Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:14])[C:6]1=[O:15].[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:14][N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][C:26]3([N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][NH:24][C:25]3=[O:32])[CH2:31][CH2:30]2)[C:6]1=[O:15]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Cn1c(=O)n(CCCI)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCN2CCC3(CC2)C(=O)NCN3c2ccccc2)c2ccccc21
Temperature: 70 °C

Procedure:
A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3,4 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 2.65 parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide is stirred and heated for 2 hours at 70° C. The reaction mixture is cooled and poured onto water, whereupon an oily precipitate is formed. The supernatant aqueous phase is decanted and the residual oil is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1 part of 8-[3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 164.4° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.COCCOC>C(#N)C>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:30])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Solvent: CC#N
Product: CC1(C)OC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (14.5 kg), Lawesson's Reagent (12.1 kg, 1.16 eq.), DME (215 kg), and acetonitrile (8.96 kg) were combined and heated to reflux for at least 4 hours at less than 16 hours to form unpurified 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile. The mixture was cooled to 18 to 28° C., quenched with water (276 kg), cooled to 10 to 20° C., stirred for at least 30 minutes, and the resulting slurry collected via filtration.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a solution of 5-bromopyridine-3-sulfonyl chloride (5 g, 17 mmol) in pyridine (10 mL) at 0° C. was added tert-butylamine (3.6 mL, 2 equiv., 34 mmol). The reaction mixture was allowed to warm to room temperature and then heated to 40° C. for 14 h. After this time the crude reaction mixture was again cooled to 0° C. and diluted with dilute HCl (0.05M, 40 mL). The reaction was stirred at 0° C. for 30 min and the resulting precipitate collected by filtration. The solid was washed with water and dried to afford the title compound as a yellow solid (2.12 g, 7.3 mmol, 42%). No further purification was required.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30](Cl)=[O:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>C1C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30]([N:1]2[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]2[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[O:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)N2C(=O)CC[C@H]2C(=O)OCc2ccccc2)cc1OC
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A solution of 17.5 g (80 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), in 150 ml of benzene is added over 1 hour to a suspension of 3.85 g (80 mmol) of sodium hydride in 15 ml of dry benzene. After stirring for 1 hour at ordinary temperature, a solution of 17.2 g (80 mmol) of 3,4-dimethoxyphenylacetyl chloride in 150 ml of benzene is run in. The mixture is heated at 55° C. for 6 hours and stirred at ordinary temperature for 15 hours, washed with 2×120 ml of water, dried and evaporated. The residue was purified by chromatography on a silica column using a chloroform/acetone mixture as the eluent. Thus gives 60% of a pure waxy product of Rf=0.46 (A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([Cl:13])[CH:9]=[CH:8]2.[Br:14]Br.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>CO>[Br:14][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11]2
Reactant: BrBr
Reactant: COc1cccc2ccc(Cl)nc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c2ccc(Cl)nc12
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of 8-methoxy-2-(chloro)quinoline CAS [74668-74-9] (1.0 g, 4.4 mmol) in MeOH (6.25 mL) was treated with a 1.5 N solution of bromine in MeOH (3.53 mL, 5.3 mmol) over 15 min period. The reaction mixture was stirred 2 h, treated with a 1 N aqueous Na2S2O3 solution (20 mL) followed by EtOAc (100 mL). The organic portion was washed with brine followed by a saturated aqueous solution of NaHCO3 followed by brine. The organic phase was dried over Na2SO4, filtered, evaporated, and purified by silica gel chromatography eluting with CH2Cl2 to afford titled compound as a colorless solid (49%). 1H NMR (CDCl3) 8.44 (dd, J=8.8, 1.2, 1H), 7.73 (dd, J=8.4, 1.2, 1H), 7.51 (dd, J=8.8, 1.2, 1 H), 6.97 (d, J=8.4, 1H), 4.06 (s, 3H). LC/MS 3.45 min, [M+1]+ 271/273.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath and pentanoyl chloride (301 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(3-phenylpyrrolidin-1-yl)pentan-1-one are collected and the solvent is removed in vacuo to give 378 mg of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)ncc1Cl

Procedure:
2-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-ethyl-3-fluoro-benzamide was prepared from 7-amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 308c. Product isolated as a white solid (96 mg, 68%). m.p.=251-253° C.; LCMS (m/e) 511 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.77 (s, 1H), 8.11 (s, 1H), 7.63 (d, 1H, J=8.6 Hz), 7.41-7.34 (m, 1H), 7.33-7.26 (m, 2H), 7.16 (s, 1H), 6.99 (d, 1H, J=8.6 Hz), 6.93 (s, 1H), 6.14-6.06 (m, 1H), 3.48-3.39 (m, 2H), 3.27 (s, 3H), 2.32-2.24 (m, 2H), 2.05-1.95 (m, 2H), 1.26 (s, 6H), 1.18 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 23.05 g of 3-methyl-4'-chlorobenzophenone, 70 cc of carbon tetrachloride, 16.02 g of N-bromosuccinimide and 90 mg benzoyl peroxide was refluxed for 4 hours and then was added to 100 cc of carbon tetrachloride. The mixture was filtered hot and the filter was washed with 100 cc of boiling carbon tetrachloride. 200 cc of the solvent were distilled off under reduced pressure and the mixture was cooled and iced for 1 hour. The mixture was vacuum filtered and the recovered crystals were empasted with iced carbon tetrachloride and dried under reduced pressure. The residue was crystallized from ethanol to obtain 17.5 g of 3-bromomethyl-4'-chlorobenzophenone melting at 138°-139° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[C:18]1(C)C=CC=C[CH:19]=1>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>[CH:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)=[CH2:19]
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: Cc1ccccc1
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+]
Product: C=Cc1ccc2c(c1)CCC2=O
Temperature: 25 °C
Yield: 48 %

Procedure:
To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7 mmol) in toluene were added vinylboronic anhydride pyridine complex (8.55 g, 35.54 mmol), Pd(PPh3)4 (0.1 g, 0.094 mmol), K2CO3 (22.88 g, 165.83 mmol). The resultant reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H2O and brine. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) afforded the title compound as a solid (1.8 g, 48%): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=7.2 Hz, 1H), 7.49 (br s, 1H), 7.44 (d, J=7.2 Hz, 1H), 6.82 (m, 1H), 5.90 (d, J=7.4 Hz, 1H), 5.42 (d, J=6.4 Hz, 1H), 3.20 (m, 2H), 2.70 (m, 2H); ESIMS m/z 159.06 ([M+H]−).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:18])[CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:8][CH2:7]2.[Br:19]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:5]1[C:4](=[O:18])[NH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:10]2
Reactant: BrBr
Reactant: Cc1[nH]c(=O)cc2c1CC(c1ccncc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(=O)c(Br)c2c1CC(c1ccncc1)CC2
Yield: 39.5 %

Procedure:
2,3,5,6,7,8-Hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline (0.4 g) obtained in Example 1 was dissolved in 6 ml of acetic acid, and a solution of 0.27 g of bromine and 1.3 ml of acetic acid was dropwise added at 45° C. After the reaction was completed, the reaction mixture was poured into water and an aqueous solution of sodium hydroxide was added to adjust the pH to 9-10. The deposit was filtered out and recrystallized from methanol. Thus, there was obtained 0.21 g of 4-bromo-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.O[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: Oc1ncccn1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCOc2ncccn2)cc1)c1ccccc1
Yield: 24 %

Procedure:
The title compound was prepared in 24% yield as light yellow crystals using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyrimidine. NMR (400 MHz; CDCl3): δ 3.11 (t, 2H), 3.42 (br s, 3H), 4.54 (t, 2H), 6.93 (t, 1H), 7.05 (d, 2H), 7.25–7.42 (m, 7H), 8.51 (d, 2H); HPLC-MS: m/z=350.2 (M+1); Rt=2.86 min.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:22])=[CH:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([Br:1])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:22])=[CH:16]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cc2cccc(OCc3ccccc3)c2[nH]c1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2c(Br)ccc(OCc3ccccc3)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of bromine (0.57 g) in acetic acid (2 mL) is added dropwise to a solution of 8-benzyloxy-3-methyl-1H-quinolin-2-one (0.94 g) and sodium acetate (0.96 g) in acetic acid (12 mL) at room temperature. The reaction mixture is stirred at room temperature for 3 hours, evaporated, the residue partitioned between water (5 mL) and ethyl acetate (5 mL), extracting a further 2× with ethyl acetate (5 mL). Combined organic extracts are dried over magnesium sulphate and purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19](O)=[O:20].Cl.[CH3:23][O:24][C:25]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:25]=2[O:24][CH3:23])[CH2:30]1)=[O:20]
Reactant: COc1cc2c(c(OC)c1)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccc(F)cc13)C2
Yield: 42.3 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 100 (42.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.76 and 3.00 (2t, 2H), 3.48 (s, 1H), 3.52 and 4.04 (2t, 2H), 3.74-3.75 (2s, 3H), 3.87 (s, 2H), 4.32 and 4.78 (2s, 2H), 6.36-6.50 (m, 2H), 7.42-7.48 (m, 1H), 7.64-7.81 (2m, 2H), 8.03-8.39 (m, 4H); MS (ESI) m/z 462 ([M+H]+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@@:10]1([F:26])[C@@H:12]2[CH2:13][C@@H:14]3[C@:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C@H:11]12)OS(=O)(=O)[O:15]3)=[O:9])[CH3:6]>CN(C)C=O.O>[CH2:22]([O:21][C:19]([C@:18]1([N:1]=[N+:2]=[N-:3])[C@H:14]([OH:15])[CH2:13][C@@H:12]2[C@H:11]1[C@@:10]2([F:26])[C:8]([O:7][CH2:5][CH3:6])=[O:9])=[O:20])[CH3:23]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H]3OS(=O)(=O)O[C@@]3(C(=O)OCC)[C@@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 34 h
Yield: 91.2 %

Procedure:
37.7 g of sodium azide was added to 109 g of (1R,1aR,1bS,4aR,5aR)-1-fluoro-3,3-dioxotetrahydro-2,4-dioxa-3λ6-thiacyclopropa[a]pentalene-1,1b-dicarboxylic acid diethyl ester dissolved in 1.10 L of N,N-dimethylformamide and 110 mL of water, and the mixture was stirred for 14 hours at 50° C. The solvent was distilled off under reduced pressure, and after the residue was dissolved in 6.48 L of diethyl ether and 177 mL of water, 516 mL of 20% (V/V) sulfuric acid was added thereto, and the mixture was stirred for 34 hours at room temperature. After the reaction solution was separated, the organic layers were twice washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=4:1), thereby yielding 88.5 g of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:23]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:24]([C:28](ON1C(=O)CCC1=O)=[O:29])[CH:25]([CH3:27])[CH3:26].CCN(CC)CC>CN(C=O)C>[NH:23]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C@H:24]([C:28]([NH:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:29])[CH:25]([CH3:26])[CH3:27]
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1

Procedure:
H-Thr(Bzl)-OBzl hemioxalate (58 g, 168.4 mmol) was suspended in DMF (700 ml) and stirred with Boc-Val-OSu (48 g, 153.1 mmol) and Et3N (16 ml) at 0° C for 1 hr, 4° C for 72 hrs and 25° C for 24 hrs. It was necessary during this time to add at intervals additional Et3N in order to maintain the pH between 7 and 8. The reaction mixture was worked up as in Example 2 to yield an oil which crystallized from EtOAc with petroleum ether, yield 40.8 g (53.5%); mp 99°-100.5° C; [α]D25 -26.0° (c 1, MeOH). Anal. Calcd for C28H38N2O6 (498.62): C, 67.45; H, 7.68; N, 5.62. Found: C, 67.57; H, 7.55; N, 5.70.
Reaction SMILES: O[C:2]1([CH3:28])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:5]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([NH:26][CH3:27])[CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:28][C:2]1[CH2:3][C:4]([NH:26][CH3:27])=[C:5]([C:22]([O:24][CH3:25])=[O:23])[CH:6]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CNC1=C(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)C(C)(O)C1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CNC1=C(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)=C(C)C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Dimethyl 6-methyl-4-methylamino-2-(4-trifluommethyl-phenyl)cyclohexa-3,5-diene-1,3-dicarboxylate (3) ##STR8## 10.0 g (25 mmol) of dimethyl 6-hydroxy-6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohex-3-ene-1,3-dicarboxylate (preparation analogous to Example II) are heated to 60° C. in 100 ml of pyridine and treated with 2.5 ml of thionyl chloride. The mixture is stirred at 60° C. for 10 minutes and concentrated, and the residue is taken up in methylene chloride, washed three times with water, dried and concentrated. The residue is grossly purified on 200 g of silica gel (petroleum ether/AcOEt=3:1) and then separated by MPLC (methylene chloride/AcOEt=30:1). Two fractions are obtained. 224 mg (2.3%) of dimethyl 4-methyl-6-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,6-diene-1,3-dicarboxylate (non-polar isomer (2)) crystallize from ether/petroleum ether. From the 2nd fraction, 2.29 g (22%) of the polar isomer, dimethyl 6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,5-diene-1,3-dicarboxylate (3) are precipitated from AcOEt as the hydrochloride (Rf =0.47 (c)).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(\COc1ccc(COc2ccc(C=O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
To a stirring solution of (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (10 g, 37 mmol) and 4-hydroxybenzaldehyde (4.5 g, 37 mmol) in THF (100 mL) was added triphenylphosphine (12.2 g, 46.5 mmol) and Diisopropyl azodicarboxylate (11.2 g, 55 mmol) at 0° C., then stirred at RT for 12 h. RM diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to pale brown oil. Crude was purified by column (100-200 silica) using 8% ethyl acetate to get the titled compound as white solid (5 g, Yield: 36.2%). 1H NMR (300 MHz, CDCl3): δ 9.81 (s, 1H), 7.74-7.77 (d, 2H), 7.58-7.61 (m, 2H), 7.24-7.29 (m, 5H), 6.97-6.99 (d, 2H), 6.85-6.87 (d, 2H), 5.13 (s, 2H), 4.98 (s, 2H), 3.98 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol), 1-(2-bromo-ethoxy)-2-methoxy-ethane (566 mg, 3.09 mmol) and Cs2CO3 (840 mg, 2.58 mmol) in DMF (5 mL) was stirred at 95° C. for 18 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound as an oil. (MH+=297.1, 1H-NMR in CDCl3: 7.77 (m, 1 or 2H) 4.31 (t, 2H); 3.85 (t, 2H); 3.54 (m, 2H); 3.48 (m, 2H); 3.35 (s, 3H); 1.31 (s, 12H)).