ml under vacuum, and the residue was chromatographed on one 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plate developed with 1:1 (v/v) toluene-ethyl acetate. The band centered at Rf 0.2 was eluted with ethyl acetate and the eluate was evaporated under vacuum to provide 2.6 mg (37%) benzyl 2-amino-carbapen-2-em-3-carboxylate as a light yellow glass; I.R. (neat film): 3450, 3330, 1780, 1690 cm-1 ; NMR (CDCl3): δ 2.81 dd (J1 =4 Hz, J2 =16 Hz, 1H), 2.93 m (2H), 3.21 dd (J1 =5 Hz, J2 =16 Hz, 1H), 5.25 d (J=13 Hz, 1H), 5.32 d (J=13 Hz, 1H), 7.37 m (5H).
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[CH2:11][C:12]([C:34](O)=[O:35])=[CH:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][CH:22]=3)=[CH:17][C:15]=2[N:16]=1)=O)(C)(C)C.[Si]([O:44][C@H:45]1[C@H:49]([O:50][Si](C(C)(C)C)(C)C)[CH2:48][NH:47][CH2:46]1)(C(C)(C)C)(C)C>>[NH2:9][C:10]1[CH2:11][C:12]([C:34]([N:47]2[CH2:48][C@@H:49]([OH:50])[C@H:45]([OH:44])[CH2:46]2)=[O:35])=[CH:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:28])=[CH:25][CH:26]=3)=[CH:17][C:15]=2[N:16]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CNC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Agent: Cl
Product: NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)N2C[C@@H](O)[C@H](O)C2)C1

Procedure:
The title compound was prepared by the procedures as described in Example 101 (Steps H and I) with conc. HCl instead of TFA using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and (3R,4R)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidin.
Reaction SMILES: [F-:1].[K+].[CH3:3][O:4][C:5](=[O:15])[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1I.COC(=O)[C:19](Cl)([F:21])[F:20]>CN(C=O)C.[Cu]I>[CH3:3][O:4][C:5](=[O:15])[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[C:19]([F:21])([F:1])[F:20]
Reactant: [F-]
Reactant: COC(=O)C(F)(F)Cl
Reactant: COC(=O)c1c(C)cc(Cl)cc1I
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(Cl)cc1C(F)(F)F
Temperature: 140 °C
Reaction time: 18 h
Yield: 67.4 %

Procedure:
CuI (1.9 g, 10 mmol) and potassium fluoride (0.58 g, 10 mmol) were added under an N2 atmosphere to a solution of 4-chloro-2-iodo-6-methyl-benzoic acid methyl ester (2.9 g, 9.4 mmol) and chloro-difluoro-acetic acid methyl ester (1.2 mL, 11 mmol) in DMF (25 mL). The mixture was stirred at 140° C. for 18 h. The reaction was cooled and the solvent evaporated. Silica gel column chromatography using 10% ethyl acetate in hexane afforded 4-chloro-2-trifluoromethyl-6-methyl-benzoic acid methyl ester (1.6 g, 67%). GC-MS: m/z 252 (M−1)+, 221 (M−31)+.
Reaction SMILES: [CH2:1](O)[CH3:2].Cl.[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:28])=[C:10]([CH2:12][CH2:13][NH:14][CH:15]2[CH2:24][CH2:23][CH2:22][C:21]3[N:20]=[C:19]([C:25]([OH:27])=[O:26])[CH:18]=[CH:17][C:16]2=3)[CH:11]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:28])=[C:10]([CH2:12][CH2:13][NH:14][CH:15]2[CH2:24][CH2:23][CH2:22][C:21]3[N:20]=[C:19]([C:25]([O:27][CH2:1][CH3:2])=[O:26])[CH:18]=[CH:17][C:16]2=3)[CH:11]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1O
Temperature: 25 °C

Procedure:
40 ml of anhydrous ethanol and 4 ml of a 4 N solution of hydrogen chloride in dioxane were added to 1.93 g (5.84 mmol) of rac-5-{[2-(5-fluoro-2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, and the mixture was stirred under reflux overnight. The reaction solution was then cooled to room temperature, and first ethyl acetate and then, slowly, saturated aqueous sodium bicarbonate solution were added. The organic phase was separated off, dried over magnesium sulphate, filtered and concentrated to dryness. This gave 1.67 g (4.66 mmol, 80% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[N:22]=[C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:24](=[O:27])[NH:25][CH:26]=1.[F:34][CH:35]([F:38])[CH2:36]I.C(=O)([O-])[O-].[K+].[K+]>>[F:34][CH:35]([F:38])[CH2:36][N:25]1[C:24](=[O:27])[C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:22][C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:26]1
Reactant: FC(F)CI
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c[nH]c(=O)c(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cn(CC(F)F)c(=O)c(N2CCOCC2)n1

Procedure:
Method 1 was followed using N-(4-methyl-3-(6-morpholino-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.), 1,1-difluoro-2-iodoethane (1.2 equiv.) and potassium carbonate (2.0 equiv.) at 60° C. 1H NMR (400 MHz, <cd3od>) δ ppm 2.39 (s, 3H) 3.81 (d, J=5.09 Hz, 8H) 4.38 (td, J=14.09, 3.91 Hz, 2H) 6.02-6.44 (m, 1H) 7.14 (s, 1H) 7.26 (d, J=8.22 Hz, 1H) 7.59 (dd, J=8.22, 1.96 Hz, 1H) 7.67-7.79 (m, 2H) 7.89 (d, J=7.83 Hz, 1H) 8.16-8.34 (m, 1H). LCMS (m/z) (M+H)=523.3, Rt=1.05 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2)=[O:12])#[N:2].Cl.[H][H]>C(O)(C)C.C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2)=[O:12]
Reactant: Cc1ccc(C#N)c(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1ccc(CN)c(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1

Procedure:
A mixture of 1-(2-cyano-5-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.54 g, 1.0 mmol), platinum oxide (0.1 g), and 5-6M HCl in isopropanol (2 mL) in acetic acid (15 mL) is hydrogenated under 50 psi hydrogen for 48 hrs. The mixture is filtered through Celite, the filtrate is evaporated under vacuum, and the residue is purified by preparative HPLC to provide the product.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=O.N1CCCCC1>C(Cl)(Cl)Cl>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([O:22][C:23]([F:24])([F:25])[F:26])=[C:14]([Cl:13])[CH:15]=1
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: Cc1cc(O)c(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)c(=O)o1
Temperature: 25 °C
Yield: 10.7 %

Procedure:
A mixture of 1.85 g of 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one, 2.25 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 20 ml of chloroform and 0.7 ml of piperidine was heated under refluxing for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography. Resulting crystals were washed with 40 ml of t-butyl methyl ether to obtain 0.40 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (1a-6]) as a yellow crystal.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]#[CH:26])#C.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:28]=1.C#C>C1C=CC=CC=1.CO.ClC1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([C:20]1[CH:19]=[CH:24][C:23]([C:27]#[CH:28])=[CH:22][CH:21]=1)#[CH:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C#Cc1ccccc1C#C
Agent: C#C
Agent: C(C#Cc1ccccc1)#Cc1ccccc1
Solvent: CO
Solvent: Clc1ccccc1
Solvent: c1ccccc1
Product: C#Cc1ccc(C#C)cc1
Reaction time: 1 h

Procedure:
A copolymer prepolymer of diphenylbutadiyne and p-diethynylbenzene was prepared in refluxing benzene solvent. The polymerization vessel was charged with 63 parts of diphenylbutadiyne, 2 parts of diethynylbenzene, 600 parts of benzene, and 2 parts of chlorobenzene. After heating to reflux, 2 parts of a catalyst mixture prepared by mixing 2 parts of nickelacetylacetonate and 4 parts of triphenylphosphine in 20 parts of benzene were added. After 1 hour, an additional 10 parts of diethynylbenzene was added. After 2 hours, 10 parts of diethynylbenzene and 2 parts of catalystsolution were added. After 3 hours, 20 parts of diethynylbenzene and 4 parts of catalyst solution were added. After a total reaction period of 7 hours, gas-liquid chromatographic analysis of the reaction mixture showed that 10% of each of the monomeric components remained. The solution was added to 5 times its volume of methanol, and 77 parts of the copolymer wasprecipitated. It had an acetylene content of 8.4% and an aromatic to olefin hydrogen ratio of 8:1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:28][CH3:29])=[CH:9][C:10]3[C:11]4[N:19]([CH2:20][CH:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:18](=O)[NH:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:30])[O:4][N:3]=1.O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN1C(=O)CCC1.C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:28][CH3:29])=[CH:9][C:10]3[C:11]4[N:19]([CH2:20][CH:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)[C:18]([N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n(CC3CCOCC3)c12
Reactant: C1COCCN1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N3CCOCC3)n(CC3CCOCC3)c12
Temperature: 120 °C
Yield: 1.8 %

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (220 mg, 0.539 mmol) (for a preparation see intermediate 14) was dissolved in POCl3 (2 ml, 21.46 mmol), PCl5 (0.2 g, 0.960 mmol) was added and the mixture was heated at 120° C. for 24 h. The reaction mixture was evaporated in vacuo to give a beige solid. The solid was dissolved in NMP (0.5 ml) and morpholine (0.3 ml, 3.44 mmol) was added, then the solution was heated in the microwave at 150° C. for 1 h. The solution was loaded onto a 20 g SCX-2 cartridge and washed with methanol (30 ml), then eluted with 2M methanolic ammonia (30 ml) and the eluant evaporated in vacuo to give a beige gum. This was dissolved in DCM (3 ml) and loaded onto a 25 g silica column, then eluted with 2M methanolic ammonia/DCM (0-10%, 25 column volumes) and product containing fractions were evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-2-(4-morpholinyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (4.7 mg, 9.84 μmol, 1.827% yield) as a beige solid. LCMS (formate) Rt 0.70 min, MH+ 478
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(#[N:46])C>>[C:1]([O:5][C:6]([N:8]([C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH2:34][C:33]1[CH:36]=[CH:37][C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]#[N:46])=[CH:31][CH:32]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Reactant: CC#N
Reactant: N#Cc1ccc(-c2ccccc2CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC(C)(C)C
Temperature: 82.5 °C

Procedure:
Methyl 2-t-butoxycarbonylamino-3-nitrobenzoate [BAN] obtained in Reference Example 3 (354 kg), a solution of 4-(2-bromomethylphenyl)benzonitrile [BMB] in acetonitrile obtained in Reference Example 4 (1), and anhydrous potassium carbonate (475 kg) were added to acetonitrile (1600 kg), and the mixture was heated (80 to 85° C.) under reflux for about 5 hours. The reaction solution was cooled, and the insoluble were separated and washed with acetonitrile (320 kg). The filtrated washing was concentrated under reduced pressure to give concentrate of methyl 2-[N-t-butoxycarbonyl-N-[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate [BBN].
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][C@H:8]([C:17]([N:19]1[C@@H:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][O:21][C:20]1=[O:31])=[O:18])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>O>[CH2:24]([C@H:23]1[CH2:22][O:21][C:20](=[O:31])[N:19]1[C:17]([C@H:8]([CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:7][C:6]([OH:32])=[O:5])=[O:18])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](CCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 1 h

Procedure:
3-(R)-(4-(S)-Benzyl-2-oxo-oxazolidine-3-carbonyl)-5-cyclohexyl-pentanoic acid tert-butyl ester (2.01 g, 4.53 mmol, 1.0 eq) was treated with a 45:50:5 CH2Cl2:TFA:H2O solution. The reaction was monitored by LC/MS and complete after 1 hour. The solution was evaporated and provided a quantitative yield of 3-(R)-(4-(S)-Benzyl-2-oxo-oxazolidine-3-carbonyl)-5-cyclohexyl-pentanoic acid as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 0.80-0.91 (m, 2H), 1.09-1.27 (m, 6H), 1.44-1.53 (m, 1H), 1.61-1.73 (m, 6H), 2.12 (s, 2H), 2.35 (dd, 1H, J=17.2, 4.0 Hz), 2.49 (dd, 1H, J=13.6, 9.6 Hz), 2.71 (dd, 1H, J=17.6, 10.8 Hz), 3.03 (dd, 1H, J=13.6, 3.2 Hz), 3.87-3.97 (m, 3H), 4.43 (m, 1H), 6.90-7.10 (m, 5H).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[CH:4]=1.[CH3:19][C:20]([NH:22][C:23]1[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=1)=[O:21].C([O-])([O-])=O.[K+].[K+].C[N:37]([CH:39]=O)C>>[NH:37]1[C:39]2[C:10](=[C:5]([C:7]3[N:8]=[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:10]4[S:11][C:3]([CH2:2][NH:29][C:27]5[CH:28]=[C:23]([NH:22][C:20](=[O:21])[CH3:19])[CH:24]=[CH:25][CH:26]=5)=[CH:4][C:5]=4[N:6]=3)[CH:4]=[CH:3][CH:2]=2)[CH:9]=[N:8]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1cccc(NCc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 from Example 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added 3-aminoacetanilide (39 mg, 0.3 mmol) and K2CO3 (50 mg, 0.4 mmol). The resulting solution stirred at room temperature overnight then was concentrated in vacuo. The residue was diluted with water and filtered. The crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 301 after reverse phase HPLC purification (39 mg). MS (Q1) 500 (M)+
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C.O>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(Cl)CCCCBr
Reactant: C1COCCN1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCCBr)N1CCOCC1
Reaction time: 3.5 h
Yield: 88 %

Procedure:
Under a nitrogen atmosphere, 5-bromovaleryl chloride (4.0 mL, 30 mmol) was added dropwise to a solution of morpholine (3.13 mL, 36 mmol) and triethylamine (6.25 mL, 45 mmol) in anhydrous THF (200 mL), and the reaction was stirred for 3.5 hours. Water (100 mL) was added, and the resulting solution was extracted with ethyl acetate (250 mL+150 mL). The combined extracts were washed with aqueous hydrogen chloride (100 mL of 1 N), water (60 mL), and brine (100 mL); dried over magnesium sulfate; filtered; concentrated under reduced pressure; and further dried under high vacuum to provide 6.60 g of 4-(5-bromopentanoyl)morpholine as a yellow oil.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:46])[NH:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:47])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:49][N:50]1[CH2:55][CH2:54][N:53]([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:52][CH2:51]1>CN(C)C=O>[F:47][C:28]1[CH:27]=[C:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:59]3[CH2:58][CH2:57][CH:56]([N:53]4[CH2:52][CH2:51][N:50]([CH3:49])[CH2:55][CH2:54]4)[CH2:61][CH2:60]3)=[O:7])[CH:24]=2)[CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38]([NH:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:46])[CH2:37][CH2:36]1)=[O:34]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Reaction time: 5 h
Yield: 29.7 %

Procedure:
To a solution of [4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methyl-4-(piperidin-4-yl)piperazine (114 mg) at room temperature, followed by stirring for 5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (28.3 mg, 30%).