Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:17](/B(O)O)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22].[ClH:26]>CCOCC>[ClH:26].[CH:17](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COCCCNc1ccc2ncc(Br)n2n1
Reactant: CCCC/C=C/B(O)O
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCOC)nn12
Yield: 54 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (43 mg, 54%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=9.7 Hz, 1H), 7.42 (s, 1H), 6.78 (dt, J=16.1, 7.0 Hz, 1H), 6.64-6.58 (m, 2H), 3.53 (t, J=6.2 Hz, 2H), 3.44 (t, J=6.2 Hz, 2H), 3.35 (s, 3H), 2.30-2.26 (m, 2H), 1.97-1.92 (m, 2H), 1.53-1.40 (m, 4H), 0.96 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 157.1, 139.2, 133.2, 130.0, 121.0, 120.6, 117.8, 114.3, 71.4, 59.0, 40.0, 34.3, 32.3, 29.4, 23.3, 14.3; HPLC tR=12.3 min, 98.6%; ES-MS: (M+H)=289 m/z.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([N:9]([CH3:21])[C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl>C(OCC)(=O)C>[NH2:1][C@H:2]([C:7]([N:9]([CH3:21])[C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](Cc1ccccc1)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)N(C)[C@@H](Cc1ccccc1)C(N)=O

Procedure:
De-(1,1-dimethylethoxy)carbonylation of Boc-Leu-MePhe-NH2 and Boc-Leu-Mephe-NH2 (mixture of isomers, 3.7 g.) with hydrogen chloride in ethyl acetate (4.4N, 25 ml.) for 2 hr. at room temperature and isolation of the product by precipitation with ether gave H-Leu-MePhe-NH2 and H-Leu-Mephe-NH2 (mixture of isomers) hydrochloride salt (2.63 g., 85% yield, m.r. 124°-127° C.).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:13][C:14]#[N:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:13][C:14]#[N:15])[CH2:3][CH2:2]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)N1CCNCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3 g (19.0 mmol) of ethyl N-piperazinecarboxylate in 25 mL of CH3CN was added 1.57 g (1.32 mL 20.1 mmol) of 2-chloroacetonitrile and 15.6 g (95 mmol) K2CO3.1½H2O. The suspension was stirred at room temperature for 16 hours. The reaction was analyzed using TLC (35% Ethyl acetate/Hexanes, product r.f. 0.38 vs. sm r.f. of 0.02). The analysis indicated the reaction was complete. The golden yellow solution was evaporated to dryness. The residue was extracted with CH2Cl2/H2O, dried with MgSO4, and concentrated.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:18]=[C:17]([NH2:19])[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)[N:10]=2)[CH2:5][CH2:4]1)#[N:2].[CH2:24]([O:26]CC)C.Cl.[OH-].[Na+]>CO>[CH3:24][O:26][C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:18]=[C:17]([NH2:19])[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)[N:10]=2)[CH2:5][CH2:4]1)=[NH:2]
Reactant: CCOCC
Reactant: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=N)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under anhydrous conditions, 6.3 g. (0.02 mole) of 2-(4-cyanopiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline is dissolved in 150 ml. of ethyl ether and 1.8 ml. (0.044 mole) of reagent grade methanol is added. The solution is cooled to 0° C. and anhydrous hydrogen chloride is added until the solution is acid to Congo red paper. The resulting mixture is stored at 0° C. for 2 hours, then allowed to warm to room temperature (25° C) overnight. The reaction mixture is made alkaline with 2N sodium hydroxide, the ether layer separated, washed with 2 × 50 ml. of water, dried over anhydrous magnesium sulfate and evaporated to dryness to obtain the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[C:9]([CH2:21][OH:22])=[N:8]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[C:9]([CH:21]=[O:22])=[N:8]1
Reactant: OCc1nn(C2CCCCO2)cc1-c1ccnc2[nH]ccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1nn(C2CCCCO2)cc1-c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of [1-(oxan-2-yl)-4-{1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl]methanol (5.5 g, 18.46 mmol) in dichloromethane (40 mL) was added the Dess-Martin reagent (11.7 g, 27.68 mmol). The reaction mixture was stirred at room temperature for three hours. When TLC showed completion of reaction, it was quenched with aqueous NaHCO3 (saturated, 100 mL) and extracted with ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:23]1([C:27]([C:29]2[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
A mixture of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (80 mg, 0.26 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (52 mg, 0.26 mmol) and caesium carbonate (172 mg, 0.53 mmol) in acetonitrile (3 mL) was stirred in a Smith Creator microwave at 160° C. for 1 hr. The solvent was removed in vacuo and ethyl acetate (50 mL) added to the residue. The organic phase was washed with water (20 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica eluting with a gradient of 0-10% methanol in DCM to give the title compound (36 mg, 31%) as a white foam. This compound was crystallised from ethyl acetate and isohexane using vapour diffusion techniques. 1H NMR δ (CDCl3): 2.12-2.19 (1H, m), 2.21-2.28 (1H, m), 2.34-2.42 (2H, m), 3.75 (3H, s), 3.88-3.93 (1H, m), 3.98-4.02 (3H, m), 4.23 (2H, t), 4.69 (2H, t), 4.95-4.97 (1H, m), 6.80 (1H, d), 6.87 (1H, t), 7.23 (1H, d), 7.27-7.30 (1H, m), 7.28-7.30 (1H, m), 8.34 (1H, d), 8.84 (1H, d), 8.98 (1H, s); m/z 465 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:23][C:24](=[O:25])[C:4]=2[CH:3]=1)[C:13]1[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:16][C:12]=1[CH2:11][CH2:10][CH2:9]3.[O:26]1CCOCC1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].CC1C=C(C)N=C(C)C=1>O.CCOC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:23][C:24](=[O:25])[C:4]=2[CH:3]=1)[C:13]1[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:16][C:12]=1[C:11](=[O:26])[CH2:10][CH2:9]3
Reactant: C1COCCO1
Reactant: O=C1OC2(CCCc3sc(-c4ccncc4)cc32)c2ccc(Cl)cc21
Agent: [Cu+2]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C1OC2(CCC(=O)c3sc(-c4ccncc4)cc32)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 3 %

Procedure:
In a 100 mL round bottomed flask was placed 5-chloro-2′-pyridin-4-yl-6′,7′-dihydro-3H,5′H-spiro[2-benzofuran-1,4′-[1]benzothiophen]-3-one (0.714 g, 1.94 mmol) (including side product) along with 1,4-dioxane (20 mL) and acetonitrile (10 mL). To the mixture was added a suspension of potassium persulfate (1.85 g, 6.84 mmol) and copper (II) sulfate pentahydrate (180 mg, 0.72 mmol) in water (20 mL) followed by γ-collidine (0.897 mL, 6.79 mmol). The mixture was stirred for 3.5 hr at 80° C. Again, to the mixture was added a suspension of potassium persulfate (1.96 g, 7.25 mmol) and copper(II) sulfate pentahydrate (20 mg, 0.08 mmol) in water (20 mL, 1000 mmol) followed by γ-collidine (0.9 mL, 7 mmol) and 1,4-dioxane (10 mL, 100 mmol). The mixture was stirred for an additional 16 hr at 80° C. The mixture was allowed to cool to rt and then diluted with EtOAc (50 mL). Insoluble materials were removed by filtration through a celite pad and the aqueous phase was separated from the filtrate. The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (FA) to obtain the title compound (22.5 mg; 3%) as an off-white crystalline solid. LCMS: (FA) ES+ 382, 384; 1H NMR (400 MHz, d6-DMSO) δ ppm 8.59 (dd, 2H), 8.07 (d, 1H), 7.89 (dd, 1H), 7.77 (d, 1H), 7.71 (dd, 2H), 7.46 (s, 1H), 2.47-3.05 (m, 4H).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:27]1[N:28]=[C:29]([NH:32]C=O)[S:30][CH:31]=1)[C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]12)=[O:8])[CH2:2][CH3:3].[ClH:35]>CO>[ClH:35].[CH2:1]([O:4][N:5]=[C:6]([C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1)[C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]12)=[O:8])[CH2:2][CH3:3]
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-[2-Propoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)(0.5 g) was suspended in methanol (15 ml). To the suspension was added conc. hydrochloric acid (0.2 ml) and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated and the residue was washed with tetrahydrofuran, collected by filtration and dried to give 7-[2-propoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer)(0.4 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH3:29])=[O:25])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reactant: CC(C)(C)CN
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCC(C)(C)C)c1

Procedure:
Example 140 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 2,2-dimethyl-1-propanamine to give the title compound (0.008 g).
Reaction SMILES: N1CCCCC1.C1C2C(COC(=O)[NH:23][C@@H:24]([CH:27]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28]3)[CH2:25][OH:26])C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[NH2:23][C@@H:24]([CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)[CH2:25][OH:26]
Reactant: O=C(N[C@H](CO)C1Cc2ccccc2C1)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: N[C@H](CO)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 225.2 %

Procedure:
20% Piperidine in DMF (15 mL) was added to a solution of 9H-fluoren-9-ylmethyl-(1S)-1-(2,3-dihydro-1H-inden-2-yl)-2-hydroxyethylcarbamate (1.05 g, 2.63 mmol) in DMF (5 mL). The reaction was stirred at 25° C. for 19 h. After solvent evaporation, the crude product was dissolved in ethyl acetate (50 mL) and dried over MgSO4, filtered and concentrated to obtain a crude yellow oil (1.05 g). Mass Spectrum (+ESI): 179 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(NC(C)C)(C)C.C([Li])CCC.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=O)[O:29]C(OCC)=[N:27][C:26]=2[CH:35]=1>CCCCCC.O1CCCC1.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:29])[C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6](=[O:8])[NH:27][C:26]=2[CH:35]=1
Reactant: O=C(O)c1ccsc1
Reactant: CCOc1nc2cc(Cl)ccc2c(=O)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c2sccc12
Temperature: 0 °C

Procedure:
A 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel and a condenser with nitrogen inlet-outlet is charged with thiophen-3-carboxylic acid (448.2 g) and tetrahydrofuran (4.7 L) and stirred to dissolution. The solution is cooled to 0° C. and diisopropylamine (245 mL) is added over 5 min. Then, a 1.6M solution of butyl lithium in hexane (4.8 L) is added over 2.5 hours while maintaining the internal temperature at 0° C. The mixture is stirred for an additional hour before being cooled to −65° C. Then 7-Chloro-2-ethoxy-benzo[d][1,3]oxazin-4-one (830 g), dissolved in tetrahydrofuran (1.7 L) is added over 1 hour. The mixture is stirred at −65° C. for 1 hour, then warmed to 0° C. over 40 min and stirred for 30 min. Then water (4 L) is added over 10 min letting the temperature be raised to 20° C. The mixture is stirred at this temperature for 16 hours before being concentrated under reduced pressure to remove the organic solvents. To the residue ethanol (11 L) and lithium hydroxide (295.5 g) are added. The mixture is heated to 60° C. over 45 min, stirred at this temperature for 3 hours, then the temperature is raised to 75° C. over 10 min and hydrochloric acid (2 L, 37% m/m) is added over 10 min under gentle reflux. The mixture is stirred for an hour at 60-65° C. The suspension is then cooled to room temperature and the solid is collected, washed 5 times with water (4.2 L total), ethanol (5 L total) and dried under vacuum (60° C., 50 mbar) to yield the title compound with a melting point of >280° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:33]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:35]=1)[CH2:12][NH:13][CH2:14][C@@H:15]([OH:32])[C@@H:16]([NH:24]C(=O)OC(C)(C)C)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1>Cl.CO.[Pd]>[NH2:24][C@@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@H:15]([OH:32])[CH2:14][NH:13][CH2:12][C:11]1[CH:10]=[C:9]([OH:8])[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[CH:33]=1
Reactant: CC(C)c1cc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)c1cc(O)cc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
A mixture of 21.2 mg (0.04 mmol) of tert-butyl (2S,3R)-4-(3-(benzyloxy)-5-isopropylbenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate and 7.7 mg of 10% Pd/C in 4 mL of 1.25M HCl in MeOH was stirred at r.t. under H2 balloon for 20.5 h. The mixture was filtered through Celite, concentrated, and reconcentrated with toluene 3 times. The amine HCl salt was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:27]CO.[OH-].[K+].IC>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH3:27])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C
Temperature: 25 °C
Reaction time: 74 h

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide (700 mg, 1.90 mmol), EtOH (22 ml), KOH (151 mg, 2.70 mmol) and iodomethane (0.26 ml, 593 mg, 4.18 mmol) were added to a microwave oven reaction vial. The reaction mixture was stirred at RT for 74 h. Then water was added and the solution was evaporated to dryness. Water was added again and the precipitation was filtered and washed with water and heptane. Flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-99:1) afforded the product, which was recrystallized in ethyl acetate, filtered at RT and washed with heptanes to afford the title compound. 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 2.39 (3H, s), 3.60 (3H, s), 4.29 (1H, distorted dd), 4.38 (1H, distorted dd), 4.55 (1H, m), 6.60 (1H, d), 7.41 (1H, s), 7.48 (1H, d), 7.54 (1H, d), 7.66 (1H, d), 7.85 (1H, dd), 7.99 (1H, d).
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1>N1CCC(O)CC1>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:42](=[O:43])[C:41]2[CH:40]=[CH:39][C:38]([S:35]([N:32]3[CH2:31][CH2:30][CH:29]([OH:28])[CH2:34][CH2:33]3)(=[O:37])=[O:36])=[CH:46][CH:45]=2)=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: OC1CCNCC1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)N2CCC(O)CC2)cc1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 506 μL of piperidin-4-ol via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 114 mg of 4-(4-hydroxypiperidin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-hydroxypiperidin-1-ylsulfonyl)benzamide. MS (Q1) 472.3 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=3)[N:9]=2)=[C:4]([S:23][CH2:24][CH3:25])[CH:3]=1.P(Cl)(Cl)([Cl:28])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:28][C:16]1[C:15]2[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[S:23][CH2:24][CH3:25])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1cc(Cl)ccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1cc(Cl)ccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 1.46 g of 2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one, 0.39 ml of phosphorus oxychloride, 538 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 90° C. for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 1.31 g of 4-chloro-2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 14).
Reaction SMILES: P(I)(I)P(I)I.[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:56][O:57][CH3:58])[C:33]([NH:35][CH:36]2[C:43](=[O:44])[N:42]3[CH:37]2[CH2:38][S:39][CH:40]([CH2:53][O:54][CH3:55])[C:41]3(O)[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:34])[N:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:56][O:57][CH3:58])[C:33]([NH:35][CH:36]2[C:43](=[O:44])[N:42]3[CH:37]2[CH2:38][S:39][C:40]([CH2:53][O:54][CH3:55])=[C:41]3[C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[O:34])[N:31]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCC1SCC2C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N2C1(O)C(=O)OC(C)(C)C
Agent: IP(I)P(I)I
Solvent: c1ccncc1
Product: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2CS1
Reaction time: 0.08 h
Yield: 23.6 %

Procedure:
4,44 g of diphosphorus tetraiodide suspended in 35 ml of pyridine was stirred for 5 minutes and then 3.058 g of 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-2-hydroxy-3-methoxymethyl-4-thia-1-azabicyclo[4,2,0]octane-2-carboxylate were added all at once and the mixture was stirred for 2 hours 40 minutes. The pyridine was distilled off and the residue was taken up in 50 ml of ethyl acetate. The mixture was filtered, and 50 ml of N hydrochloric acid were added to the liltrate which was vigorously stirred. The organic phase was decanted, washed with water, dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica with a methylene chloride-ethyl acetate mixture (85-15) and the recovered fractions were concentrated to dryness and crystallized from methanol to obtain 703 mg of 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-3-methoxymethyl-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].Cl[S:17]([OH:20])(=[O:19])=[O:18]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Product: O=[N+]([O-])c1ccccc1-c1ccccc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2′-Nitrobiphenyl (5 g) was added slowly to chlorosulfonic acid (25 mL) at room temperature and stirring was continued for 2 hours. The mixture was carefully dripped into ice water and extracted with DCM. The solvent was evaporated and the residue purified by column chromatography (petrol/ethyl acetate) to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1.[OH-].[Na+].I[CH3:19]>C(O)C>[CH3:19][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]1[C:2]([Cl:1])([Cl:14])[Cl:15]
Reactant: CI
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)c2ccccc2OC1C(Cl)(Cl)Cl
Reaction time: 0.25 h

Procedure:
3,4-Dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (prepared as described in Example 3--5 g.) was suspended in ethanol (100 ml.), 63 ml. of a solution of sodium hydroxide (1.0 g.) in ethanol (83 ml.) was added, and the mixture was stirred for 15 minutes to obtain a clear solution. Iodomethane (5 ml.) was added, and the solution was boiled under reflux for 30 minutes. The solvents were evaporated, and the residue was dissolved in a mixture of toluene and ethyl acetate (7:3 by volume) and chromatographed on silica, eluting with the same solvent mixture. The first 100 ml. of eluate was collected, the solvent was evaporated and the residue crystallised on trituration with petroleum ether (b.p. 60°-80° C.) to give 3,4-dihydro-3-methyl-2-trichloromethylbenzo[e]-[1,3]-oxazin-4-one, m.p. 82°-84° C.