Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[C:5](=[O:6])[C:4]([S+:14]([O-])[CH3:15])=[CH:3]1.FC1C=C2C(C(=S)C(C)=CN2C)=CC=1.[Cl:31]N1C(=O)CCC1=O>>[Cl:31][CH2:15][S:14][C:4]1[C:5](=[O:6])[C:7]2[C:8](=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc([S+](C)[O-])c(=O)c2ccc(F)cc21
Reactant: O=C1CCC(=O)N1Cl
Agent: Cc1cn(C)c2cc(F)ccc2c1=S
Product: Cn1cc(SCCl)c(=O)c2ccc(F)cc21

Procedure:
In other embodiments, the synthesis of racemic monochloroflosequinan is carried out as a three step procedure, as described in more detail in Example 2. Briefly, in the first step, racemic flosequinan is reduced to desoxyflosequinan (7-fluoro-1-methyl-3-methylthio-4-quinolone). In the second step, desoxyflosequinan is chlorinated using N-chlorosuccinimide, to produce chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone). In the third step, chlorodesoxyflosequinan is subjected to oxidation to produce 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (monochloroflosequinan). Such oxidation may be accomplished using hydrogen peroxide.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][CH:9]([C:16]([N:35]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]2)=[O:18])[N:8]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:12]1
Reactant: OC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1CC(C(=O)N2CCC(O)CC2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]4-sulfonyl chloride, and 4-piperidinol, the title compound was obtained in 68% purity by HPLC. MS(ESI+): m/z=458.
Reaction SMILES: C([Li])CCCCC.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16]C)=O)=[O:11].Br[CH2:26][Cl:27].Cl>CCCCCC.O1CCCC1.O>[CH2:18]([C@H:13]([NH:12][C:10](=[O:11])[O:9][CH3:8])[C:14](=[O:16])[CH2:26][Cl:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reactant: ClCBr
Agent: Cl
Agent: [Li]CCCCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Yield: 37 %

Procedure:
41.7 ml of a 2.6 molar solution of hexyllithium in hexane were added dropwise at -80° C. to a solution of 9.50 g of methyl (S)-2-methoxycarbonylamino-3-phenyl-propionate and 3.22 ml of bromochloromethane in 60 ml of tetrahydrofuran. Subsequently, a further 2.14 ml of bromochloromethane were added and the mixture was again treated with 23 ml of hexyllithium solution, a further 1.54 ml of bromochloromethane were added and the mixture was again treated with 7.7 ml of hexyllithium solution. The solution was treated at -80° C. with 15 ml of 20% methanolic hydrochloric acid, warmed to 22° and diluted with 100 ml of water and 40 ml of tetrahydrofuran. The phases were separated, the organic phase was washed with saturated sodium chloride solution, dried and concentrated. The residue was recrystallized from 40 ml of ethyl acetate and 160 ml of hexane and the crystallizate was dried, yielding 3.83 g (37%) of pure methyl (S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate, m.p. 121°-122° C. IR (KBr): 3336s (NH), 1737s and 1686s (C=O), 1535s (amide II).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H].C>C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH2:10]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Br
Reactant: [H][H]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Nc1ccc(Cl)c(Cl)c1Br
Yield: 86.1 %

Procedure:
A solution of 2-bromo-3,4-dichloronitrobenzene (23.5 g) in toluene was treated at 25°-35° C. for 1.25 hours with hydrogen in the presence of charcoal containing 5% platinum. The solution was then filtered and the filtrate was evaporated to dryness. The brown solid thus obtained was dissolved in diethyl ether and the solution was treated with decolourising charcoal and filtered. Evaporation to dryness of the filtrate gave 2-bromo-3,4-dichloroaniline (18.0 g), m.p. 78°-80° C. in the form of a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:11]([CH3:13])[C:10]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)C(=O)O
Solvent: O
Product: CC(=NNc1ccc(Cl)cc1)C(=O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
75.7 g of hydrochloric salt of parachlorophenylhydrazine was dissolved into 350 ml of water. 37.2 g of pyruvic acid was added into the solution. After stirring for 30 minutes at 70° C. while heating, and then cooling, precipitated crystals were filtered out, washed, and dried. These crystals were recrystallized from isopropyl acohol to obtain 57 g of 2-(p-chlorophenylhydrazono)propionic acid having a melting point of 196° to 197° C. (decomposed).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14].CC(C)([O-])C.[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:5]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])[CH:6]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Br)c[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cn1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
Methyl 4-bromo-1H-pyrrole-2-carboxylate (250 mg, 1.23 mmol) and 2-bromo-1-(4-chloro-phenyl)-ethanone (315 mg, 1.35 mmol) were dissolved in DMF (50 mL). The reaction mixture was cooled to 0° C. before potassium tert-butoxide (125 mg, 1.11 mmol) was added to the reaction mixture in small portions. The resulting suspension was allowed to warm to room temperature then stirred for 10 min. The reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried and concentrated in vacuo to give a residue that was purified using flash chromatography (Biotage SP4, 40 g cartridge, 0-15% EtOAc gradient in n-hexanes) to give the target compound methyl 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (244 mg) contaminated with an impurity. The mixture was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].CC(C)([O-])C.[K+].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])/[C:22](/[O:21][CH2:20][CH2:19][O:18][CH3:17])=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COCCOCC(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCCO/C(=C\c1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: -20 °C
Yield: 31.2 %

Procedure:
4-(Benzyloxy)benzaldehyde (3.00 g; 14.0 mmole) and benzyl 2-(2-methoxyethoxy)acetate (4.23 g; 17.0 mmole) were dissolved in dry tetrahydrofuran (100 ml) and cooled to −20° C. Potassium tert-butoxide (1.91 g; 17.0 mmole) dissolved in dry tetrahydrofuran (10 ml) was slowly added and the reaction was stirred over night at −20° C. The reaction was quenched with acetic acid (0.85 g; 14.0 mmole). The crued product was isolated, redissolved in toluene and refluxed over night with p-toluenesulfonic acid (0.24 g; 1.4 mmole) in a Dean-Stark apparatus to separate the water. The solution was cooled, washed with sodium hydrogene carbonate, dried with magnesium sulfate and evaporated. Purification of the crude product with preparativ HPLC (Kromasil C8, 10 μm, 50×500 mm) using acetronitrile (50-70%) in ammonium acetate buffer (pH 7) as mobil phase gave 1.83 g (29% yield) of (Z)-3-[4-(benzyloxy)phenyl]-2-(2-methoxyethoxy)-2-propenoic acid benzyl ester.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:10][C:9](=[O:11])[CH:8]=[CH:7]1>CN(C)C=O.C(OCC)(=O)C>[N:1]([CH:6]1[CH2:10][C:9](=[O:11])[CH:8]=[CH:7]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C=CC(Br)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1C=CC(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of sodium azide (2.12 g, 32.6 mmol) in dimethylformamide (15 mL) cooled to 0° C. was added dropwise with stirring 4-bromocyclopent-2-enone (DePuy, C. H.; Isaks, M.; Eilers, K. L.; Morris, G. F. J. Org. Chem. 1964. 29, 3503; 3.5 g, 21.7 mmol) in dimethyl-formamide (5 mL) over a period of 5 min. The reaction mixture was stirred at 0° C. for 30 min and diluted with ethyl acetate (20 mL). The reaction mixture was washed with water (2×20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo to furnish an oily residue. Purification of the crude oil by flash column chromatography (10-15% ethyl acetate in hexane) gave 1.9 g (71%) of 4-azidocyclopent-2-enone as a light-yellow oil.
Reaction SMILES: [CH:1]12[CH2:8][CH:4]([CH2:5][C:6]1=O)[C:3]1[CH:9]=CC=C[C:2]2=1.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15]C1>>[CH:4]12[CH2:8][CH:1]([CH2:6][CH2:5]1)[CH2:2][CH:3]2[CH:9]1[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:13]1
Reactant: c1ccc2c(c1)OCO2
Reactant: O=C1CC2CC1c1ccccc12
Product: c1ccc2c(c1)OC(C1CC3CCC1C3)O2

Procedure:
benzobicyclo[2.2.1]heptan-2-one is converted to 2-(benzobicyclo[2.2.1]hept-2-yl)-1,3-benzodioxole in 93.5% yield.
Reaction SMILES: [CH2:1]([Cl:5])[C:2](=[CH2:4])[CH3:3].[CH3:6][N:7]([S:11]Cl)[C:8]([F:10])=[O:9].C(Cl)[Cl:14]>>[CH3:6][N:7]([S:11][C:2]([CH3:3])([CH2:4][Cl:14])[CH2:1][Cl:5])[C:8]([F:10])=[O:9]
Reactant: CN(SCl)C(=O)F
Reactant: ClCCl
Reactant: C=C(C)CCl
Product: CN(SC(C)(CCl)CCl)C(=O)F

Procedure:
To a solution of 1.35g of methallyl chloride in 25 ml of methylene chloride was added 2.15g of N-methyl-N-chlorosulfenyl carbamoyl fluoride. The solution was heated to reflux for 45 min. and concentrated to 1.68g of pale yellow oil. Infra-red (neat) 5.57 (C=O), 6.9, 7.0, 7.26, 7.65, 8.45, 9.15, 10.42, 12.3, 13.3 and 14.1μ. NMR (CDCl3) δ 1.39 (s), 3H; 3.36 (d), J = 1.0 HZ, 3H, 3.92 (s), 4H.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.C1C=CC(N[S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=CC=1>C1COCC1>[F:35][C:34]([F:37])([F:36])[S:31]([O:22][C:19]1[CH2:18][CH2:17][C:16]2([O:15][CH2:14][CH2:13][O:23]2)[CH2:21][CH:20]=1)(=[O:33])=[O:32]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine, (6.24 mL, 44.2 mmol) in THF (60 mL) at −78° C. under argon was slowly added n-butyllithium (17.7 mL, 44.2 mmol, 2.5 M in hexanes). The mixture was stirred for 30 min at that temperature before 1,4-cyclohexanedione mono-ethylene ketal (6.00 g, 38.4 mmol) was added slowly as a solution in THF (20 mL). The mixture was stirred for an additional 30 min at −78° C. and then n-phenyltriflamide (13.7 g, 38.4 mmol) was slowly added as a suspension in THF (50 mL). This mixture was stirred overnight with gradual warming to room temperature. The solvent was removed in vacuo and the remaining oil was partitioned between 3:1 ethyl acetate/hexane and water. The layers were separated and the organic layer was washed with water (3×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate.
Reaction SMILES: CS[CH2:3][C@H:4]([N:6]1[C:14]2[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5].O[O:22][S:23]([O-:25])=O.[K+].[CH3:27]O>O>[CH3:27][S:23]([CH2:5][C@H:4]([N:6]1[C:14]2[C:9](=[C:10]([C:17]([F:19])([F:18])[F:20])[C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:3])(=[O:25])=[O:22]
Reactant: CO
Reactant: CSC[C@@H](C)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: C[C@H](CS(C)(=O)=O)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To an ice-cold solution of (R)-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.560 g, 1.88 mmol) in MeOH (10 mL) was added a solution of Oxone (4.04 g, 6.57 mmol) in water (10 mL). After 50 min, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using 100% CH2Cl2 to give (R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile as a white foam that was crystallized from CH2Cl2/hexanes to afford a white solid (0.508 g, 79% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J=8.6 Hz, 1H), 8.12 (d, J=3.5 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 6.87-6.84 (m, 1H), 5.43-5.35 (m, 1H), 4.01 (dd, J=14.8, 8.6 Hz, 1H), 3.83 (dd, J=14.8, 4.9 Hz, 1H), 2.77 (s, 3H), 1.59 (d, J=6.8 Hz, 3H); MS (ESI): m/z 331 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: C=CCn1c(C(=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Yield: 60.8 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and allyl bromide were reacted by the same way with the example 45-1 to obtain the titled compound (190 mg, yield: 60.8%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].[CH:18](OC(=O)C)=[O:19]>ClCCl.C(OCC)(=O)C>[CH:18]([NH:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17])=[O:19]
Reactant: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: CC(=O)OC=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1[C@@H](NC=O)C(=O)N1C(C(=O)OC)=C(C)C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (500 mg) in dichloromethane (5 ml) was added acetic formic anhydride (0.34 ml) at 0°. After stirring at the same temperature for one hour, the mixture was diluted with ethyl acetate (35 ml) and washed with a dilute aqueous sodium bicarbonate. The aqueous layer was saturated with sodium chloride and extracted with dichloromethane. The extracts were combined, washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (2.5 g) eluting with 10-30% acetone in dichloromethane afforded methyl 2-[(3R,4R)-3-formamido-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (485 mg).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=2[O:27]1>C1(C)C=CC=CC=1.C(O)C.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>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:31]2[CH:30]=[CH:29][C:28]3[O:27][CH2:26][O:34][C:33]=3[CH:32]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
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: Cc1ccccc1
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc3c(c2)OCO3)C1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 44.7 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (200 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium carbonate, and 150 mg of (3,4-methylenedioxy)benzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 100 mg of 2,2-dimethyl-4-(3,4-methylenedioxyphenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.60 (s, 6H), 3.07 (s, 3H), 5.99 (s, 2H), 6.74 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.94 (d, J=8.7 Hz, 2H). IR (cm−1): 1697, 1503, 1404, 1245, 1148, 959, 770.
Reaction SMILES: [NH:1]([C:3]([CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=O)[NH2:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[N:25].Br[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:39][N:38]3[CH:47]=[CH:48][N:49]=[C:37]3[N:36]=2)=[CH:31][CH:30]=1)[CH3:28]>CN(C=O)C.CO>[C:41]1([C:40]2[C:35]([C:32]3[CH:33]=[CH:34][C:29]([CH:27]([N:8]4[CH2:7][CH2:6][CH:5]([C:3]5[N:25]=[C:24]([C:19]6[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=6)[NH:2][N:1]=5)[CH2:10][CH2:9]4)[CH3:28])=[CH:30][CH:31]=3)=[N:36][C:37]3[N:38]([CH:47]=[CH:48][N:49]=3)[CH:39]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(Br)c1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: N#Cc1ccccn1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(c1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1)N1CCC(c2n[nH]c(-c3ccccn3)n2)CC1
Reaction time: 20 h

Procedure:
To a solution of 0.2 g 2-(5-Piperidin-[1,2,4]triazol-3-yl)-pyridine*2HCl (prepared from tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate and pyridine-2-carbonitrile according to a procedure described in U.S. Pat. No. 4,011,218 or WO2005100344) in 7 ml DMF are added 120 mg of the product obtained in step 2 dissolved in 1 ml methanol and the mixture is stirred for 20 h. The mixture is concentrated and the crude product is purified by reversed phase HPLC (Water, 10 mM NH4COOH, pH 3.7/ACN)
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 100.3 %

Procedure:
The title compound (129 mg) was prepared as in Example 177, Steps C and D, using 204 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 194 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.28 (d, J=7.7 Hz, 2H), 7.12 (d, J=7.7 Hz, 2H), 4.32 (m, 1H), 3.34-3.33 (m, 2H), 3.12-3.10 (m, 2H), 2.70-2.68 (m, 2H), 2.33 (s, 3H), 1.30 (d, J=6.6 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].N1C=CC=CC=1.[CH2:19]([O:21][C:22]([CH2:24][S:25](Cl)(=[O:27])=[O:26])=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]([CH2:24][S:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:27])=[O:26])=[O:23])[CH3:20]
Reactant: COC(=O)Cc1ccccc1N
Reactant: CCOC(=O)CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CS(=O)(=O)Nc1ccccc1CC(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 82.7 g of methyl 2-aminophenylacetate (see Example l) in 1.2 l of toluene is added 42 ml of pyridine and the mixture is stirred at room temperature. To this mixture is added a solution of 93.2 g of ethoxycarbonylmethylsulfonyl chloride in 150 ml of toluene in a dropwise manner over a period of 30 minutes, maintaining the temperature of the reaction below 10° by means of an ice-water bath. After stirring at 0° for an additional 1 hour, the mixture is poured into 50 ml of ice-water, the organic layer is separated and washed with 150 ml of cold dilute hydrochloric acid followed by 150 ml of brine. The toluene extract is dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield methyl 2-(ethoxycarbonylmethylsulfonylamino)-phenylacetate as an oil which is used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]([C:6]([Cl:8])=[O:7])=[CH:4][CH:3]=[N:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>O1CCOCC1>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:5]3[O:1][N:2]=[CH:3][CH:4]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)c1ccno1
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)c4ccno4)CC3)nc(N)c2cc1OC
Product: Cl
Reaction time: 16 h
Yield: 95.5 %

Procedure:
A solution of isoxazole-5-carbonyl chloride (1.33 g., 0.01 mole) in dioxane was added to a solution at 30° C. of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.94 g., 0.01 mole) in dioxane. The mixture was stirred at reflux for three minutes, then at room temperature for 16 hours. Filtration gave the title compound (4.02 g., 94% yield). Recrystallization from aqueous methanol gave a product having a m.p. of 270° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([CH3:14])([CH3:13])[CH3:12].CN(C)CCN(C)C.C([Li])CCC.[I:28]I>CCOCC.O1CCCC1>[CH3:10][O:9][C:6]1[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[I:28]
Reactant: COc1ccc(OC)c(C(C)(C)C)c1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C)c(OC)cc1I
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A stirred solution of 3.00 g (15.5 mmol) of 1,4-dimethoxy-2-t-butyl-benzene (obtained by methylation of t-butyl hydroquinone with sodium hydride and methyl iodide in tetrahydrofuran) and 2.52 g (21.7 mmol) of tetramethylethylenediamine in 50 mL of anhydrous ether under nitrogen is cooled to 0° C. and 8.66 mL (21.7 mmol) of n-butyllithium (2.5M in hexane) is added over a 5 minute period. The mixture is warmed to 22° C., stirred for 18 hours and then cooled back to 0° C. The reaction is quenched with 7.86 g (30.9 mmol) of iodine in 30 mL of tetrahydrofuran and partitioned between ethyl acetate (200 mL) and 10% NaHSO3 (300 mL). The organic layer is washed with water (50 mL), brine (50 mL), dried (MgSO4) and evaporated to give a brown, partially crystalline oil which is chromatographed on silica gel (eluting with 98:2 hexane/ethyl acetate) to give crude product which is recrystallized from hexane to obtain 2,5-dimethoxy-4-t-butylphenyl iodide m p 80.5°-82.5° C.)