Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]([C:13]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[C:14]([F:17])([F:16])[F:15])=[C:8](F)OCC>C(O)C>[Cl:6][CH:7]([C:13]([O:18][CH2:19][CH3:20])([O:21][CH2:22][CH3:23])[C:14]([F:15])([F:16])[F:17])[CH2:8][C:13]([O:18][CH2:19][CH3:20])=[O:21]
Reactant: CCOC(F)=C(Cl)C(OCC)(OCC)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)CC(Cl)C(OCC)(OCC)C(F)(F)F
Yield: 151.8 %

Procedure:
100 ml of 50% strength sulfuric acid were added to 100 g of 2-chloro-I,4,4,4-tetrafluoro-1,3,3-triethoxy-but-1-ene in 200 ml of ethanol and the mixture was stirred under reflux for 3 hours. It was poured onto water and extracted with methylene chloride. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo. The residue was distilled in vacuo. 79 g of ethyl 2-chloro-4,4,4-trifluoro-3,3-diethoxybutanecarboxylate of boiling point 48° C. under 0.2 mbar were isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[Br:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:26][CH2:25][CH2:24][Br:23])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCBr

Procedure:
A mixture of 7.6 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 25 ml 1,3-dibromopropane and 2.0 g of anhydrous potassium carbonate in 200 ml of anhydrous acetone was stirred at reflux. Additional 2.0 g portions of potassium carbonate were added at 3, 7, 21, 47 and 55 hours. After a total reflux time of 78 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield 4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]butanoic acid ethyl ester as a slightly impure oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C

Procedure:
A solution of 2,4-dicloro-5-nitropyrimidine (930 mg) in DCM (40 mL) was treated with DIEA (0.9 mL) and trans-4-aminocyclohexanol (345 mg) at −78° C. for 6 hours. The mixture was allowed to slowly warm to room temperature and stirred for 12 more hours. The solvent was evaporated and the crude mixture was purified by silica gel chromatography (DCM:EtOAc 70:30) to provide 630 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>CC(N(C)C)=O>[N:64]1([C:20]([C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:23]=[CH:24][C:9]([NH:8][C:6]4[CH:5]=[C:4]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:10][CH:11]=3)[CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1
Reactant: C1COCCN1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)N4CCOCC4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy} pyridine-2-carboxylic acid (Example 20, 0.15 g, 0.38 mmol) in dry DMA (3 mL) was added HATU (0.14 g, 0.38 mmol) and DIEA (0.15 g, 1.13 mmol). The solution was stirred at rt for 0.5 h, followed by addition of morpholine (0.16 g, 1.88 mmol). The resulting solution was stirred at rt overnight, followed by prep-HPLC separation to give 77 mg (35%) pure product. 1H NMR (DMSO-d6) δ 10.79 (s, 1H), 8.40 (s, 1H), 7.85 (m, 2H), 7.74 (m, 2H), 7.60 (m, 3H), 7.21 (m, 2H), 7.00 (m, 2H), 6.59 (s, 1H), 3.49 (m, 8H); MS ES 469 (M+H)+, calcd 469.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=N/S(C2SC=CC=2)(=O)=O)/[CH:3]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([NH2:35])(=[O:34])=[O:33]>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:35][S:32]([C:23]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)(=[O:34])=[O:33])[CH:3]=1
Reactant: NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1C(Cl)=CC(=NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc21

Procedure:
5.2.35 N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)naphthalene-2-sulfonamide (12f) was prepared according to the procedure for (12a) except using naphthalene-2-sulfonamide, TiCl4.2THF and THF as solvent which afforded the title compound 594.8 mg (77.9%) as a yellow solid, m.p.: 200-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14]C(=O)C2C3C(=CC=CC=3)CCN2)[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]([N:34]1[CH:38]=[CH:37]N=[CH:35]1)(N1C=CN=C1)=[O:28].[BH4-].[Na+]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:27]([N:34]2[CH2:35][CH2:5][C:6]3[C:37](=[CH:4][CH:3]=[CH:2][CH:7]=3)[CH2:38]2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)C1NCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 183.7 %

Procedure:
Beta-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-delta-oxo-isoquinolinepentanoic acid, (14 g) in EtOAc (300 mL) was treated with carbonyldiimidazole (7.25 g) and N,N-dimethylaminopyridine (440 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (6.7 g) in H2O (150 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (500 mL) and washed with 1N HCl (1×200 mL), sat. NaHCO3 (1×200 mL) and water (1×200 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (12.4 g). Mass spectrum (CI): 378.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26]([OH:28])=O)([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:25])([CH3:24])[C:26]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[O:28])[CH:17]=1)[C:10]([CH3:29])([CH3:30])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N3CCN(C)CC3)c1)N2
Yield: 90.8 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), 1-methyl-piperazine (0.67 mL, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (10 mL) and triethyl-amine (1.7 mL, 12 mmol) was stirred at 25° C. for 24 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-{3-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethylamino]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.895 g, 91%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C29H40N4O3 (M+H)+: 493.67, observed: 493.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.125 g, 0.49 mmol) and anhydrous pyridine (40 mL) was warmed with a heat gun to dissolve the solid. The resulting solution was allowed to cool to ambient temperature. A solution of 2-phenoxybenzoyl chloride (0.11 g, 0.47 mmol) in pyridine (5 mL) was added. The reaction mixture was maintained at ambient temperature for 18 hours and then concentrated under vacuum. The resulting solid residue was purified by flash chromatography (silica gel eluting with 9:1 dichloromethane:methanol) to provide 0.12 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxybenzamide as a white solid, m.p. 93-94° C. 1H NMR (500 MHz, DMSO-d6) δ 8.23 (t, J=6.0 Hz, 1H), 8.14 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.54 (dd, J=8.0, 1.5 Hz, 1H), 7.43 (dt, J=8.0, 1.5 Hz, 1H), 7.42 (dt, J=8.0, 1.5 Hz, 1H), 7.30 (t, J=8.0 Hz, 2H), 7.22 (t, J=8.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.07 (t, J=8.0 Hz, 1H), 6.89 (m, 3H), 6.59 (broad s, 2H), 4.55 (t, J=7.0 Hz, 2H), 3.23 (q, J=6.0 Hz, 2H), 1.81 (quintet, J=7.0 Hz, 2H), 1.47 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 451.2004 (451.2008 calcd for C27H25N5O2)
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C:24]([CH:26]3[CH2:30][CH2:29][CH2:28][N:27]3C(OC(C)(C)C)=O)=[O:25])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:38])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.Cl>C(OCC)(=O)C>[O:39]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C:24](=[O:25])[C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:38])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C3CCCN3C(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)[C@@H]3CCCN3)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbamoyl}pyrrolidine-1-carboxylate (250 mg, 0.44 mmol) in ethyl acetate (5 mL) was added a solution of hydrochloride in ethyl acetate (4 N, 20 mL) dropwise in an ice-water bath. After being stirred at room temperature for 14 hours, the reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC to give 104.8 mg of the desired product (yield was 48%). MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1 H), 7.88-7.84 (m, 2 H), 7.63-7.59 (m, 1 H), 7.54 (s, 1 H) 7.49-7.44 (m, 2 H), 7.39-7.37 (m, 2 H), 7.00 (s, 1 H), 5.04 (s, 2 H), 4.40 (s, 2 H), 4.16-4.12 (t, J=5.2 Hz, 1 H), 3.64 (s, 2 H) 3.15-3.01 (m, 3 H), 2.39 (s, 3 H), 2.23-2.20 (m, 1 H), 1.95-1.90 (m, 1 H), 1.80-1.75 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.CCOC(C)=O>C(#N)C>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([O:11][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:3][C:2]=1[NH2:1])([O-:10])=[O:9]
Reactant: Nc1cc(O)ccc1[N+](=O)[O-]
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1cc(OCc2ccc3ccccc3n2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-4-nitrophenol (5.0 g, 32 mmol) in acetonitrile (162 mL) was added 4N NaOH (16.2 mL, 4 N) followed by 2-(chloromethyl)quinoline hydrochloride (7.6 g, 34 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction was then heated to 80° C. for 4 h. The reaction mixture was cooled to RT and concentrated to dryness. Water was added to the residue to give a dark orange solid that was isolated by filtration. Trituration using EtOAc then afforded the title compound. MS (ESI): mass calcd. for C16H13N3O3, 295.10; m/z found, 296.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J=8.5, 1H), 8.02 (dd, J=10.0, 9.2, 2H), 7.83-7.75 (m, 1H), 7.68 (d, J=8.5, 1H), 7.66-7.60 (m, 1H), 7.55 (d, J=3.0, 1H), 7.32 (dd, J=9.2, 3.0, 1H), 7.28 (s, 2H), 7.03 (d, J=9.3, 1H), 5.34 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][N:7]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH3:2]>N1CCCCC1.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][N:7]([C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCN
Reaction time: 1 h

Procedure:
3-{Ethoxycarbonylmethyl-[6-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-amino}-propionic acid ethyl ester AB (11.5 g, 21.3 mmol) was dissolved in 20% piperidine in dimethylformamide at 0° C. The solution was continued stirring for 1 h. The reaction mixture was concentrated under vacuum, water was added to the residue, and the product was extracted with ethyl acetate. The crude product was purified by conversion into its hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].Br[CH:12]([CH2:17][CH2:18][Br:19])[C:13](OC)=[O:14]>CN(C)C=O>[Br:19][CH2:18][CH2:17][CH:12]1[C:13](=[O:14])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[S:10]1
Reactant: COc1ccc(N)c(S)c1
Reactant: COC(=O)C(Br)CCBr
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)SC(CCBr)C(=O)N2
Temperature: 0 °C
Yield: 65.3 %

Procedure:
A solution of 3.10 g of 2-amino-5-methoxythiophenol and 5.20 g of methyl 2,4-dibromobutyrate in 30 ml of dimethylformamide was stirred at room temperature for 2 hours. The mixture was poured into ice-water and the resulting crystals were collected by filtration and washed with water. Recrystallization from methanol gave 3.94 g (65.2%) of 2-(2-bromoethyl)-7-methoxy-2H-1,4-benzothiazin-3(4H)-one as prisms, m.p. 142°-143° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([N:3]1[C:4]([CH3:17])([CH3:16])[CH2:5][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:7][C:2]1([CH3:18])[CH3:1])[CH:26]=[CH2:25]
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(C)(C)CC(N2CCCCCC2=O)CC1(C)C
Temperature: 80 °C

Procedure:
Following the general procedure of Example 3, 12.1 g (0.05 mole) of the compound prepared in Example 1 is dissolved in 75 ml of N,N-dimethylformamide containing a suspension of 10.6 g (0.1 mole) of sodium carbonate. To this mixture is then added 14.6 g (0.05 mole) of allyl bromide and the reaction mixture is then heated at 80° C. for two hours. The solvent is then removed in vacuo and the residue is vacuum distilled at 171°-176° C./0.7 mm to give 7.6 g of the above named product.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=[CH2:2].CC(C)([O-])C.[K+].[CH:24]([Br:27])(Br)[Br:25]>>[Br:25][C:24]1([Br:27])[CH2:2][CH:1]1[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: BrC(Br)Br
Reactant: C=Cc1ccc(OC(C)(C)C(=O)OCC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)Oc1ccc(C2CC2(Br)Br)cc1

Procedure:
Ethyl 2-[p-(2,2-dibromocyclopropyl)phenoxy]-2-methylpropionate was prepared from 23.4 g. of ethyl 2-(p-vinylphenoxy)-2-methylpropionate, 39.2 g. of potassium t-butoxide and 198 g. of bromoform according to the procedure described above in Example 1, part (b). The product was isolated and hydrolyzed without further purification.
Reaction SMILES: [OH2:1].CN(N=[C:6]([CH3:20])[CH2:7][CH2:8][C:9]1[S:13][C:12]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[N:11][CH:10]=1)C>O1CCCC1>[O:1]=[C:6]([CH3:20])[CH2:7][CH2:8][C:9]1[S:13][C:12]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[N:11][CH:10]=1
Reactant: O
Reactant: CCCC(=O)Nc1ncc(CCC(C)=NN(C)C)s1
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ncc(CCC(C)=O)s1
Yield: 95 %

Procedure:
To a stirred solution of 200 mg (1 mmol) of cupric acetate in 10 ml of water 141 mg (0.5 mmol) of N-[5-(3-dimethylaminoimino-butyl)-1,3-thiazol-2-yl]-butanamide in 10 ml of tetrahydrofuran were added. After 2 hours the solvent was removed under reduced pressure, a mixture of aqueous ammonium chloride and ammonium hydroxide was added and the product extracted with methylene chloride to give after drying and concentration 114 mg (95% yield) of the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:23]4[C:18](=[C:19](Br)[CH:20]=[C:21]([O:35][CH3:36])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1(C2C=CC([NH-])=CC=2)CCOCC1.[CH3:51][N:52]1[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:23]4[C:18](=[C:19]([N:55]5[CH2:56][CH2:57][CH2:58][N:52]([CH3:51])[CH2:53][CH2:54]5)[CH:20]=[C:21]([O:35][CH3:36])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(OCOCC[Si](C)(C)C)c2c1
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [NH-]c1ccc(N2CCOCC2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCCN(C)CC2)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(OCOCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a yellow-green suspension of 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid (Reference Example 27c) (4-morpholin-4-yl-phenyl)-amide (1.155 g, 1.96 mmol), N-methyl homopiperazine (0.39 mL, 3.14 mmol), and 4 Å sieves in 30 mL anhydrous toluene was added Pd2(dba)2 (90.0 mg, 0.098 mmol) and BINAP (0.358 g, 0.58 mmol). The resulting reddish brown mixture became lighter in color upon treatment with cesium carbonate (2.544 g, 7.81 mmol). The reaction mixture was heated at reflux under nitrogen for 17 hours. The clear brown solution was cooled to room temperature, concentrated, and then purified by flash chromatography on silica gel using a slow gradient of 95:5 to 50:50 methylene chloride:methanol to afford the desired product (0.989 g, 81%). 1H NMR (300 MHz, DMSO, d6) δ 9.88 (s, 1H, NH), 7.73 (s, 1H, ArH3), 7.68 (d, 2H, Jo=8.9 Hz, ArH2′ & H6′), 7.00 (d, 2H, Jo=8.9 Hz, ArH3′ & H5′), 6.94 (d, 1H, Jm=2.7 Hz, ArH5), 6.66 (d, 1H, Jm=2.7 Hz, ArH7), 5.62 (s, 2H, OCH2O), 3.87 (s, 3H, OCH3), 3.80 (t, 2H, J=8.0 Hz, OCH2CH2Si), 3.73 (t, 4H, J=4.7 Hz, OCH2CH2N), 3.63 (t, 2H, J=5.9 Hz, ArNCH2CH2CH2NCH3), 3.33 (bs, 2H, ArNCH2CH2NCH3), 3.09 (t, 4H, J=4.7 Hz, OCH2CH2N), 2.97 (bs, 2H, ArNCH2CH2NCH3), 2.69 (bs, 2H, ArNCH2CH2CH2CH3), 2.35 (s, 3H, NCH3), 2.09 (bs, 2H, ArNCH2CH2CH2NCH3), 0.94 (t, 2H, J=8.0 Hz, OCH2CH2Si), −0.03 (s, 9H, Si(CH3)3; Mass Spec.: calc. for [C33H47N5O5Si+H]+ Theor. m/z=622; Obs.=622.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:16]I>>[CH3:16][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Reactant: CI
Product: CC(C)[C@@H](C(=O)O)N(C)c1ccc(Cl)cc1

Procedure:
The α-cyano-m-phenoxybenzyl ester of N-(4-chlorophenyl)valine is reacted with methyl iodide using the procedure of Example 2 to yield the α-cyano-m-phenoxybenzyl ester of N-methyl,N-(4-chlorophenyl)valine, MS m/e 448.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].C([Si](C)(C)[O:18][CH2:19][CH2:20][O:21][C:22]1[C:29]([CH3:30])=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[CH3:31])(C)(C)C.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C)C(=O)C.O.C1COCC1.CO>[OH:18][CH2:19][CH2:20][O:21][C:22]1[C:29]([CH3:30])=[CH:28][C:25]([C:26]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=3[CH3:12])[N:1]=2)=[CH:24][C:23]=1[CH3:31]
Reactant: Cc1cc(C)c(C(N)=O)c(N)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Temperature: 155 °C
Reaction time: 14 h
Yield: 23.7 %

Procedure:
A mixture of 2-amino-4,6-dimethylbenzamide (0.2 g, 1.22 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.376 g, 1.22 mmol), sodium hydrogensulfite (0.22 g, 1.22 mmol) and p-toluenesulfonic acid (0.116 g, 0.61 mmol) in N,N-dimethyl acetamide (10 mL) was stirred at 155° C. for 14 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The solid crashed out and was collected by filtration to afford impure product. The solid was re-dissolved in THF (30 mL) and mixed with TBAF in THF (5 mL, 5 mmol). The reaction mixture was stirred at room temperature for 14 h and concentrated using a rotary evaporator to afford an oily residue. Further purification by column (SiO2, EtOAc/DCM/MeOH=12:4:1) yielded an off-white solid. This solid was diluted with MeOH (10 mL) to make a slurry. The solid was collected by filtration and washed with MeOH to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one (98 mg, 24%) as a white solid. Selected data: MS (ES) m/z: 339.10; MP 259.6-261.2° C.