Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([F:16])[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:17][CH3:18])=[CH:9][CH:10]=3)[C@@:5]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:4]=2[CH:3]=1.C([Li])CCC.N#N.[O:31]1[CH2:34][C:33](=[O:35])[CH2:32]1>C1COCC1>[NH2:23][C:20]1[O:21][CH2:22][C@:5]2([N:19]=1)[C:6]1[CH:7]=[C:8]([O:17][CH3:18])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:4]2=[CH:3][C:2]([C:33]2([OH:35])[CH2:34][O:31][CH2:32]2)=[CH:15][C:14]=1[F:16]
Reactant: O=C1COC1
Reactant: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(Br)cc(F)c1O2
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(C3(O)COC3)cc(F)c1O2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a RBF was added (S)-2′-bromo-4′-fluoro-7′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine (2.17 g, 5.72 mmol, prepared as described in Method BB40 but using 4-bromo-2-fluorophenol and 2-bromo-5-methoxybenzoic acid) and THF (30 mL). The resulting mixture was then cooled to −78° C. and butyllithium solution, 2.5M in hexanes (8.01 mL, 20.03 mmol, Aldrich) was added drop wise under N2. The resulting mixture was then stirred at −78° C. for 15 min. Then, oxetan-3-one (1.031 g, 14.31 mmol, Molbridge LLC) in THF (3 mL) was added slowly. After addition, the mixture was stirred at −78° C. for 1.5 h under N2. Then, the mixture was quenched with saturated sodium bicarbonate solution (5 mL) at 0° C. and the mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was then dissolved in MeOH (30 mL) and silica gel was added. The solvent was removed and the solid mixture was purified by silica gel flash column chromatography using ISCO instrument (solid loading, 50%-100% EtOAc/hexane, then 10% MeOH in DCM) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 373 (M+H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[CH:22]=[N:21][N:20]=[C:19]2[CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])=[O:9].[Br:37]N1C(=O)CCC1=O>>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:19]([CH2:23][N:24]3[C:28](=[O:29])[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4[C:25]3=[O:34])=[N:20][N:21]=[C:22]2[Br:37])=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])=[O:9]
Reactant: O=C(c1ccccc1Br)c1cc(C(F)(F)F)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Product: O=C(c1ccccc1Br)c1cc(C(F)(F)F)ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 1, 5-trifluoromethyl-2-[3-phthalimidomethyl-4H-1,2,4-triazol-4-yl]-2'-bromobenzophenone is reacted with N-bromosuccinimide to form 5-trifluoromethyl-2-[3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]-2'-bromobenzophenone.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=O)C.[CH3:26][NH2:27]>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:7]2[CH2:6][C:4](=[O:3])[N:27]([CH3:26])[CH2:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CN
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)C1CN(C)C(=O)CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
A title compound was prepared by the same method as in Example 4, except that it was prepared from the compound of Example 3 and methylamine, and recrystallized with ethylacetate/hexane to obtain a white solid (yield 73%)
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[CH:28]([NH:31][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])([CH3:30])[CH3:29]
Reactant: CC(C)N
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC(C)C)c(=O)n12
Reaction time: 0.08 h

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mole) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -16° C. during 30 minutes. After stirring for 5 minutes, 5.2 g (0.088 mol) of isopropylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 40 minutes, then the mixture is stirred for 1 hour at the same temperature and thereafter maintained under cooling by ice.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][N:22]4[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][N:22]4[CH2:25][C:26]([OH:28])=[O:27])=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]=12
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(N3CCn4c(c(Cl)c5ccccc54)C3=O)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1ccc2ccc(N3CCn4c(c(Cl)c5ccccc54)C3=O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
tert-Butyl 2-(6-(10-chloro-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indol-1-yl)acetate (2.22 mmol, 1.0 equiv.) was dissolved in DCM (15 ml); TFA (3 ml) was added, and the mixture was stirred for 2 h at 25° C. The solvent was concentrated under reduced pressure, and the residue was taken up in DCM (60 ml), washed with water (25 ml) and sat. NaCl solution (25 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. Yield: 91%
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:35])[NH:15][CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH:9]1C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:20]1([CH2:19][CH2:18][CH2:17][CH:16]([NH:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[O:35])[CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1CC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
4-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-methylpiperidine-1-carboxylic acid tert-butyl ester (56) (1.62 g; 3.29 mmol) is dissolved in methylene chloride (50 mL) at ambient temperature. Trifluoroacetic acid (50 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (30 mL) and water (200 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (200 mL) then extracted with methylene chloride (3×100 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.23 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH3:8])[C:3]=1[C:13]#[N:14].[CH3:15][N:16]=[C:17]=[O:18].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>O1CCCC1>[CH3:15][NH:16][C:17]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH3:8])[C:3]=1[C:13]#[N:14])=[O:18]
Reactant: CN=C=O
Reactant: CCCCN(C)c1nsc(N)c1C#N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CCCCN(C)c1nsc(NC(=O)NC)c1C#N
Yield: 46.1 %

Procedure:
In the manner of Example XI, part D, 7 g of 5-amino-3-(butylmethylamino)-4-cyanoisothiazole, 4.1 ml (4 g) of methyl isocyanate, and a catalytic amount of dibutyltin diacetate in 50 ml of tetrahydrofuran were allowed to react. The volatile materials were removed under reduced pressure and the residue was crystallized from 35 ml of 70:30 diethyl ether:hexane to yield solid material, mp 102° (decomposes). This material was recrystallized from 70 ml of 40:60 diethylether:hexane to yield 4.1 g of 1-methyl-3-(3-(butylmethylamino)-4-cyano-5-isothiazolyl)urea mp 169°-170°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[C:3]=1[F:12].Br[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=2)=[C:4]([F:11])[C:3]=1[F:12]
Reactant: OB(O)c1ccc(Br)c(F)c1F
Reactant: Nc1cnc(Br)cn1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cnc(-c2ccc(Br)c(F)c2F)cn1
Temperature: 80 °C
Yield: 33 %

Procedure:
A mixture of (4-bromo-2,3-difluorophenyl)boronic acid (400 mg, 1.69 mmol) and 5-bromopyrazin-2-amine (588 mg, 3.38 mmol was suspended in EtOH (5.6 ml) and toluene (5.7 mL) The resulting mixture was treated with aqueous Na2CO3 (2.0 N, 4.2 mL, 8.45 mmol). The resulting mixture was then sparged with nitrogen through the mixture for 10 min, and then Pd(PPh3)4 (98 mg, 0.085 mmol) was added. The reaction vessel was sealed and heated at 80° Celsius for 17 hours. The reaction mixture was cooled to rt and then partitioned between saturated aqueous NH4Cl and EtOAc. The organic layer was dried over MgSO4 and concentrated to dryness. The residue was suspended in DCM and the solid isolated by filtration to afford the title compound (160 mg, 33%), which was used without further purification. MS (ESI): mass calcd. for C10H6BrF2N3, 284.97; m/z found, 286.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.01 (d, J=1.2, 1H), 7.68-7.56 (m, 2H), 6.87 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:14])[C:4]([C:1](=[O:3])[CH3:2])=[CH:5]2)=[CH:24][CH:23]=1
Reactant: CC(=O)c1c[nH]c2ccccc2c1=O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cn(Cc2ccc(F)cc2)c2ccccc2c1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 22.4 %

Procedure:
A solution of 3-acetyl-4(1H)-quinolinone (1a) (0.8 g, 45 mmol) in dry DMF (40 mL) was treated with anhydrous K2CO3 (0.86 g, 62 mmol) and 4-fluorophenylmethylbromide (2.46 g, 13 mmol) and the resulting suspension was stirred for 1.5 hours at 100° C. After cooling, water was added (100 mL) and the precipitate that formed was filtered, washed with water, light petroleum ether in turn and then dried under IR lamp to provided compound 2a (0.86 g, 65%); mp 213-214° C. (toluene). Analogs 2b (R1═C1, R2═H) and 2c (R1═H, R2═Cl) were similarly prepared by this method. Compound 2b: 92% yield; mp 214-216° C. (toluene/cyclohexane); compound 2c: 73% yield; mp 185-187° C. (toluene/cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1.[C:21](OCC)(=[O:23])C.C(=O)(O)[O-].[Na+]>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:20][CH:21]=[O:23])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(C)=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC=O)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (600 mg, example 35) was dissolved in formic acid (2.4 ml) and kept for 15 min at reflux temperature. After standing over night an ice/water mixture was added followed by ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted 3 times with dichloromethane. The organic layers were combined, dried (magnesium sulphate), filtered and concentrated in vacuo to yield 588 mg of the title compound.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH2:4][F:5].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:19][C:14]2[C:15]([O:17][CH3:18])=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(C(CF)CF)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(C(CF)CF)CC2

Procedure:
2-{5-Chloro-2-[3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide was prepared from 3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (60 mg, 60%). LCMS (m/e) 581 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, 1H, J=8.3 Hz), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (d, 1H, J=8.0 Hz), 7.62-7.53 (m, 1H), 7.51 (s, 1H), 7.28-7.21 (m, 1H), 6.67 (s, 1H), 4.75-4.67 (m, 2H), 4.64-4.57 (m, 2H), 3.89 (s, 3H), 2.91-2.81 (m, 6H), 2.76 (s, 6H), 2.75-2.70 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([CH2:18][O:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)=O)[CH2:9][O:10]CC1C=CC=CC=1)([CH3:4])(C)C.Cl.C(O[CH2:37][CH3:38])(=O)C.C(O[CH2:43][CH3:44])(=O)C>>[CH:38]1[C:37]2[CH:4]([CH2:1][O:5][C:6]([N:7]3[C@@H:8]([CH2:9][OH:10])[CH2:18][O:19][CH2:20][C@H:21]3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=3)=[O:31])[C:43]3[C:44](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:24]=2[CH:23]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1ccc(F)c(F)c1)COCc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1[C@@H](CO)COC[C@H]1c1ccc(F)c(F)c1
Reaction time: 18 h

Procedure:
To a solution of {(S)-2-benzyloxy-1-[2-(3,4-difluorophenyl)-2-oxoethoxymethyl]ethyl}carbamic acid t-butyl ester (26.8 g) in ethyl acetate (50 mL) was added a 4 N hydrochloric acid/ethyl acetate solution (100 mL), and the resultant solution was stirred at room temperature for 2.5 hours. Solvent was removed by distillation under reduced pressure, and the resultant product was twice subjected to azeotropy with toluene. The resulting residue was diluted with a mixed solvent of ether/heptane (1/1, 300 mL) to form a solid. The supernatant was decanted off, and the residue solid was dried under reduced pressure. To a solution of the residue solid in methanol (200 ml) was added 10% palladium-carbon (9.1 g, 50% water content). Under a hydrogen atmosphere, this mixture was stirred for 18 hours. The catalyst was then filtered off, and the filtrate was concentrated by distillation under reduced pressure. The resulting product was then diluted with ethyl acetate and saturated sodium bicarbonate water. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure. The resultant residue was diluted with tetrahydrofuran (120 mL) and saturated sodium bicarbonate water (120 mL). To this solution was added 9-fluorenylmethyl chloroformate (16.6 g) while cooling with ice. The temperature of the solution was returned to room temperature, and the solution was then stirred for 14 hours. The reaction solution was diluted with ethyl acetate and water, and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was diluted with ethyl acetate (50 mL) and heptane (5 mL). The resultant solution was then left to stand for 4 days at 4° C. The precipitated solid was collected by filtering, to thereby obtain the titled compound (7.19 g). The filtrate was purified by silica gel column chromatography (hexane/ethyl acetate 4/1→1/1), and again solidified using ethyl acetate. The titled compound (3.69 g) was collected by filtering. The physical properties of the compound were as follows.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH:26]6[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]6)[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[NH:29]1[CH2:28][CH2:27][CH:26]([N:24]2[CH:25]=[C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)[CH:22]=[N:23]2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2ccc(Cn3nnc4ccc(-c5cnn(C6CCNCC6)c5)nc43)cc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.6 %

Procedure:
To a solution of example 156 (0.063 g, 0.123 mmol) in dichloromethane (1 ml) was cooled to 0° C., TFA (0.356 g, 2.47 mmol) was added and warmed to RT. After 12 h, the reaction mixture was poured in ice water and pH was adjusted to 10-11 with 10% NaOH solution and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as an off-white solid (0.021 g, 42%). M.P.: 188-191° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.55 (s, 1H), 8.51 (d, J=8.6 Hz, 1H), 8.38 (d, J=7.8 Hz, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 8.01 (m, 2H), 7.82 (m, 2H), 7.53 (q, J=4.2 Hz, 1H), 6.11 (s, 2H), 4.29 (m, 1H), 3.07 (m, 2H), 2.63 (m, 2H), 1.99 (m, 2H), 1.86 (m, 2H). MS (m/z): 411.28 (M++1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]1[CH:19]=[CH:18][C:11]([C:12](N(OC)C)=[O:13])=[CH:10][CH:9]=1>>[Br:7][C:8]1[CH:19]=[CH:18][C:11]([C:12]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Reactant: Brc1nccs1
Product: O=C(c1ccc(Br)cc1)c1nccs1
Yield: 98 %

Procedure:
The title compound was prepared from 2-bromothiazole and 4-bromo-N-methoxy-N-methylbenzamide following the general method of Method 1. The crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate, 7:3, as the eluent affording 0.52 g (98% yield) of the title compound as a yellow crystals: mp 74-75° C.; 1H NMR (400 MHz, CDCl3) δ 8.32 (m, 2 H), 8.02 (d, J=3.0 Hz, 1 H), 7.67 (d, J=3.0 Hz, 1 H), 7.60 (m, 2 H); 13C NMR (100.5 MHz, CDCl3) δ 183.4, 167.9, 145.3, 134.2, 133.0, 132.2, 129.6, 127.0; MS (TSP) m/z 268, 279 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=2)[C:5]([CH3:22])=[CH:4][C:3]=1[OH:23].CN.[I:26]I>CCO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:20])[CH3:21])[CH:10]=2)[C:5]([CH3:22])=[C:4]([I:26])[C:3]=1[OH:23]
Reactant: COCOc1ccc(Cc2cc(C)c(O)cc2C)cc1C(C)C
Reactant: II
Agent: CN
Solvent: CCO
Solvent: O
Product: COCOc1ccc(Cc2cc(C)c(O)c(I)c2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of 2,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol (intermediate for the synthesis of compound 7-17; 0.35 g, 1.11 mmol) in EtOH (5.0 mL) and CH3NH2 40% in water (2.5 mL) was added iodine (0.34 g, 1.33 mmol) and KI (0.27 g 1.66 mmol) in H2O (3 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h, quenched with brine (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:3) to afford 2,5-dimethyl-6-iodo-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol as a colorless oil (0.32 g, 64%): 1H NMR (300 MHz, CDCl3): δ 7.02 (d, J=2.4 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.88 (s, 1H), 6.75 (dd, J=2.4, 8.4 Hz, 1H), 5.20 (s, 2H), 3.95 (s, 2H), 3.51 (s, 3H), 3.35-3.30 (m, 1H), 2.39 (s, 3H), 2.30 (s, 3H), 1.22 (d, J=6.9 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethylacetate (9:1); Rf=0.6.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[CH3:18][N:19]=[C:20]=[O:21]>CO>[CH3:18][NH:19][C:20](=[O:21])[NH:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1
Reactant: Cc1cn([C@H]2C[C@H](N)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CN=C=O
Solvent: CO
Product: CNC(=O)N[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO
Reaction time: 1 h

Procedure:
To a solution of 7 (0.48 g, 2.00 mmol) in 15 ml of methanol, methyl isocyanate (0.13 g, 2.20 mmol) was added slowly. The solution was stirred at 0° for 1 h, during which period, white crystals precipitated out. The product was collected by filtration, washed with cooled methanol, and dried, to give 0.54 g (90%). The compound softened at 114° and effervesced at 120°; TLC: Rf 0.38. Anal. (C12H18N4O5) C, H, N.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O)(=O)C.[N:19]([O-])=[O:20].[Na+]>O>[N:19](=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[OH:20]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C=NO)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three necked one liter flask, fitted with a thermometer, a dropping funnel and a magnetic stirrer were placed 173 g. (0.9 mole) of benzyl acetoacetate [The benzyl acetoacetate was prepared as described by Baker et al., J. Org. Chem. 17, 91 (1952)] and 130 ml. of glacial acetic acid. The contents were cooled in an ice-salt bath and a solution of 69 g. (1 mole) of sodium nitrite in 130 ml. of water was added over a period of half an hour; the temperature was kept at 0° to 10° C. After the reaction mixture was stirred for one hour at room temperature, 400 ml. of water was added and the stirring was continued for an additional two hours. The reaction mixture was extracted three times with 200 ml. portions of diethyl ether. The diethyl ether extracts were combined, washed once with water, three times with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous sodium sulfate, the diethyl ether solution was evaporated leaving 16 as a clear oil which solidified upon trituration with petroleum ether (30°- 60°) to give 186.5 g. (93.2%) of white solid. Its NMR spectrum was consistent with the assigned structure. Generally the product was used as such in subsequent reaction but it can be recrystallized from toluene, m.p. 81°- 82° C. ##STR143##