Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH3:10].Cl.C(OCC)(=O)C>C1COCC1>[OH:11][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)c1ccccc1
Yield: 96 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 3.96 g (6.50 mmol, 0.65 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.20 g (10 mmol) of acetophenone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.99 g of the desired product (yield 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH3:11].[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(#N)C.C(OCC)(=O)C>[O:19]=[C:18]1[C:17](=[O:22])[C:16]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:10][CH3:11])=[C:15]1[O:14][CH2:12][CH3:13]
Reactant: CCc1cc(C#N)ccc1N
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOc1c(Nc2ccc(C#N)cc2CC)c(=O)c1=O
Reaction time: 24 h
Yield: 23.6 %

Procedure:
4-Amino-3-ethylbenzonitrile (2.00 g, 13.7 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.30 g, 13.5 mmol) in acetonitrile (5 mL). After refluxing the mixture for 24 h a second portion of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.15 g, 6.76 mmol) was added and heating was continued for an additional 24 h. The reaction mixture was diluted with ethyl acetate (45 mL), stirred vigorously and filtered free of undissolved solid. The filtrate was concentrated and the resulting residue was purified by chromatographed (CH3OH/CH2Cl2) and trituration with ether to afford 0.86 g (24%) of product as a light yellow solid: 1H NMR (DMSO-d6): δ 10.57 (s, 1H), 7.77-7.66 (m, 2H), 7.31 (d, 1H), 4.71 (q, 2H), 2.73 (q, 2H), 1.37 (t, 3H), 1.13 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:4]/[C:3]2[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=2[F:1])/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=Cc1c(F)ccc(F)c1F
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2c(F)ccc(F)c2F)cc1OC
Yield: 86.1 %

Procedure:
2,3,6-Trifluorobenzaldehyde (320 mg) and 3,4-dimethoxybenzyl cyanide (354 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (549 mg, yield: 86%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:42][C:41]3[CH:43]=[CH:44][C:38]([CH2:37][N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)=[CH:39][CH:40]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1ccc(Cn2cncn2)cc1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(Cn3cncn3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-1,2,4-triazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>CN(C=O)C.C1COCC1.O>[CH3:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[N:6]([CH2:17][C:18]([OH:20])=[O:19])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc2[nH]c(=O)oc2cc1C
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1C)oc(=O)n2CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 6-methyl-5-(methyloxy)-1,3-benzoxazol-2(3H)-one (1.76 g, 9.8 mmol) in DMF (20 mL) was added NaH (470 mg, 11.8 mmol) in two portions. The reaction mixture was stirred for 30 minutes at room temperature, and ethyl bromoacetate (1.09 mL, 9.8 mmol) was added. The reaction mixture was stirred for 3 hour until all starting material was consumed, then poured into cold water (100 mL). The precipitate which formed was collected by filtration, washed with water, and dried in the air to afford a pale solid. This solid was dissolved in THF (20 mL) and NaOH (2.0 M, 4.9 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours, poured into cold water (100 mL), and extracted with EtOAc (2×100 mL). The aqueous layer was acidified with HCl (6 N) to pH˜1, extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with brine, and dried (Na2SO4). The solvent was removed via rotovap to give the title compound (2.16 g, 93%) as a pale solid. MS (ES) m/e 238 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:24]#[C:25][C:26]3([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:4][CH:3]=1>C(OC(=O)C)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH2:24][CH2:25][C:26]3([OH:31])[CH2:27][CH2:28][CH2:29][CH2:30]3)=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(C#CC2(O)CCCC2)c(-c2ccc(Cl)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCC2(O)CCCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
5-(4-Chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(1-hydroxy-cyclopentylethynyl)-nicotinamide (120 mg, 0.27 mmol) was dissolved in ethylacetate (15 mL) and hydrogenated in the presence of palladium on charcoal (10%) at room temperature and atmospheric pressure. After filtration and evaporation of the solvent the residue was purified by chromatography on silica gel with a ethyl acetate: methanol gradient to yield the product as colorless foam, MS (ISP) 443.1, 445.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:9])[CH3:8])C.C(O)C.[OH-].[K+]>O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][CH2:5][C:4]([OH:19])=[O:3])=[CH:11][C:12]=1[CH3:18]
Reactant: CCOC(=O)CCC(C)(C)c1ccc(OC)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)(C)CCC(=O)O)cc1C
Temperature: 60 °C
Yield: 96.8 %

Procedure:
To a solution of 4-(4-methoxy-3-methylphenyl)-4-methyl-pentanoic acid ethyl ester (Compound 4, 6.8 g, 25.8 mmol) and 20 mL of absolute ethyl alcohol was added aqueous 5 M KOH (6 mL). The resulting solution was heated in an 60° C. bath for 24 h. The solution was cooled to room temperature, diluted with water and washed once with 2:1 hexane:ethyl acetate solution, and the layers were separated. The aqueous layer was acidified with HCl 2 N to pH=0-1 and the product extracted three times with ethyl acetate. The combined organic extracts were washed with brine, and dried over MgSO4, and filtered. The solvent was removed to give 5.9 g (97%) of the title compound as a dark oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[CH3:25][O:26][C:27](=[O:44])[C:28]([CH3:43])([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C@@H:37]2[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]2)[CH:32]=1)[CH3:29]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:13]([N:39]2[CH2:40][CH2:41][CH2:42][C@@H:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:28]([C:27]([O:26][CH3:25])=[O:44])([CH3:29])[CH3:43])[CH:32]=3)[CH2:38]2)=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)(C)Oc1cccc([C@@H]2CCCNC2)c1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Oc1cccc([C@@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
4-(Trifluoromethyl)benzyl alcohol (0.88 g, 5.0 mmol) was dissolved in toluene (5 mL) and followed by the addition of 1,1′-carbonyldiimidazole (0.89 g, 5.5 mmol). The resulting mixture was stirred under nitrogen at rt for 1 h. A solution of (3S)-2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid methyl ester (Preparation 2; Method E) (1.39 g, 5.0 mmol) in toluene (8 mL) was then introduced and the reaction mixture was heated at 60° C. for 2 h. After cooling, the reaction solution was diluted with ethyl acetate (30 mL) and washed with 1 M HCl (30 mL) and brine (30 mL). The separated organic layer was dried over sodium sulfate and concentrated to yield 2.43 g (100%) of (3S)-3-[3-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a light yellow oil: 1H NMR (CDCl3) δ 1.58 (s, 8H), 1.77 (br m, 1H), 2.00 (br m, 1H), 2.61 (br, 1H), 2.80 (br, 2H), 3.74 (s, 3H), 4.21 (br s, 2H), 5.19 (s, 2H), 6.63 (dd, 1H), 6.72 (s, 1H), 6.83 (br d, 1H), 7.16 (t, 1H), 7.46 (br s, 2H), 7.60 (d, 2H); MS m/z (relative intensity) 479 (M+, 25), 420 (20), 395 (20), 276 (20), 220 (60), 202 (42), 176 (45), 159 (100).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:26]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[CH2:2][C:3]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:6][CH2:7][CH3:8])=[O:4])(=[O:25])=[O:24])=[CH:21][CH:22]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCNCCC
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCCN(CCC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with di-n-propylamine and 4-tert-butyl-N-p-tolyl-benzenesulfonamide
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:17]1([N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[C:17]1([N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:25])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1cccc(NC(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 42.6 %

Procedure:
A mixture of 3-amino-N-phenylbenzamide (2.0 g, 9.4 mmol), diphenylcarbamoyl chloride (2.2 g, 9.4 mmol) and triethylamine (2.6 mL, 19 mmol) in ethanol (10 mL) was heated to reflux for 4.5 hours. The mixture was cooled and concentrated, water was added, the slurry was acidified with 1 N HCl and the solid was collected, washed with water, dried and recrystallized from acetone/hexanes, to give a colorless solid (1.63 g, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10](C)([O-])C.[K+].C(I)C>C(O)C>[CH2:9]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH3:10]
Reactant: Nc1ccccc1S
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCI
Product: CCSc1ccccc1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.8 %

Procedure:
2-Aminothiophenol (5.0 g, 40 mmol, Lancaster Synthesis Inc., Windham, N.H.) was stirred in dry ethanol (100 mL) and cooled in an ice bath. Potassium t-butoxide (4.5 g, 40 mmol) was added portionwise over 15 minutes and the mixture was stirred for an additional 45 minutes. Ethyl iodide (3.3 mL, 41 mmol) was added dropwise over 15 minutes and the mixture was allowed to warm to room temperature and stirred for 45 minutes. The mixture was filtered and the filtrate evaporated to dryness in vacuo. The resulting residue was treated with dichloromethane (100 mL) and filtered and the resulting filtrate was evaporated to dryness in vacuo to give 2-(ethylthio)aniline (5.2 g).
Reaction SMILES: [NH2:1][C:2]1[NH:7][CH2:6][C:5]2=[C:8]([CH3:15])[N:9]=[C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:4]2[N:3]=1.[CH3:16][Mg]I.[Cl-:19].[NH4+]>CCOCC>[ClH:19].[NH2:1][C:2]1[NH:7][CH:6]([CH3:16])[C:5]2=[C:8]([CH3:15])[N:9]=[C:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[N:4]2[N:3]=1
Reactant: [Cl-]
Reactant: Cc1nc(CC(C)C)n2c1CNC(N)=N2
Reactant: C[Mg]I
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1nc(CC(C)C)n2c1C(C)NC(N)=N2
Product: Cl
Reaction time: 8 h

Procedure:
2-Amino-3,4-dihydro-7-isobutyl-5-methylimidazo [5,1-f]-as-triazine (Example 3f) (2 g.) in dry ether (50 ml) was added to methyl magnesium iodide (prepared from magnesium (1.17 g.) and methyl iodide (2.56 ml.)) in ether (50 ml.). The mixture was heated under reflux for 2 hours and kept overnight. Aqueous ammonium chloride (100 ml., 1%) was added and the ether layer was separated. The aqueous layer was kept for 4 days and the solid that crystallised was collected and crystallised from a mixture of ethanol and ethyl acetate and had m.p. 265°-267°. (The hydrochloride had m.p. 142°-143°).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])(=[O:24])=[O:23])=[O:20])=[CH:17][C:16]=1[O:34][CH3:35])(O)=[O:2].Cl.CN(C)CCCN=C=NCC.Cl.[CH3:49][C@H:50]([CH2:53][C:54]([F:57])([F:56])[F:55])[CH2:51][NH2:52]>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:35][O:34][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:2])[NH:52][CH2:51][C@H:50]([CH3:49])[CH2:53][C:54]([F:57])([F:56])[F:55])[CH:5]=2)[N:9]([CH3:13])[CH:8]=1)[C:19]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])(=[O:24])=[O:23])=[O:20]
Reactant: C[C@@H](CN)CC(F)(F)F
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Reaction time: 2 h
Yield: 104.5 %

Procedure:
To a mixture of 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (103.5 g), 4-dimethylaminopyridine (112.4 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (51.8 g) in tetrahydrofuran (distilled from sodium benzophenone ketyl) (2.0 L), which had been stirred for 2 hours, was added (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride (42.6 g); and the reaction mixture was stirred overnight (about 18 hours, incomplete reaction) then heated to reflux for two hours (complete reaction). The cooled reaction mixture was diluted with ethyl acetate (2 L) washed with 1N hydrochloric acid (twice) and brine, dried (MgSO4) and evaporated. The residue (138.6 g) was combined with impure product from similar procedures (28.0 g) and purified by flash chromatography, eluting with methylene chloride:ethyl acetate (sequentially, 1:0, 9:1 and 3:1) to afford a solid which was triturated twice with ether to give crude (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)-indol-3-ylmethyl]-N-(2-methylphenylsulphonyl)benzamide (135.2 g) which was recrystallized from ethanol (1.2 L) and acetone (0.3 L) (concentrated by boiling to about 0.9 L and refrigerated) and dried under vacuum to provide form B (117.1 g, 65% recovery) as a white crystalline solid; mp 141.5°-143.5° C.; NMR (300 MHz, DMSO-d6): 1.01 (d, 3H, CH3), 2.0-2.2 (m, 2H, CF3CH2), 2.3-2.5 (m, 1H, CHCH3), 2.61 (s, 3H, ArCH3), 3.23 (br t, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.92 (s, 3H, OCH3), 4.07 (s, ArCH2Ar'), 7.13 (s, 1H), 7.17 (d, 2H), 7.38-7.69 (m, 6H), 7.72 (d, 1H), 8.05 (d, 1H), 8.11 (s, 1H), 8.46 (br t, 1H, NHCO). Analysis for C31H32F3N3O5S: Calculated: C, 60.48; H, 5.24; N, 6.83 Found: C, 60.47; H, 5.27; N, 6.67.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[C:41]([Cl:43])[C:40]([O:44][CH3:45])=[CH:39][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.FC(F)(F)C(O)=O>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:42]=[C:41]([Cl:43])[C:40]([O:44][CH3:45])=[CH:39][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[N:8]=[CH:7][N:6]=1
Reactant: COc1cc(Nc2ncnc3cc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2ncnc3cc(OCCCN4CCNCC4)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 292 %

Procedure:
A mixture of 4-(2,4-dichloro-5-methoxyanilino)-7-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.12 g) and trifluoroacetic acid (2 ml) was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The resultant solid was isolated and dried under vacuum. The solid was dissolved in diethyl ether and 6M hydrogen chloride gas in diethyl ether (0.5 ml) was added. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.112 g); NMR Spectrum: (DMSOd6 and CF3CO2H) 1.9–2.1 (m, 2H), 2.15 (d, 2H), 2.28–2.4 (m, 2H), 3.4 (m, 2H), 3.4–3.9 (m, 10H), 3.92 (s, 3H), 3.95 (m, 2H), 4.39 (t, 2H), 5.2 (m, 1H), 7.0 (d, 1H), 7.2 (d, 1H), 7.78 (s, 1H), 7.82 (s, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 562 and 564.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl)([O-:16])=[O:15]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N+:14]([O-:16])=[O:15])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(Cc2ccccc2[N+](=O)[O-])CC1

Procedure:
In 20 volume parts of ethanol is dissolved 2.16 parts of o-nitrobenzyl chloride, followed by the addition of 1.02 parts of N-methyl piperazine and 1.3 parts of potassium carbonate. The mixture is reacted under reflux for 1 hour. The reaction mixture is then filtered and the solvent is removed from the filtrate by distillation under reduced pressure. The residue is extracted with water-ether (1:1). The ethereal layer is taken and dried over anhydrous sodium sulfate and the solvent is then distilled off. This procedure gives N1 -methyl-N4 -(2-nitrobenzyl)piperazine as a brown colored oily substance. Infrared absorption spectrum (liquid film)cm-1 : 1610, 1538.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:10]([O:17][C:18]([NH:20][C@H:21]1[C@H:24]([O:25][C:26](=O)[CH3:27])[NH:23][C:22]1=[O:29])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1COCC1>[CH2:10]([O:17][C:18]([NH:20][C@H:21]1[C@H:24]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:23][C:22]1=[O:29])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1.[CH2:10]([O:17][C:18]([NH:20][C@H:21]1[C@@H:24]([O:25][C:26]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:27]=2)[NH:23][C:22]1=[O:29])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1C(=O)N[C@@H]1Oc1ccccc1)OCc1ccccc1
Product: O=C(N[C@@H]1C(=O)N[C@H]1Oc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of phenol (2.82 g 30 mmole) in THF (30 ml) and 1N NaOH (26 ml, 26 mmole), (3S, 4S)-3-benzyloxycarbonylamino-4-acetoxy-azetidin-2-one (5.56 g, 20 mmole) in THF (40 ml) and H2O (20 ml) is added at 0° C. The mixture is stirred at 0° C for 1 hour and then at room temperature for 30 min. After removal of solvent, the residue is dissolved in ethyl acetate, washed with water, brine and dried over sodium sulphate. After removal of solvent, the residue is purified by silica gel column chromatography using hexane-ethyl acetate as eluent. 2.75 g of (3S, 4S)-3-benzyloxycarbonylamino-4-phenoxy-azetidin-2-one (A), 890 mg of (3S, 4R)-3-benzyloxycarbonylamino-4-phenoxy-azetidin-2-one (B) and 1.08 g of a mixture of (A) and (B) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:37]([S:40](Cl)(=[O:42])=[O:41])([CH3:39])[CH3:38].N1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][S:40]([CH:37]([CH3:39])[CH3:38])(=[O:42])=[O:41])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CC(C)S(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)C(C)C)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reaction time: 76 h
Yield: 11.2 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (5 mL) was added at 0° C. potassium bis(trimethylsilyl)amide (0.91 M in tetrahydrofuran, 1.51 mL, 1.38 mmol). After stirring for 15 min at this temperature isopropylsulfonyl chloride (319 mg, 2.24 mmol) was added and stirring was continued at ambient temperature for 76 h. Further isopropylsulfonyl chloride (107 mg, 0.75 mmol) and pyridine (454 mg, 5.74) were added and stirring was continued for 24 h. The resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane 50:30:20 to 20:60:20) afforded the title compound (29 mg, 11%) as a yellow solid. MS: m/e 455.2 [M+H]+.