Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][C:8](=S)[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([NH:24][NH2:25])(=O)[CH3:22].C([OH:30])CCC.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH3:22])=[N:24][N:25]=[C:10]3[CH2:9][C:8](=[O:30])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CC(=O)NN
Reactant: S=C1CC(=S)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CCCCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2

Procedure:
A solution of 3 g. (0.01 mole) of 8-chloro-1-phenyl-4-thio-1H-1,5-benzodiazepin-2,4-(3H,5H)-dione and 8-chloro-1-phenyl-1H-1,5-benzodiazepin-2,4-(3H,5H)-dithione and 2 g. (0.024 mole) of acethydrazide in 300 ml. of n-butanol is refluxed for 24 hours. During this period nitrogen is bubbled through the reaction mixture. The solution is evaporated to dryness in vacuo and the residue is treated with cold water which gives 2.7 g. of yellow material. This material was found by thin layer chromatography (SiO2, 10% methanol; 90% chloroform) to be a mixture of three compounds and was chromatographed on 300 g. of silica gel using 3% methanol:97% chloroform as an eluting solvent. Fractions 12-19 (100 ml. each) were combined and concentrated giving 1.2 g. of product. This was recrystallized from absolute ethanol giving 800 mg. of white 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3 -a][1,5]benzodiazepin-5(6H)-one as white crystalline product of melting point 297°-298° C.
Reaction SMILES: [NH2:1][C:2]([CH2:40][CH3:41])([CH2:38][CH3:39])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[C:42](Cl)(=[O:44])[CH3:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:38]([C:2]([NH:1][C:42](=[O:44])[CH3:43])([C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])[CH2:40][CH3:41])[CH3:39]
Reactant: CCC(N)(CC)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)(NC(C)=O)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1

Procedure:
A solution of 2-Amino-2-ethyl-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.100 g, 0.178 mmol), acetyl chloride (0.014 g, 0.178 mmol) and DIEA (0.069 g, 0.534 mmol) were stirred at room temperature in DCM (3 ml) for 2 hours. Solvent was removed and compound was purified by RP-HPLC to yield 0.072 g (67%). 1H NMR (400 MHz, CDCl3) 7.67 (m, 1H), 7.40-7.29 (m, 2H), 7.18 (m, 2H), 7.09 (m, 1H), 6.99 (m, 2H), 4.60 (m, 1H) 4.04 (br, 2H), 3.32-3.23 (m, 4H), 2.74 (m, 2H), 2.57 (s, 3H), 2.36 (m, 2H), 2.20 (m, 2H), 2.01 (s, 3H), 1.92 (m, 6H), 1.82-1.63 9 (m, 10H), 0.78 (br, 5H). ES-LCMS m/z 602 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:20]=[N:1][C:2]2[C:3]([C:13]=1[OH:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)=[O:16])[CH3:19]
Reactant: COc1ccc(N)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1O

Procedure:
3-Amino-6-methoxypyridine (12.41 g) and diethyl ethoxymethylene malonate (20.2 ml) in Dowtherm A (400 ml) was heated at reflux, under argon for 1 h. The cooled reaction mixture was poured onto pentane (1 litre). The precipiated solid was collected by filration, washing with pentane. Drying afforded the title compound (24.78 g, crude).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](N(OC)C)=[O:17])=[CH:11][CH:10]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.[CH2:35]1[CH2:39]OC[CH2:36]1.C([Mg]Br)#CC>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:17])[C:36]#[C:35][CH3:39])=[CH:11][CH:10]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:24][CH:23]=1
Reactant: CON(C)C(=O)Cc1ccc(Nc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Reactant: C1CCOC1
Agent: CC#C[Mg]Br
Product: CC#CC(=O)Cc1ccc(Nc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
In a round bottom flask with stirbar was added 2-{4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methoxy-N-methyl-acetamide (275.0 mg; 0.604 mmol; 1.0 eq.), suspended in THF (2.5 ml; 30.857 mmol; 51.1 eq.). The suspension was cooled to 0° C. At this temperature was added 1-propynylmagnesium bromide (12.1 ml; 6.037 mmol; 10.0 eq.) drop by drop at constant temperature to afford a red solution. After complete addition, the reaction mixture was stirred 30 min at room temperature. The reaction suspension was quenched with aqueous solution of ammonium chloride, and extracted with EtOAc (3×). The combined organic phase were dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was dissolved in DMSO and purified by preparative HPLC to afford 1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-yn-2-one (68 mg, 17% yield) as light yellow solid. MS: m/z=435 [M+H]+. 1H-NMR (DMSO-d6) □δ 8.43 (bs, 1H), 8.28 (s, 1H), 7.46 (t, 2H), 7.42 (d, 2h), 7.37 (d, 2H), 7.31-7.13 (m, 7H), 6.99 (bs, 2H), 3.87 (s, 2H), 2.04 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([CH2:21]O)([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].[Li].C([Li])CCC.[F:29][CH:30]([P:32](=[O:39])([O:36]CC)[O:33]CC)[F:31].CP(=O)(OC)OC>>[F:29][C:30]([P:32](=[O:33])([OH:39])[OH:36])([F:31])[CH2:21][C:2]([NH2:1])([CH2:3][OH:4])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Agent: COP(C)(=O)OC
Agent: [Li]
Agent: [Li]CCCC
Product: CCCCCCCCc1ccc(CCC(N)(CO)CC(F)(F)P(=O)(O)O)cc1

Procedure:
The title compound was prepared from 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol (FrY 720) using procedures analogous to those described in EXAMPLE 2, except that lithium dilsopropylamide was substituted for n-butyllithium in Step C and diethyl difluoromethylphosphonate was substituted for dimethyl methylphosphonate in Step C: Mass spectrum (NH3—CI) 422 (M+H).
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([OH:33])[CH:5]=1)([CH3:3])[CH3:2].[C:34]1([CH2:40][O:41][C:42](=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:29])([F:30])[F:31])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:33][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][C:42]([O:41][CH2:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:49])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(CCCCCO)OCc1ccccc1
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: ClCCl
Product: CC(C)c1cc(OCCCCCC(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A mixture of 4-isopropyl-6-hydroxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (6 g; 12.46 mmol), 6-hydroxyhexanoic acid phenylmethyl ester (4.2 g;14.96 mmol), DEAD (4.35 g; 24.9 mmol) and(Ph)3P (6.54 g; 24.93 mmol) in methylene chloride (100 ml) was combined with cooling in ice/water and then was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel; 20-80% ethyl acetate/hexane) to afford 2.5 g (29%) of 4-isopropyl-6-[5-(phenylmethyloxycarbonyl)pentyloxy]-2-(1-phenyl-3-trifluoromethyl pyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)5C(O)OCH2H) as a solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C@@H:10]([OH:19])[CH2:11][N:12]([CH3:18])[S:13](=[O:17])(=[O:16])[NH:14][CH3:15])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C@@H:10]([OH:19])[CH2:11][N:12]([CH3:18])[S:13](=[O:17])(=[O:16])[NH:14][CH3:15]
Reactant: CNS(=O)(=O)N(C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNS(=O)(=O)N(C)C[C@H](O)[C@@H](N)CC1CCCCC1
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 89.1 %

Procedure:
A sample of the resultant compound from Example 121 (501 mg, 1.27 mmol) was dissolved in 3 ml CH2Cl2, cooled to 0° C. under a dry nitrogen atmosphere, and treated with 3 ml trifluoroacetic acid. The solution was stirred for 5.5 h, then the solvents were removed under reduced pressure, and the residue was basified with 1.0M aq. Na2CO3. The product was extracted with 4×20 ml CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to yield 332 mg (89%) of (2S,3S)-3-amino-4-cyclohexyl-2-hydroxy-1-(methyl(methylsulfamoyl)amino)butane as a white powder. 1H NMR (CDCl3) δ0.8-1.45 (several bm, 8H), 1.6-1.8 (bm, 5H), 1.9 (vbm, 3H), 2.75 (s, 3H), 2.85 (m, 1H), 2.94 (s, 3H), 3.21 (dd, 1H), 3.30 (dd, 1H), 3.48 (m, 1H). Mass spectrum: (M+H)+ =294.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:20])[C:17]([OH:19])=O)[C:3]=12.[C:21]1([C:27](=[N:34][C:35]#[N:36])[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].O>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:20])[C:17]([N:31]3[CH2:30][CH2:29][N:28]([C:27](=[N:34][C:35]#[N:36])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:33][CH2:32]3)=[O:19])[C:3]=12
Reactant: N#CN=C(c1ccccc1)N1CCNCC1
Reactant: O=C(O)C(=O)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#CN=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3c(-n4ccnn4)ncc(F)c23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 3 %

Procedure:
2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (100 mg), (phenyl(piperazin-1-yl)methylene)cyanamide (77 mg), DEPBT (108 mg) and iPr2NEt (0.2 ml) were combined in DMF (2 ml). The reaction mixture was stirred at room temperature for 17 hours before diluted with 10% Na2CO3 in water (5 ml). The aqueous solution was extracted with EtOAc (3×20 ml). The organic layer was combined, dried over MgSO4 and concentrated. The residue was tritarated with MeOH (5 ml) and the resultant solid was collected by filtration to give ((4-(2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperazin-1-yl)(phenyl)methylene)cyanamide (5 mg).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[O:20][CH:21]=[CH:22][N:23]=1>>[O:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][C:15]([CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:16]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Nc1ncco1
Product: O=C(Nc1ncco1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p.=232-235° C., MS: m/e=292 (M+) was prepared in accordance with the general method of example 31 from 9H-xanthene-9-carbonyl chloride and 2-amino-oxazole.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.[C:12](#N)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[OH2:21]>O1CCCC1.CCOCC>[C:13]1([C:12]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O
Reactant: Brc1ccsc1
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccsc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
The solution containing 0.937 mL (10 mmol) of 3-bromothiophene, 3 mL of tetrahydrofuran, and 8 mL of ether was cooled to −78° C. under N2. To the cooled solution was then added 4 mL of n-BuLi ([2.5] M in hexane) drop wise, while maintaining the reaction temperature below −70° C. The reaction solution turned to light yellow suspension. The suspension was allowed to stir 15 min at <−70° C. After 15 min, a solution containing 1.02 mL (10 mmol) of benzonitrile and 3 mL of tetrahydrofuran was added drop wise while maintaining the reaction temperature below −70° C. After the addition, the reaction suspension was allowed to stir 1 hr at −78° C. and slowly warmed to −10° C. over 2 hr. After 2 hr the reaction was stopped by adding 10 mL of H2O and 30 mL of 2N HCl. The aqueous solution was separated from the organic phase. The aqueous phase was washed with ether (2>20 mL). The washed aqueous solution was then heated to reflux for 2 hr. After 2 hr, the solution was cooled. To the cooled solution was added 30 mL of ether. The aqueous solution was removed. The organic solution was finally washed with brine, dried over MgSO4, and concentrated under reduced pressure. The concentrated sample was purified by flashy chromatography (hexane:ethyl acetate, from 4 to 6 % ethyl acetate over 16 column volume) to obtain 1.36 gm (72.3%) of a clear oil; 1H NMR 300 MHz (CDCl3) δ 7.93 (t, 1H), 7.83-7.86 (m, 2H), 7.26-7.61 (m, 5H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:27])=[C:15]([CH:26]=1)[C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH3:25])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:27][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:26][C:15]=1[C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH3:25])=[O:17]
Reactant: CC1CCCCC1OC(=O)c1cc(N)ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCCC1OC(=O)c1cc(NC(=O)c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Benzoyl chloride (5.2 g, 0.037 mole) was added slowly at room temperature to a stirred mixture of 2-methylcyclohexyl 5-amino-2-chlorobenzoate (10 g, 0.037 mole), triethylamine (4.0 g, 0.04 mole) dissolved in methylene chloride (100 ml). This reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then washed with water (200 ml), 3% HCl solution (100 ml), 2% NaOH solution (100 ml) and water (100 ml), dried (magnesium sulfate) and filtered. The solvent was evaporated off to give a brown oil which was crystallized with ethyl/hexane to give 2-methylcyclohexyl 2-chloro-5-(benzoylamino)benzoate as a white solid (5 G, m.p. 121°-122° C.)
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]1)=[N+:2]=[N-:3].[C:17]1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=CC(C)=O)[CH:22]=CC=C[CH:18]=1>C1(C)C=CC=CC=1>[CH3:22][C:17]1[N:1]([CH2:4][CH:5]2[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]2)[N:2]=[N:3][CH:18]=1
Reactant: CC[C@@H](C(N)=O)N1CC(CN=[N+]=[N-])CC1=O
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC[C@@H](C(N)=O)N1CC(Cn2nncc2C)CC1=O
Temperature: 80 °C

Procedure:
In a 50 ml 3 necked flask, fitted with magnetic stirrer and reflux condenser under inert atmosphere, 1 g (4.44 mmoles, 1 eq) of (2S)-2-[4-(azidomethyl)-2-oxo-1-pyrrolidinyl]butanamide 32 is suspended in 20 ml of toluene. 1.55 g (4.88 mmoles, 1.1 eq) of 1-(triphenylphosphoranylidene)acetone are added, and the mixture is heated up to 80° C. for 24 hours. After cooling down, the mixture is concentrated to dryness and purified by Prep LC (1 kg SiO2, CH2Cl2/MeOH/NH4OH, 94.5:5:0.5). It is suspended in 15 ml of water and lyophilised to give 240 mg of pure 52 as a clear oil, 42%.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[NH:6][C:5]1=[O:23])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=O.[K+].C=O>O1CCOCC1.O.C1C=CC=CC=1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[N:6][C:5]1=[O:23])([CH3:2])[CH3:3]
Reactant: COc1cccc(C2NC(=O)N(C(C)C)c3cc(C)ccc32)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=O
Agent: [K+]
Solvent: C1COCCO1
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc(-c2nc(=O)n(C(C)C)c3cc(C)ccc23)c1

Procedure:
1.555 g of 3,4-dihydro-1-isopropyl-4-(3-methoxyphenyl)-7-methyl-2(1H)-quinazolinone in 40 ml of p-dioxane is charged to a vessel having a dropping funnel, agitation means and thermometer. The charged vessel is cooled in a water bath (running water at 14°); a solution of 0.88 g of potassium permanganate in 20 ml of water is placed in the dropping funnel, which is then added dropwise to the vessel with stirring during which temperatures range from 15° to 18° C). The reaction mixture is then allowed to rise to room temperature (26°), at which it is stirred for 2 hr. 20 min.; 0.38 ml of aqueous formaldehyde (37%) is then added, and the mixture stirred for 10 minutes. The mixture is then filtered through celite (diatomaceous earth), and the filtrate retained. The filter cake is then washed with 75 ml of water/p-dioxane (20:15), the washings and filtrate are combined, extracted four times with 20 ml portions methylenechloride. The combined extracts are then evaporated to dryness to obtain a residue which is taken up in 100 ml benzene, 100 ml of petroleum ether added thereto, the solution filtered through 0.5 g of charcoal, (at room temperature) and then evaporated to dryness to obtain 1-isopropyl-4-(3-methoxyphenyl)-7-methyl-2(1H)-quinazolinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3Br)[CH2:15]2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)#[CH:32]>CN(C)C=O.[Pd].C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:32]#[C:31][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:15]2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S(=O)(=O)N2Cc3cccc(Br)c3C2)cc1OC
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2Cc3cccc(C#Cc4ccccn4)c3C2)cc1OC
Temperature: 90 °C
Reaction time: 72 h
Yield: 12.5 %

Procedure:
2-(3,4-Dimethoxybenzenesulphonyl)-4-bromoisoindoline (0.19 g), triethylamine (0.10 ml), 2-ethynylpyridine(0.06 g) and bis (triphenylphosphine)palladium(II)chloride (10%) in anhydrous N,N-dimethylformamide(2 ml) were stirred together under an inert atmosphere and heated to 90° C. After 20 hours further 2-ethynylpyridine(0.12 g) and palladium catalyst (20%) were added and heating continued for 3 days. The reaction mixture at room temperature was diluted with ethyl acetate, filtered through a pad of silica and the filtrate evaporated in vacuo to yield a yellow residue. Purification by column chromatography, eluting with a 20-100% ethyl acetate in hexane gradient afforded the title compound (25 mg).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([OH:15])=[O:14])=[O:7])=[CH:4][CH:3]=1.[CH3:18]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15][CH3:18])=[O:14])=[O:7])=[CH:16][CH:17]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of trans-2-(4-bromobenzoyl)cyclopentanecarboxylic acid (2.0 g, 6.26 mmol) in MeOH (70 mL) was added 2,2-dimethoxypropane (1.63 g, 15.65 mmol) and HCl (4.0 M in dioxane) (1.0 mL). The resulting solution was stirred at 40° C. overnight and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 7 to 11% ethyl acetate in hexanes to afford methyl trans-2-(4-bromobenzoyl)cyclopentanecarboxylate (1.62 g, 83%). 1H NMR (400 MHz, CD2Cl2) δ 1.70-1.95 (m, 4H), 2.08-2.21 (m, 2H), 3.40 (m, 1H), 3.64 (s, 3H), 4.04 (m, 1H), 7.64 (m, 2H), 7.86 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#[N:7].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:15][N:14]=[C:6]([NH2:7])[C:5]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: NO
Reactant: COc1cc(C#N)cc(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(OC)cc(C(N)=NO)c1
Yield: 41.6 %

Procedure:
The title compound was prepared following the procedure described for of Intermediate-53 using of 3,5-dimethoxybenzonitrile (1.0 g, 6.12 mmol), ethanol (20 mL), hydroxylamine hydrochloride (0.634 g, 9.23 mmol) and potassium carbonate (2.53 g, 18.40 mmol) to afford 0.500 g of the desired product. 1HNMR (DMSO-d6): δ 3.75 (s, 6H), 5.79 (s, 2H), 6.49 (s, 1H), 6.84 (s, 2H), 9.62 (s, 1H); MS [M+H]+: 197.11.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25]O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]#[N:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C#N)cc1OCc1ccccc1
Yield: 87.4 %

Procedure:
3-Benzyloxy-4-methoxybenzaldehyde (50 g, 0.21 mol) was added to a solution of sodium acetate (33.9 g, 0.41 mol) and hydroxylamine hydrochloride (28.73 g, 0.41 mol) in acetic acid (200 ml) and the resulting suspension was heated to reflux for 18 h. After cooling, the reaction mixture was partitioned between CH2Cl2 and H2O and the aqueous phase was further extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and evaporated to afford the subtitle compound as a buff-coloured solid (43.9 g, 89%). Rf 0.70 (toluene/EtOAc 4/1, v/v).