Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12](Br)[N:13]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:25]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2nc(Br)cnc2N)cc1
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2nc(-c3ccnc(N4CCOCC4)c3)cnc2N)cc1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A suspension of the compound prepared in Example 12 (7.6 g), Pd(PPh3)4 (3.3 g), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (8.3 g), and Na2CO3 (9.1 g, 85 mmol) in a 3 to 1 mixture of dioxane/water (280 mL) was degassed with a stream of nitrogen for 10 minutes. The reaction was heated at 90° C. overnight, at which time LC/MS indicated the reaction was complete. The mixture was concentrated, diluted with aqueous saturated sodium bicarbonate solution (200 mL) and extracted with EtOAc (3×200 mL). The organic layers were combined, dried over Na2SO4, and evaporated under reduced pressure. The crude product was obtained as a brown oil which was precipitated from DCM (50 mL) to give a dark yellow solid. The solid was filtered and triturated with a 1 to 1 solution of DCM/EtOAc (3×50 mL) to give the title compound (8.4 g) having the following physical data as a light yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([O:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][CH:22]=1)=O.[O-]S([O-])(=O)=O.[Mg+2].[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+].N#N>ClCCl.C1COCC1.O>[Si:1]([O:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][CH2:19][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:25][CH:26]=2)=[C:12]([O:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1N
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Agent: N#N
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1NCc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of the amine 6 (91 mg, 0.34 mmol) and tert-butyl 4-formylphenylcarbamate (75 mg, 0.34 mmol) in dry dichloromethane (1.7 ml) was added a finely ground 1:1 mixture of MgSO4 and Na2SO4 (20 mg) and the mixture was stirred under N2 at room temperature for 3 days. The suspension was filtered through a 0.4 micron Whatman™ cartridge (GE Healthcare Biosciences, Pittsburgh, Pa.), the solvent was removed with a stream of dry N2 and the remaining red oil was dissolved in 1.2 ml dry THF and 0.2 ml anhydrous EtOH. Under vigorous stirring, sodium borohydride (14 mg, 0.37 mmol) was added and the mixture was stirred at room temperature for 30 min. Water (100 μl) was added and the solvent was stripped with a stream of N2. THF (1.5 ml) was added, the mixture was filtered through a 0.4 micron Whatman cartridge, dried with a stream of N2 and used crude in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])S[C@@H:5]2[C:7]([Br:11])([Br:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13].[OH-].[Na+].Cl.[S:19](=[O:22])(O)[O-:20].[Na+].[Cl-].[Na+]>C(OCC)(=O)C.O.ClCCl>[CH3:1][C:2]1([CH3:15])[S:19](=[O:22])(=[O:20])[C@@H:5]2[C:7]([Br:10])([Br:11])[C:8](=[O:9])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)O
Reactant: O=S([O-])O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C(Br)(Br)[C@H]2S1(=O)=O
Reaction time: 0.83 h

Procedure:
To the dichloromethane solution of 6,6-dibromopenicillanic acid from Preparation A was added 300 ml of water, followed by the dropwise addition over a period of 30 minutes of 105 ml of 3N sodium hydroxide. The pH stabilized at 7.0. The aqueous layer was removed and the organic layer was extracted with water (2×100 ml). To the combined aqueous solutions was added, at -5° C., a premixed solution prepared from 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water, until the pink color of the permanganate persisted. The addition took 50 minutes and 550 ml of oxidant were required. At this point 500 ml of ethyl acetate was added and then the pH was lowered to 1.23 by the addition of 105 ml of 6N hydrochloric acid. Then 250 ml of 1M sodium bisulfite was added during 10-15 minutes at ca. 10° C. During the addition of the sodium bisulfite solution the pH was maintained at 1.25 -1.35 using 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride and the two phases were separated. The aqueous solution was extracted with additional ethyl acetate (2×150 ml) and the combined ethyl acetate solutions were washed with brine and dried (MgSO4). This afforded an ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1-dioxide
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:5][N:4]=1.[CH3:20][NH2:21]>C(O)C>[CH3:20][NH:21][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][C:6]2[CH:5]=[N:4][C:3]([C:2]([F:19])([F:18])[F:1])=[N:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: CN
Reactant: O=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Solvent: CCO
Product: CNCc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
4-{[2-(Trifluoromethyl)pyrimidin-5-yl]oxy}benzaldehyde was stirred with 33% methylamine in 95% ethanol (30 mL) at reflux for 1 hour and then concentrated. The residue was re-dissolved in 95% ethanol, 10% palladium/carbon was added, and the mixture was hydrogenated at room temperature under atmospheric pressure for 30 minutes. The reaction was performed on a 5.0 mmol scale with a yield of 95%.
Reaction SMILES: OC1C=CC(S[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([NH2:18])[CH:10]=2)=CC=1.[H-].[Na+].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([SH:31])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([NH2:18])[CH:10]=2)[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1
Reactant: Nc1cc(Sc2ccc(O)cc2)ccc1[N+](=O)[O-]
Reactant: COc1ccc(OC)c(S)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(OC)c(Sc2ccc([N+](=O)[O-])c(N)c2)c1

Procedure:
Using the general method described for 4-(4-hydroxyphenylsulphanyl)-2-amino-nitrobenzene in Example 2, except that one equivalent of NaH was used, 4-(3,6-dimethoxyphenylsulphanyl)-2-amino-nitrobenzene (4.19 g) was prepared from 3,6-dimethoxybenzenethiol (2.55 g; 15 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:34]=[C:35]([F:39])[C:36]([F:38])=[CH:37][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:48]=[N+:49]=[N-:50].[Na+].Cl>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:27][CH2:28][C:29]([F:33])([F:32])[CH2:30][CH2:31]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]4[NH:50][N:49]=[N:48][N:21]=4)=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:34]=[C:35]([F:39])[C:36]([F:38])=[CH:37][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(C)c1OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nnn[nH]2)cc(C)c1OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 150 °C
Reaction time: 72 h

Procedure:
To a solution of 0.16 g (0.29 mmol) 4-[2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-ethoxy]-3,5-dimethyl-benzonitrile in 4 ml o-xylene were added 0.198 g (1.44 mmol) triethylamine hydrochloride and 0.094 g (1.45 mmol) sodium azide and heated for 21 h at 150° C. (oil bath temperature). Another 0.198 g (1.44 mmol) triethylamine hydrochloride and 0.094 g (1.45 mmol) sodium azide were added and the reaction mixture was heated for another 4 h and after cooling down to room temperature stirred 3 days. The reaction was then poured onto 1M aqueous hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The solid was suspended in acetonitrile, filtered, washed with acetonitrile and dried under high vacuum. White solid (77%). MS (Turbo Spray): m/z=599.194 [M+H].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C@@H:10]([C:12]([O:14]C(C)(C)C)=[O:13])[CH3:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:35]>>[ClH:35].[N:1]1([CH2:7][CH2:8][N:9]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C@@H:10]([C:12]([OH:14])=[O:13])[CH3:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[C@H](C(=O)OC(C)(C)C)N(CCN1CCOCC1)S(=O)(=O)c1ccc(Sc2ccccc2)cc1
Agent: Cl
Product: C[C@H](C(=O)O)N(CCN1CCOCC1)S(=O)(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 25 °C

Procedure:
N-[2-(4-morpholinyl)ethyl]-N-[[4-(phenylthio)-phenyl]sulfonyl]-D-alanine, 1,1-dimethylethyl ester from Example 3d (4.33 g, 8.55 mmol) in 6 N HCl (71 mL) was refluxed for 20 minutes, and upon cooling to room temperature a white solid precipitated. The solid was collected, washed with water, and dried in a 40° C. vacuum oven to give N-[2-(4-morpholinyl)ethyl]-N-[[4-(phenylthio)-phenyl]sulfonyl]-D-alanine, monohydrochloride, as a white solid (2.38 g, 57% yield): anal. calc'd for C21H26N2O5S2.1.2HCl: C, 51.02; H, 5.55; N, 5.67. Found: C, 50.94; H, 5.41; N, 5.57.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15]CC)=[O:14])=CC2[C:10]([CH:11]=1)=[CH:9]C=C(O)C=2.[I-].C(=O)([O-])[O-:20].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:9][C:10]([CH2:11][C:2]([CH2:3][C:13]([OH:15])=[O:14])=[O:1])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(O)ccc2cc1O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 55 °C

Procedure:
A solution of ethyl 3,7-dihydroxy-2-naphthoate (62 mg, 0.26 mmole) (the acid was obtained from Aldrich and it was converted to the ester using standard techniques) 2 mg, and iodide 2 (242 mg) in dimethylforamide (0.5 ml) was heated at 55° C. with potassium carbonate (175 mg) for 4 hours. An additional amount of the iodide 2 (80 mg) was added to the mixture which was heated at 55° C. overnight. The mixture was worked up with water (50 ml) and ethyl acetate (2×75 ml). The ethyl acetate extracts were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated. The crude product was purified on a silica gel column (hexane:ethyl acetate, 1.5:1) to provide the triacetate of 17 (130 mg, 65% yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[NH:13][C:12](=[O:21])[C:11]1=[O:22])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].F[B-](F)(F)F.[O:28]=[N+:29]=[O:30].O>C(Cl)Cl>[CH2:6]([O:5][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:29]([O-:30])=[O:28])=[C:17]([F:20])[CH:18]=2)[NH:13][C:12](=[O:21])[C:11]1=[O:22])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: O=[N+]=O
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2ccc(F)cc21)OCC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
615 mg of (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is mixed in 60 ml of methylene chloride with 743 mg of nitronium tetrafluoroborate. The batch is stirred for 2 hours at room temperature. It is mixed with 50 ml of water and, after separation of the organic phase, it is extracted three times with methylene chloride. The collected organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 350 mg of (6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH2:33])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH2:33])[N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(N)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 6-1 (46 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 6-2.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH:3]=[CH:4][CH:5]=O.[CH:8]([S:11]([CH2:14][C:15]#[N:16])(=[O:13])=[O:12])([CH3:10])[CH3:9].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:15]([C:14]([S:11]([CH:8]([CH3:10])[CH3:9])(=[O:13])=[O:12])=[CH:5][CH:4]=[CH:3][N:2]([CH3:7])[CH3:1])#[N:16]
Reactant: CC(C)S(=O)(=O)CC#N
Reactant: CN(C)C=CC=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)S(=O)(=O)C(C#N)=CC=CN(C)C
Yield: 67 %

Procedure:
3-Dimethylaminoacrolein (17 ml, 0.17 mol) and isopropylsulphonylacetonitrile (25 g, 0.17 mol) were dissolved in toluene (250 ml) and piperidine (1 ml) and acetic acid (2.5 ml) were then added. The solution was heated under reflux in a water separator until no more water was formed (about 3 hours). On cooling, crystals formed which were filtered off under suction and dried to give 26 g 1-cyano-1-isopropylsulphonyl-4-dimethylamino-1,3-butadiene as yellow-brown crystals, m.pt. 102°-104° C. The remaining toluene was then extracted with water (2×50 ml), dried over sodium sulphate and evaporated under vacuum to give about 15 g of a brown syrup. This was then purified over silica using ethyl acetate as eluant to give a further 8.8 g 1-cyano-1-isopropylsulphonyl-4-dimethylamino-1,3-butadiene crystals. Yield: 90.2% of the theoretical.
Reaction SMILES: [C:1]1([CH:11]([N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:12])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:11]([NH2:13])[CH3:12])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1
Reactant: CC(c1ccc2cccccc1-2)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)c1ccc2cccccc1-2
Temperature: 30 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
2-[1-(Azulen-1-yl)ethyl]-isoindole-1,3-dione (16.8 g) prepared in Example 72, Step B was dissolved in ethanol (400 mL), added with hydrazine monohydrate (3.1 g, Wako Pure Chemical Industries), and stirred at 30° C. for 72 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was added with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel chromatography (NH-DM1020, Fuji Silysia, hexane:ethyl acetate=3:1-1:1) to obtain 9.26 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][C:7]([CH3:21])=[N:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=3)[C:4]=2[CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([N:8]1[C:7]([CH3:21])=[CH:6][C:5]2[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=2)=[N:9]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C1
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C=C1C
Temperature: 0 °C

Procedure:
A solution of 1.5 g (4.6 mmoles) of 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-5H-2,3-benzodiazepine in 15 ml of acetic anhydride is stirred in an oil bath of 130 to 140° C. for 5 hours. The reaction mixture is poured onto about 200 g of crushed ice and the separated crystals are filtered off. The crude product is recrystallized from acetonitrile. Thus 0.78 g (46%) of the desired compound melting at a temperature of 192 to 194° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=[C:5]2[CH3:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[C:26]1[C:30]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[C:29]([CH:48]([CH3:50])[CH3:49])[O:28][N:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[Cl:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=1[C:26]1[C:30]([CH2:31][O:32][C:33]2[CH:34]=[CH:35][C:36]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=[C:5]4[CH3:17])=[CH:37][CH:38]=2)=[C:29]([CH:48]([CH3:50])[CH3:49])[O:28][N:27]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCOC(=O)c1nc(C)c2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1nc(C)c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 60 °C
Yield: 90.9 %

Procedure:
Palladium(II)acetate (2.7 mg, 12.1 μmol) was added to ethyl 6-bromo-4-methyl-2-quinazolinecarboxylate (71.1 mg, 240.9 μmol), 3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}methyl)isoxazole (176.4 mg, 361.4 μmol), triphenylphosphine (6.3 mg, 24.1 μmol), and potassium phosphate (179.0 mg, 843.2 μmol). Then, dioxane (2.4 mL) was added to the mixture, followed by water (24.1 μL), and the reaction mixture was heated open to the atmosphere at 60° C. in an oil bath for 14 hours, then allowed to cool to room temperature. Water was added, followed by ethyl acetate, and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:1 ethyl acetate:hexanes to give 126.2 mg (91%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinazolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.44 (d, J=2 Hz, 1H), 8.34 (dd, J=9, 2 Hz, 1H), 8.15 (d, J=9 Hz, 1H), 7.81 (d, J=9 Hz, 2H), 7.65-7.62 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 4.90 (s, 2H), 4.41 (q, J=7 Hz, 2H), 3.48 (septet, J=7 Hz, 1H), 3.03 (s, 3H), 1.36 (t, J=7 Hz, 3H), 1.35 (d, J=7 Hz, 6H). ESI-LCMS m/z 576 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH:23][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:13]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(Cl)cccc1Cl)c1ccccc1CO2
Yield: 88.1 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of Compound A and 0.76 g of 2,6-dichloroaniline in place of aniline to obtain 1.38 g of Compound 6.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[OH-].[Na+].Cl>>[Cl:1][C:2]1[C:3]2=[C:8]3[N:7]([CH:6]([CH3:13])[CH2:5][CH2:4]2)[CH:24]=[C:18]([C:19]([OH:21])=[O:20])[C:17](=[O:16])[C:9]3=[CH:10][C:11]=1[Cl:12]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1CCc2c(ccc(Cl)c2Cl)N1
Agent: Cl
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1CCc2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 160 °C
Yield: 49.8 %

Procedure:
A mixture of 3.2 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine and 3.2 g of diethyl ethoxymethylenemalonate was allowed to react by heating at 160° C. for 30 minutes. Then 13 g of polyphosphoric acid prepared from 6.5 g of phosphorus pentoxide and 6.5 g of phosphoric acid was added to the mixture and the resulting mixture was allowed to react by heating at 140° to 150° C. for 1 hour. After completion of the reaction, the mixture was poured onto 100 g of ice, followed by rendering the mixture to pH 4 to 5 with a 40% aqueous sodium hydroxide solution to precipitate crystals. The crystals were collected by filtration, dried and mixed with 50 ml of a 10% aqueous sodium hydroxide solution. The mixture was allowed to react at 100° to 110° C. for 1 hour. After cooling, the reaction mixture was rendered acidic with concentrated hydrochloric acid to precipitate crystals. Recrystallization of the crystals thus-obtained from ethanol gave 2.3 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid having a melting point of 269° to 271° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.S([O-])([O-])(=[O:31])=S.[Na+].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][C:16]([C:17](=[O:31])[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)cc(C#N)c2C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)cc(C(N)=O)c2C1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A solution of 8-cyano-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (3.87 g, Reference Example 4(a)) in methanol (200 mL) was treated with a 10M aqueous solution of sodium hydroxide (10.45 mL), then with a 27.5% w/w aqueous solution of hydrogen peroxide (0.74 mL). After stirring at 50° C. for 0.75 hour the reaction mixture was further treated with a 27.5% w/w aqueous solution of hydrogen peroxide (0.74 mL). After further stirring at 50° C. for 2 hours the reaction mixture was then further treated with a 27.5% w/w aqueous solution of hydrogen peroxide (0.74 mL). After further stirring at 50° C. for 1.5 hours the reaction mixture was allowed to cool to room temperature and treated with a saturated aqueous solution of sodium thiosulfate (20 mL). After stirring at room temperature for 15 minutes the reaction mixture was evaporated and then treated with ethyl acetate (650 mL) and water (150 mL). The organic phase was separated, washed with water (150 mL) and then dried over sodium sulfate. The organic phase was then evaporated to give the title compound (4.06 g) as a white solid, m.p. 208–210° C. MS: 342 [MH]+.