Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:16][CH3:17])=[C:6]([Cl:15])[CH:7]=[C:8]([N+:12]([O-])=O)[C:9]=1[O:10][CH3:11])([O-:3])=[O:2].C1CCCCC=1>[Pd].C(O)C>[NH2:12][C:8]1[C:9]([O:10][CH3:11])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([O:16][CH3:17])=[C:6]([Cl:15])[CH:7]=1
Reactant: COc1c(Cl)cc([N+](=O)[O-])c(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1c(N)cc(Cl)c(OC)c1[N+](=O)[O-]

Procedure:
A mixture consisting of 0.2 mole (52.5 g) of 3,5-dinitro-2,4-dimethoxychlorobenzene and 15.9 g of palladium on charcoal (10%) in 260 ml of absolute ethanol containing 110 ml of cyclohexene was heated to reflux for 1 hour.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][N:17](C)[CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=13.ClC(OC(Cl)C)=O>ClC(Cl)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=13
Reactant: CN1CCc2ccc(F)c3c4c(n(c23)CC1)CCCC4
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Fc1ccc2c3c1c1c(n3CCNCC2)CCCC1
Temperature: 25 °C
Yield: 30 %

Procedure:
To a solution of 8-fluoro-3-methyl-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.37 g, 3.48 mmole) in dichloroethane (100 mL) was added 1-chloroethyl chloroformate (1.0 mL, 9.18 mmole) and the mixture refluxed for 24 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo and replaced with methanol (100 mL) and refluxed for another 3 hours. The reaction mixture was then cooled to room temperature and the solvent removed in vacuo. The dark residue was dissolved in methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 3% methanol in dichloromethane) provided 0.27 g of the title compound. 0.23 g of the above solid was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 177-179° C. MS (ESI) m/z 259 ([M+H]+).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([OH:39])[CH:37]=2)[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:39][C:36]1[CH:37]=[C:38]2[C:33]([CH2:32][CH2:31][N:30]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])=[CH:34][CH:35]=1
Reactant: Oc1ccc2c(c1)NCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ccc(O)cc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 mg (0.37 mmol) 2,3-dihydro-1H-indol-6-ol, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:22]=[O:23])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1(C)CCSc2ccc(Br)cc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCSc2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.4 g (36.6 mmol) of 4,4-dimethyl-6-bromothiochroman and 100 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 16.1 ml of an n-butyllithium solution (2.5M in hexane) were added dropwise at -78° C. and stirring was carried out for 30 min. 2.7 ml (38.4 mmol) of DMF were then added dropwise and the mixture was permitted to heat to room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporating the solvents, 6.1 g (81%) of the expected aldehyde were recovered in the form of a yellow oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:25]#[N:26])(C)C>[I-].[Zn+2].[I-].CCOCC>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:25]#[N:26])=[CH:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Product: N#CC1=CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 15 h
Yield: 44 %

Procedure:
6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one from Preparation 1 above (4.0 g, 14 mmol), trimethylsilyl cyanide (10.0 g, 100 mmol) and Zinc Iodide (0.25 g) were combined and stirred under nitrogen for 15 hours. The reaction mixture was then diluted by addition of 200 mL of Et2O, washed with cold water, and the organic layer was dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was dissolved in 250 mL of toluene, and 0.5 g of paratoluene sulfonic acid was added. The reaction mixture was refluxed for three hours, cooled, and the solvent was removed under reduced pressure. The crude product was eluted through silica under medium pressure with 5% EtOAc in hexanes to yield 1.8 g (6.1 mmol, 44%) of (racemic) 6-benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile as an oil. MS: 296 (M+H)+.′
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.19 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]>C(O)(=O)C.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:13]2[C:12]3[C:17](=[CH:18][CH:9]=[C:10]([N+:28]([O-:30])=[O:29])[CH:11]=3)[N:16]([O:6][CH2:5][CH2:4][O:3][CH3:2])[CH2:15][N:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Reactant: COCCO
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: COCCON1CN=C(Nc2ccc(Cl)cc2F)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Sodium (148 mg, 6.4 mmol) was added to 2-methoxyethanol (10 ml), the mixture stirred for 15 minutes to give a complete solution and the volatiles removed by evaporation. The residue was dissolved in DMSO (5 ml) and 7-chloro-4-(4-chloro-2-fluoroanilino)-6 nitroquinazoline hydrochloride (500 mg, 1.3 mmol) was added. The mixture was stirred at ambient temperature for 18 hours then diluted with a solution of acetic acid (1 ml) in water (20 ml). The resulting precipitate was collected by filtration, washed with water, dried and purified by column chromatography eluting with methylene chloride/methanol (96/4). The purified product was recrystallized from methylene chloride/isohexane to give 4-(4-chloro-2-fluoroanilino)-1-(2-methoxyethoxy)-6-nitroquinazoline (304 mg, 60%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH:9]([OH:13])[CH2:10][O:11][CH3:12].C(N(CC)CC)C>ClCCl>[CH3:6][O:7][CH2:8][CH:9]([O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][O:11][CH3:12]
Reactant: COCC(O)COC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(COC)OS(C)(=O)=O
Reaction time: 72 h

Procedure:
4.3 mL of methanesulfonyl chloride was added dropwise at 5° C. to a stirred solution of 6.0 g of 1,3-dimethoxy-propan-2-ol and 9.0 mL of triethylamine in 60 mL of dichloromethane. Stirring was continued for 72 hours at room temperature, followed by extraction with water. The combined organic extracts were dried (sodium sulfate) and concentrated and the residue purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v) yielding 2.5 g of methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester as an oil. EI-MS: 198 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(F)c(Br)c1

Procedure:
3-Bromo-4-fluorophenylacetic acid (2.35 g, 9.0 mmol) was treated with concentrated sulfuric acid (2 mL) in ethanol (100 mL) at reflux for 2 hours. Purification by silica gel chromatography provided the title compound.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:12][CH:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCC.O1CCCC1>[C:19]([N:17]1[CH:13]([O:12][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][C:16]1=[O:18])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
16 cm3 of a 1.6M solution of butyllithium in hexane is added at -70° C. to 4.5 g of 5-n-hexyloxy pyrrolidin-2-one in solution in 130 cm3 of anhydrous tetrahydrofuran. Agitation is carried out for 20 minutes at -70° C. and under the same conditions a solution of 3.4 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. After allowing to return to ambient temperature and concentration under reduced pressure, the residue is chromatographed on silica (eluent: toluene-ethyl acetate 8-2). 3.3 g of the product sought is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH3:16].[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([N:19]1[N:20]=[CH:21][CH:22]=[N:18]1)[N:6]2[CH3:16]
Reactant: c1c[nH]nn1
Reactant: CC(O)CCc1nc(N)c2nc(Br)n(C)c2n1
Solvent: CN(C)C=O
Product: CC(O)CCc1nc(N)c2nc(-n3nccn3)n(C)c2n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-amino-8-bromo-9-methyl-9H-purin-2-yl)butan-2-ol (1.4 g, 4.56 mmol) in anhydrous DMF (20 ml) were added CsCO3 (5.9 g, 18.24 mmol) and 1H-1,2,3-triazole (1.2 g, 1.0 ml, 18.24 mmol). The mixture was stirred overnight at 90° C. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (DCM/MeOH: 93/7).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[C:16]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=3)[CH2:8]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Solvent: CO
Product: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1

Procedure:
A 30 gallon glass-lined reactor was charged with a solution containing equal parts of 3-(3-trifluoromethylphenoxy)azetidine and diphenylmethane in methanol as obtained from the catalytic hydrogenolysis of 78.32 moles of 1-diphenylmethyl-3-(3-trifluoromethylphenoxy)azetidine. The methanol was distilled off at a pressure of 150 mm Hg until the reactor temperature reached 65° C. The reactor was flushed with nitrogen and charged with 117.4 moles of urea. Heating was continued to approximately 135° C. and held at 135° C. until thin layer chromatographic analysis showed the azetidine derivative to be consumed. When the reaction was complete the mixture was cooled to approximately 80° C. A 30 gallon receiver equipped with an agitator was charged with 80 L of petroleum ether (80°-110° C. boiling range) and the contents of the reactor drained into the receiver with the agitator at high speed. The mixture was slowly cooled to 50° C. and held at that temperature for 5-6 hours. The resulting slurry was then pumped onto a vacuum filter and the filter cake compressed under a rubber dam for 4-5 hours to remove as much solvent as possible.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].[Cl:12][C:13]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].Cl>C(O)C.O>[Cl:12][C:13]1[N:20]=[C:19]([S:11][C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: Fc1ccc(S)c(F)c1
Reactant: N#Cc1ccc(Cl)nc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(Sc2ccc(F)cc2F)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
A solution of 362 mg (1.05 eq) of potassium hydroxide in 10 mL of ethanol is added, under nitrogen, to a solution of 698 μL (6.16 mmol) of 2,4-difluorobenzenethiol in 30 mL of ethanol. The reaction medium is stirred at room temperature for 15 minutes and then cooled in ice before adding a solution of 1.015 g (0.95 eq) of 2,6-dichloronicotinonitrile in 30 mL of ethanol. The reaction medium is stirred for 2 hours at 0-5° C. 63 mL of a 0.1N HCl solution is added to stop the reaction. Water is added and the producted is extracted with ethyl acetate. The organic phase is dried on anhydrous magnesium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 94:6) to yield 1.09 g (66%) of 2-chloro-6-(2,4-difluorophenylthio)-nicotinonitrile in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][O:25][C:21](=[O:24])[CH:22]=[CH:23][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:3]=1
Reactant: Brc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Reaction time: 0.33 h

Procedure:
Crude aryl bromide (14) (100 mg, 0.18 mmol), methyl acrylate (18 mg, 0.21 mmol), triethylamine (71 mg, 0.70 mmol), tri(o-toly)phosphine (5 mg, 0.016 mmol) and palladium(II) acetate (12 mg, 0.054 mmol) in acetonitrile (2 mL) was heated in a CEM Discover microwave for 45 minutes at 90° C. More tri(o-toly)phosphine (3 mg) and palladium(II) acetate (3 mg) were added and the reaction mixture retreated in the microwave for 20 minutes; palladium(II) acetate (2 mg) was then added and the process repeated for a further 25 minutes. The solvent was removed under a stream of nitrogen gas, water was added, and the organics extracted with EtOAc, washed with water, dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was partially purified by column chromatography. Yield: 51 mg, 60%; LC-MS tr 1.82 min; HPLC Purity: 70%; MS (ES+) m/z 348 (M+H)
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[O:18][CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]([OH:23])[CH2:21][N:22]=2)[CH:14]=[CH:15][CH:16]=1>ClCCCl>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[O:18][CH:19]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:20]([O:23][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:21][N:22]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: OC1CN=C(c2cccc(Cl)c2)OC1c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2cccc(Cl)c2)OC1c1ccccc1
Yield: 49.1 %

Procedure:
Phenyl isocyanate (1.43 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(3-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (3.55 g) in 1,2-dichloroethane (45 cc). The solution is heated to reflux for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 2.5 cm in diameter [eluent: cyclohexane/ethyl acetate (7:3 by volume)], collecting 20-cc fractions. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-2-(3-chlorophenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (2.4 g), m.p. 126° C., is obtained.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([OH:5])=O.CN1CCOCC1.Cl.[NH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([NH:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:5]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)O)ccc2-3)cc1
Reactant: CS(=O)(=O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)NCCS(C)(=O)=O)ccc2-3)cc1
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a solution of 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (example 127, 35 mg, 0.096 mmol) in DMF (1 mL) was added 4-methylmorpholine (0.064 mL, 0.58 mmol), 2-aminoethylmethylsulfone hydrochloride (27.7 mg, 0.17 mmol), and BOP (77 mg, 0.17 mmol). The reaction mixture was stirred overnight and was then purified by preparative HPLC (Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min). Fractions containing the desired product were combined and dried via centrifugal evaporation to give 2-hydroxy-N-(2-(methylsulfonyl)ethyl)-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (8.3 mg, 0.018 mmol, 18.4% yield): product HPLC ret. time=2.54 min. (condition F); LC/MS M+1=468; 1H NMR (400 MHz, 1:1 CD3OD and CDCl3) δ ppm 7.87 (1H, d, J=8.36 Hz), 7.67 (2H, d, J=8.14 Hz), 7.40-7.50 (2H, m), 7.31 (2H, d, J=8.36 Hz), 5.06 (1H, s), 3.73 (2H, t, J=6.49 Hz), 3.19-3.30 (2H, m), 2.94 (3H, s), 2.57-2.70 (2H, m), 1.60-1.77 (2H, m), 0.94 (3H, t, J=7.37 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 30 °C
Reaction time: 7 h

Procedure:
0.91 g of 1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.82 g of toluene and 0.36 g of thionyl chloride were fed, and the mixture was heated to 30° C. 0.56 g of n-tributylamine was slowly added in dropwise. The mixture was heated to 70° C., and stirred for 7 hours. The mixture was cooled to room temperature, and separated by adding iced water. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. 0.86 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:22][C:23]([NH2:25])=[NH:24].[ClH:26].C[O-].[Na+]>CO.O>[NH2:24][C:23]([NH2:25])=[N:22][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:11][C:2]=1[CH3:1].[ClH:26]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N2CCCCC2)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(N2CCCCC2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 1 h

Procedure:
A solution of 20 g of methyl 2-methyl-4-piperidino-5-methylsulfonylbenzoate [obtainable by reacting piperidine with 2-methyl-4-chloro-5-methylsulfonylbenzoic acid followed by esterification] and 30 g of guanidine, which has been liberated beforehand from the guanadine hydrochloride using sodium methylate, is stirred in 160 ml of methanol at 50° over a period of twenty hours. After cooling to 0°, water is added, stirring is continued for 1 hour and the precipitate which forms is separated off. Recrystallization from dichloromethane/methanol gives N-diaminomethylene-2-methyl-4-piperidino-5-methylsulfonylbenzamide, m.p. 222°-224°, hydrochloride m.p. 275°-276°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:18]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:21]([O:20][C:18](=[O:19])[NH:25][C:26]1[CH:27]=[CH:28][C:29]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:30][CH:31]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(NC(=O)OC(C)(C)C)cc2)cn1
Yield: 5 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 4-(N-Boc-amino)phenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (10 mg, 5%) which was obtained as a white solid (ESI). MS: m/e=417.0 [M+H]+.