Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([CH3:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a suspension of tert-butyl 9-((2-chloro-5-methylpyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (332.2 mg, 0.84 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (252.2 mg, 1.89 mmol) in n-BuOH (8 mL) was added DIPEA (445.9 mg, 3.45 mmol). The reaction mixture was stirred at 150° C. in a sealed tube for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as yellow oil (0.38 g, 99%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:22])[C@H:11]([NH2:21])[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:30]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:2]([O:9][C:10](=[O:22])[C@H:11]([NH:21][S:43]([C:40]1[CH:39]=[CH:38][C:37]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:42][CH:41]=1)(=[O:45])=[O:44])[CH2:12][C:13]([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: N[C@H](CC(=O)N1CCOCC1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCOCC1)NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of the title B compound, (2R)-amino-4-morpholin-4-yl-4-oxobutyric acid benzyl ester hydrochloride (420 mg, 1.28 mmol) in 5 mL of dichloromethane is treated with triethylamine (345 mg, 2.82 mmol) followed by a solution of 4-phenoxybenzenesulfonyl chloride (345 mg, 1.28 mmol) in 2 mL of dichloromethane. The reaction is stirred for 16 h, then partitioned between dichloromethane and water. The organic solution is washed with brine, dried over anhydrous MgSO4 and concentrated. Chomatography on silica gel (eluant; 3% MeOH in dichloromethane) affords 430 mg (64%) of (2R)-(4-phenyloxybenzenesulfonylamino)-4-morpholin-4-yl-4-oxobutyric acid benzyl ester as a white foam.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39]Cl)=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42]>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:39][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:37][CH:38]=2)=[CH:28][C:27]=1[C:41]([F:42])([F:43])[F:44]
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 60 °C
Yield: 26.7 %

Procedure:
To a suspension of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (75 mg, 0.343 mmol) and DIPEA (0.163 ml, 0.934 mmol) in DCM (2 mL) was added 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (100 mg, 0.311 mmol). The solution was heated at 60° C. overnight. Purification via MDAP then afforded the title compound (42 mg, 26.7% yield). LCMS: rt=3.49 min, [M+H+]=505
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].I(Cl)(=O)=O.[I:10](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C1(C)C=CC=CC=1.[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[C:35]([CH2:41][C:42]([CH3:44])=[CH2:43])[C:34]=1[OH:45]>CO>[I:10][CH2:43][C:42]1([CH3:44])[CH2:41][C:35]2[C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]([CH3:32])[C:34]=2[O:45]1
Reactant: C=C(C)Cc1c(C)cc(C)c(C)c1O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(C)c2c(c1C)OC(C)(CI)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 183.4 %

Procedure:
Calcium carbonate (1.37 g, 13.7 mmol) and benzyltrimethylammonium dichloroiodate (4.04 g, 11.6 mmol) were sequentially added to a solution of toluene (20 mL)/methanol (10 mL) containing 2,3,5-trimethyl-6-(2-methylprop-2-en-1-yl)phenol (1.00 g, 5.26 mmol) synthesized in Reference Example 2 under ice-cooling condition, and the mixture was stirred at 0° C. for 30 minutes. After that, the reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added to the residue to separate an organic layer. The organic layer was washed with 10% sodium sulfite aqueous solution and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0-95:5) to give 3.05 g of the title compound (yield: 92%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl.[CH2:19]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH3:20]>C(O)C>[CH2:19]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:20]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@H](C)Nc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.2 %

Procedure:
Under a nitrogen atmosphere, triethylamine (82.1 g, 0.813 mole) was added to a stirred suspension of 2-chloro-3-nitropyridine (51.4 g, 0.325 mole) and (S)-alanine ethyl ester hydrochloride (75 g, 0.488 mole) in absolute ethanol (500 ml). After refluxing for 10.5 hr. and stirring at room temperature overnight, the solvents were evaporated under reduced pressure. The residue was triturated in 500 ml of ethyl acetate, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was washed three times with water, dried over sodium sulfate, filtered and evaporated to an oil weighing 85.6 g. A 1.25-g sample of the oil was eluted through 20 g of silica gel with isopropyl ether as the eluting solvent to give a pure fraction. The solvent was evaporated and the residual oil was dissolved in methylene chloride, filtered, and evaporated to an oil which was dried under high vacuum at 50° C. overnight to give 0.9 g of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:57][O:58][C@H:59]([CH3:69])[C@H:60]([NH:64][C:65]([O:67][CH3:68])=[O:66])[C:61]([OH:63])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:57][O:58][C@@H:59]([CH3:69])[C@H:60]([NH:64][C:65]([O:67][CH3:68])=[O:66])[C:61]([N:45]1[CH2:46][C@@H:47]([CH3:49])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:63]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)[C@@H](NC(=O)OC)[C@H](C)OC)[nH]2)ccc1-4)C(C)C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (20 mg, 0.079 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (8 mg, 0.04 mmol), HATU (12 mg, 0.03 mmol) and DMF (0.5 mL), then N-methylmorpholine (0.009 mL, 0.078 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S,3S)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (7.5 mg, 35%).
Reaction SMILES: C[O:2][C:3](=[O:54])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][S:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([O:42]C)=[O:41])=[C:34]([CH3:44])[CH:33]=4)=[CH:24][C:23]=3[C:45]([F:48])([F:47])[F:46])=[C:18]([C:49]([F:52])([F:51])[F:50])[CH:17]=2)=[CH:8][C:7]=1[CH3:53].[OH-].[Na+].O.Cl>C(O)C>[C:40]([CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([S:31][CH2:30][CH2:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][S:12][C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:54])=[O:2])=[C:7]([CH3:53])[CH:8]=4)=[CH:17][C:18]=3[C:49]([F:50])([F:51])[F:52])=[C:23]([C:45]([F:48])([F:47])[F:46])[CH:24]=2)=[CH:33][C:34]=1[CH3:44])([OH:42])=[O:41]
Reactant: COC(=O)COc1ccc(SCCCc2ccc(-c3ccc(CCCSc4ccc(OCC(=O)OC)c(C)c4)cc3C(F)(F)F)c(C(F)(F)F)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(SCCCc2ccc(-c3ccc(CCCSc4ccc(OCC(=O)O)c(C)c4)cc3C(F)(F)F)c(C(F)(F)F)c2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [4-(3-{4′-[3-(4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester (example 25) (102 mg, 0.12 mmol) in ethanol (5 ml) was added aqueous 1N NaOH (0.5 ml). The reaction mixture was stirred for 3 hours at room temperature and the evaporated. Water (10 ml) and 1 N HCl (0.6 ml) was added to the residue and the mixture was extracted with methylene chloride (2×30 ml). The combined organic phases were dried (MgSO4), filtered and evaporated to give the title compound in 96 mg (98%) yield.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[O:31][CH3:32])[CH2:5][CH2:4][CH2:3]1.CN(C1C=CC=CN=1)C.Cl.CN(C1C=CC=CN=1)C.[C:53]([O:57][C:58]([NH:60][C@H:61]([C:66](O)=[O:67])[CH2:62][CH2:63][S:64][CH3:65])=[O:59])([CH3:56])([CH3:55])[CH3:54].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.C(O)(=O)C.CO>[C:53]([O:57][C:58]([NH:60][C@H:61]([C:66]([O:1][CH:2]1[C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[O:31][CH3:32])[CH2:5][CH2:4][CH2:3]1)=[O:67])[CH2:62][CH2:63][S:64][CH3:65])=[O:59])([CH3:56])([CH3:55])[CH3:54]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(O)c2cc(Cl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 121.2 %

Procedure:
5-Hydroxy-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g), dimethylaminopyridine (0.83 g) and dimethylaminopyridine hydrochloride (0.72 g) are dissolved in chloroform (15 ml), and thereto are added N-tert-butoxycarbonyl-L-methionine (0.56 g) and dicyclohexylcarbodiimide (0.93 g), and the mixture is stirred at room temperature for 3 hours. To the mixture are added methanol (3 ml) and acetic acid (0.7 ml), and the mixture is stirred at room temperature for 30 minutes. The insoluble materials are removed by filtration, and to the filtrate is added 5% aqueous sodium hydrogen sulfate solution, and the mixture is extracted with dichloromethane. The dichloromethane layer is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent is evaporated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=150:1) to give 5-(N-tert-butoxycarbonyl-L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.27 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][C@H:21]([C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[NH:43][C:27](=[O:28])[CH2:26][NH:25][C:23](=[O:24])[C@H:21]([CH3:22])[NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When equivalent quantities of N-t-butoxycarbonyl-L-tyrosyl-L-alanylglycine and L-phenylalanyl-L-methionine benzyl ester are reacted according to the procedure detailed in Example 12, there is obtained N-t-butoxycarbonyl-L-tyrosyl-L-alanylglycyl-L-phenylalanyl-L-methionine benzyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5]O.[N+](C1C=C2C(=CC=1)N=CN=C2)([O-])=O.[C:23]([NH:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](=O)[NH:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[N+:38]([O-:40])=[O:39])(=[O:25])[CH3:24].BrC1C=C(C=CC=1)N.Cl.N>O=P(Cl)(Cl)Cl.C(O)(C)C>[C:23]([NH:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=3)=[N:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[N+:38]([O-:40])=[O:39])(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Reactant: ONc1cccc(Br)c1
Agent: Cl
Agent: N
Agent: O=[N+]([O-])c1ccc2ncncc2c1
Solvent: Nc1cccc(Br)c1
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 45 %

Procedure:
7-Acetamido-4-(3-bromoanilinol-6-nitroquinazoline. A solution of 7-acetamido-6-nitro-3H-quinazolin-4-one (5.00 g, 20 mmol) in POCl3 (250 mL) is heated under reflux for 2 h, the excess of POCl3 is removed under vacuum, and the residue is dissolved in CH2Cl2 and washed with aqueous Na2CO3 solution. Workup gives the crude 4-chloro derivative, which is coupled directly with 3-bromoaniline in isopropanol as above, and the resulting hydrochloride is converted directly to the free base, by treatment with aqueous NH3, to give 7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline (3.60 g, 45%). 1H NMR (DMSO) δ10.56 (1H, s), 10.29 (1H, s), 9.34 (1H, s), 8.70 (1H, s), 8.19 (1H, brs), 7.97 (1H, s), 7.88 (1H, d, J=6.0 Hz), 7.43-7.35 (2H, m), 2.13 (3H, s).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[OH:22])=[O:16].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30](O)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([O:22][C:21]1[CH:20]=[CH:19][S:18][C:17]=1[C:15]([O:14][CH3:13])=[O:16])[CH3:31]
Reactant: CC(O)c1ccccc1Cl
Reactant: COC(=O)c1sccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1sccc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Yield: 50.6 %

Procedure:
DEAD (2.6 mL, 16.4 mmol, 1.3 Eq.) was added dropwise to a stirred solution of methyl-3-hydroxythiophene-2-carboxylate (2.0 g, 12.6 mmol, 1.0 Eq.), 1-(2-chlorophenyl)ethanol (2.57 g, 16.4 mmol, 1.3 Eq.) and triphenylphosphine (4.31 g, 16.4 mmol, 1.3 Eq.) in ahydrous THF (30 mL) at 0° C. under nitrogen. The reaction was allowed to warm to ambient temperature overnight. The crude reaction mixture was absorbed onto SiO2 and purified by column chromatography eluting with 0 to 10% EtOAc/petroleum ether to give the sub-title compound as a white solid (1.89 g, 6.37 mmol, 50%); 1H NMR (400 MHz, CDCl3) δ 1.72 (3H, d), 3.87 (3H, s), 5.78 (1H, quint), 6.65 (1H, d), 7.21-7.32 (3H, m), 7.38 (1H, dd), 7.55 (1H, dd).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH2:12].N1C=CC=CC=1.[CH:20]([O:23][C:24](Cl)=[O:25])([CH3:22])[CH3:21]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:24]([O:23][CH:20]([CH3:22])[CH3:21])=[O:25]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1cc(Br)c(Cl)cc1N
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)c(Cl)cc1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 2-Amino-5-bromo-4-chloro-benzoic acid methyl ester (2.08 g, 7.86 mmol) and pyridine (1.91 ml, 23.6 mmol) in dichloromethane (75.0 ml) was added 1.00N isopropylchloroformate in toluene dropwise. The mixture was stirred for 16 hours at room temperature. The mixture washed with 0.500N HCl(aq) (100 ml), and brine (3×100 ml), then dried (Na2SO4) and concentrated to an oil. Purification by silica gel chromatography (gradient eluent, 0-10% ethyl acetate in hexane) provided 5-Bromo-4-chloro-2-isopropoxycarbonylamino-benzoic acid methyl ester (2.53 g, 92%) as a white crystalline material. MS (ES+): 350, 352 (M+H).
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[CH:16][C:15](N)=[N:14]2)=[CH:9][CH:8]=1.S(=O)(=O)(O)O.[Br-:32].[Na+].Br>O.C(#N)C>[Br:32][C:15]1[CH:16]=[C:17]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)[N:14]=1
Reactant: [Br-]
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(SC)cc2)cc1
Agent: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: COc1ccc(-n2nc(Br)cc2-c2ccc(SC)cc2)cc1
Reaction time: 1 h
Yield: 25.7 %

Procedure:
A solution of sodium nitrite (492 mg) in water (0.6 ml) was added dropwise to a mixture of 1-(4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazol-3-amine (2 g) and sulfuric acid (1.2 ml) in water (3 ml) and acetonitrile (6 ml) at 5° C., and the mixture was stirred at the same temperature for 1 hour. The mixture was added portionwise to a mixture of cuprous bromide (1.25 g), sodium bromide (1.2 g) and hydrobromic acid (3.3 ml) in water (6 ml) at 70° to 80° C. during a period of 15 minutes, and the resulting mixture was stirred at 80° C. for 30 minutes. The aqueous layer was removed by decantation and the oily residue was extracted with toluene. The extract was washed with water, dried, and concentrated in vacuo. The residue (1.1 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of chloroform and n-hexane (2:1) to give crystals of 3-bromo-1-(4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole (0.62 g).
Reaction SMILES: [CH2:1]([NH2:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C(N(CC)CC)C.[C:19]([O:22][CH:23]([CH3:27])[C:24](Cl)=[O:25])(=[O:21])[CH3:20]>C1COCC1.ClCCl>[CH2:1]([NH:11][C:24](=[O:25])[CH:23]([O:22][C:19](=[O:21])[CH3:20])[CH3:27])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: CC(C)=CCC/C(C)=C/CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)C(=O)NC/C=C(\C)CCC=C(C)C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a cold solution of geranyl amine (7 g) and triethyl amine (6 g) in THF (50 ml) was added dropwise a solution of 2-acetoxypropanoyl chloride (9 g) in dichloromethane (15 ml) at a temperature between 6° C. and 13° C. over a period of 20 minutes. Stirring was continued at room temperature for 2 hrs. The white precipitate (triethylamine HCl salt) was filtered and the filtrate was evaporated. The residue was dissolved in DCM (100 ml), washed twice with 50 ml of aqueous 5% HCl solution and twice with water (2×50 ml) and evaporated to dryness to yield 12.6 g of a colourless oil. The yield was 90%, the purity was 95% according to NMR analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[C:20]([NH:21][C:22](=O)[CH:13]2[CH2:12]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:33][C:34]([F:39])([F:38])[C:35](O)=[O:36].Cl>ClCCl.C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[C:20]([N:21]([C:35](=[O:36])[C:34]([F:39])([F:38])[F:33])[CH2:22][CH:13]2[CH2:12]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1Nc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC12
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN2c3ccccc3N(C(=O)C(F)(F)F)CC2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 2 ml portion of THF solution containing 100 mg (0.30 mmol) of 3-benzyloxycarbonyl-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one was cooled to 0° C., mixed with 59 μl (0.59 mmol) of borane-dimethyl sulfide complex and stirred overnight at room temperature. The reaction solution was mixed with ice water, stirred for 30 minutes and extracted with ethyl acetate. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure, and the thus obtained residue was recrystallized from ethyl acetate-hexane to obtain crude crystals. A 97 mg portion of the crude crystals were dissolved in 2 ml of dichloromethane, and the solution was mixed with 125 μl (0.90 mmol) of triethylamine and 64 μl (0.45 mmol) of anhydrous trifluoroacetic acid and stirred overnight at room temperature. The reaction solution was poured into ice water, acidified by adding 1 N hydrochloric acid and then extracted with ethyl acetate. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure, and the thus obtained residue was purified by a silica gel chromatography (30 cc; elution by ethyl acetate-hexane=1:5) to obtain 94 mg (74% in yield) of the title compound.