Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])[N:13]=2)=[N:6][CH:7]=1.O.[NH2:28][NH2:29]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:28][NH2:29])=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Solvent: O
Solvent: CCO
Product: NNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 75 °C
Yield: 83.1 %

Procedure:
To a mixture of methyl 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate (1.00 g, 2.303 mmol) (Example 315) in 15 mL EtOH was added hydrazine monohydrate (8.835 mL, 11.51 mmol) and the mixture heated at 75° C. for 4 hours. The reaction was cooled to ambient temperature and quenched with water and the solids were filtered to give the title compound (0.831 g, 83.10% yield) as off white solids there were used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](O)[C:3]=1[CH3:9].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH3:9]
Reactant: Nc1ccccc1
Reactant: Cc1c(O)ncnc1Cl
Product: Cc1c(Cl)ncnc1Nc1ccccc1

Procedure:
Synthesized according to the method of reagent preparation 49 using 6-chloro-5-methylpyrimidin-4-ol and aniline in step 1.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:14]1[N:15]=[CH:16][N:17]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:18]=1)/[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1.Cl.C(=O)(O)[O-].[Na+]>CO.[Zn]>[NH2:11][C:7]1[CH:6]=[C:5](/[C:4](/[C:14]2[N:15]=[CH:16][N:17]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])[CH:18]=2)=[CH:3]/[O:2][CH3:1])[CH:10]=[CH:9][CH:8]=1
Reactant: CO/C=C(/c1cccc([N+](=O)[O-])c1)c1cn(S(=O)(=O)N(C)C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CO/C=C(/c1cccc(N)c1)c1cn(S(=O)(=O)N(C)C)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 46A (0.15 g, 0.43 mmol) in methanol (0.70 mL) was cooled to 0° C., treated with concentrated HCl (0.35 mL), treated with zinc (0.28 g, 4.3 mmol) in portions, stirred at ambient temperature for 20 minutes, neutralized with aqueous sodium bicarbonate solution (15 mL) and extracted with ethyl acetate (4×20 mL). The combined ethyl acetate extracts were dried (Na2SO4) and concentrated to provide the desired product.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH:21]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)/[C:29](=[N:33]/[OH:34])/[CH2:28][CH2:27][CH2:26]2)=[CH2:22].[CH:35]([O:38][C:39]1[CH:50]=[CH:49][C:42]([C:43](OC(C)C)=O)=[C:41]([C:51]([F:54])([F:53])[F:52])[CH:40]=1)([CH3:37])[CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH:35]([O:38][C:39]1[CH:50]=[CH:49][C:42]([C:43]2[O:34][N:33]=[C:29]3[C:30]4[C:25]([CH2:26][CH2:27][C:28]=23)=[CH:24][C:23]([CH:21]=[CH2:22])=[CH:32][CH:31]=4)=[C:41]([C:51]([F:52])([F:53])[F:54])[CH:40]=1)([CH3:37])[CH3:36]
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)cc1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a heat gun dried 50 mL 2-necked flask was added butyllithium (1.406 mL, 3.51 mmol) followed by 2 mL of anhydrous THF under a nitrogen atmosphere. The flask was cooled to 0° C. and diisopropylamine (0.49 mL, 3.51 mmol) was added dropwise over a period of 1 min. The contents were stirred at 0° C. for 15 min. To the LDA solution, 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.219 g, 1.171 mmol) dissolved in 1 mL of THF was added dropwise over a period of 1 min. at 0° C. The orange-red solution was stirred at 0° C. for 25 min. Isopropyl 4-isopropoxy-2-(trifluoromethyl)benzoate (Preparation 17A, 0.340 g, 1.171 mmol) dissolved in 1 mL of THF was added dropwise over a period of 1 min. at 0° C. and the contents were stirred at 0° C. for 10 min. The reaction mixture was partitioned between 1N hydrochloric acid (5 mL) and ethyl acetate (10 mL)-THF. The 1N hydrochloric acid layer was back extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to yield a dark oil. To this oil was added toluene (5.00 mL). The contents were sonicated for 2 min. and p-toluenesulfonic acid monohydrate (0.446 g, 2.343 mmol) was added at room temperature. The contents were heated at 110° C. for 25 min. The reaction mixture was concentrated and partitioned between dichloromethane (15 mL) and saturated aqueous sodium bicarbonate (10 mL). The dichloromethane layer was dried over sodium sulfate, concentrated, and subjected to silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.225 g, 0.563 mmol, 48% yield) as an oil. LC/MS M+1=400.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>CO>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:10]([CH3:9])(=[O:12])=[O:11])=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(O)cc1
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
To a cold suspension of 4-aminophenol (5.45 g, 49.9 mmol) in MeOH (62 ml), methanesulfonyl chloride (1.95 ml, 25.2 mmol) was added under stirring maintaining the temperature between 10 and 15° C. The resulting solution was allowed to warm to RT and stirred for 2 hours. The solvent was removed under vacuum, and the residue was suspended in HCl 1N (62 ml); the insoluble was collected by filtration, washed with water, dried and purified by filtration through a silica gel pad (DCM:MeOH=100:15) affording N-(4-hydroxyphenyl)methanesulfonamide as a brown solid (1.35 g, 7.21 mmol, 28.6% yield).
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3](O)[OH:4].S(O)(O)(=O)=O.[NH2:13][C:14]1[N:15]=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH2:29][CH2:30][CH3:31])[NH:17][C:18](=[O:21])[C:19]=1[NH2:20]>C=O.CO>[CH2:29]([O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:16]1[NH:17][C:18](=[O:21])[C:19]2[NH:20][C:3](=[O:4])[CH:2]=[N:13][C:14]=2[N:15]=1)[CH2:30][CH3:31]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCOc1ccccc1-c1nc2ncc(=O)[nH]c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A solution of chloral hydrate (1.74 g) in 50% aqueous methanal (10 ml) was added over 10 minutes to a stirred solution of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.89 g) in 50% aqueous methanol (60 ml) at 80° C. and the reaction mixture was stirred at 80° C. for 1.5 hours. The cooled reaction mixture was filtered to remove an orange brown solid which was discarded. On standing overnight the filtrate afforded a crude solid product (0.96 g) which was collected and washed with dilute aqueous potassium bicarbonate and water. The crude product together with another sample (0.20 g) similarly prepared was eluted from a silica column with chloroform. The combined fractions containing product were evaporated under reduced pressure to afford a solid (0.54 g) which was recrystallized from acetonitrile to afford the title compound, 0.39 g, m.p. 232-233.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:44])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:44])=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)cc1NS(C)(=O)=O
Yield: 8.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl)methanesulfonamide was hydrolyzed with lithium hydroxide (65 mg, 1.56 mmol) in THF/Methanol/water (10/3/2 mL). This yielded 22 mg (8.4% yield) of pure compound after purification by flash chromatography. 1H NMR (DMSO-d6, 300 MHz): δ 11.9 (s, 1H), 9.07 (s, 1H), 8.519-8.515 (d, 2H), 7.827-8.23 (d, 2H), 7.56-7.43 (m, 3H), 7.21-7.04 (m, 4H), 5.36 (s, 2H), 3.90 (s, 3H), 3.03 (s, 3H), 2.21-2.17 (d, 6H). MS: m/z=520.1 (M+1), HPLC: 95.74% (Method-B).
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][C:44]=1[C:50]([F:53])([F:52])[F:51]>>[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:45][C:44]=1[C:50]([F:51])([F:52])[F:53]
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3ccc(Cl)c(C(F)(F)F)c3)c2cc1N

Procedure:
Starting material: N4-(4-chloro-3-(trifluoromethyl)phenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 4-chloro-3-(trifluoromethyl) aniline; other starting materials were prepared as example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:7]=2)[CH2:4][C@H:3]1[NH2:17].Cl[C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:1][C:2]1([CH3:18])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:7]=2)[CH2:4][C@H:3]1[NH:17][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=1
Reactant: CC1(C)[C@H](N)C[C@@H]1c1ncn(C2CCCCO2)n1
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2C[C@H](c3ncn(C4CCCCO4)n3)C2(C)C)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A mixture of (1R,3S)-2,2-dimethyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)cyclobutanamine (340 mg, crude) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (210 mg, 1.14 mmol) and DIEA (450 mg, 3.50 mmol) in isopropanol (5 mL) was stirred at 90° C. for 1 h. After removal of the solvent, the residue was purified by silica gel column chromatography (10%-30% ethyl acetate in petroleum ether) to afford the title compound (290 mg, 0.727 mmol, 65% yield for two steps). MS (ESI) m/z 400.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:44]=[CH:43][C:9]2[N:10]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[C:27]([C:29]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])[CH:26]=[CH:25][C:24]=3I)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[F:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:44]=[CH:43][C:9]2[N:10]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:24]([C:49]5[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=5)=[CH:25][CH:26]=[C:27]([C:29]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])[CH:28]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4I)ccc3c1)n2C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Temperature: 90 °C

Procedure:
A mixture of 200 mg (0.29 mmol) Compound 419d 62 mg (0.44 mmol) 4-fluorophenyl-boronic acid, 32 mg (0.029 mmol) Pd(PPh3)4 and 2 mL sat. NaHCO3 in 16 mL degassed MeOH was heated at 90° C. under Ar overnight. The mixture was evaporated to dryness, the residue was taken up in CH2Cl2 and purified on silica gel using CH2Cl21MeOH as eluent to yield 197 mg orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[CH:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:28])[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[CH:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:28])[C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)=[O:16])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: C#Cc1ccc(Cl)cc1-c1ccn(C(C)C(=O)Nc2ccc(C(=O)OC)cc2)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Product: C#Cc1ccc(Cl)cc1-c1ccn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)c1

Procedure:
15 mg (0.03 mmol) of methyl 4-({2-[4-(5-chloro-2-ethynylphenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 2.8F) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 4 mg (purity 92%, 28% of theory)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:10]([CH3:22])([CH3:21])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2([CH3:22])[CH3:21])=[CH:15][CH:16]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC1(C)CNCCC1c1ccc(Cl)cc1
Yield: 71.4 %

Procedure:
A solution of 1-benzyl-4-(4-chlorophenyl)-3,3-dimethylpiperidine (4.8 g, 15.29 mmol) and 1-chloroethyl chloroformate (1.667 mL, 15.45 mmol) in dichloroethane (40 mL) was stirred overnight at room temperature, then refluxed for 3 hours. The solution was concentrated in-vacuo. The residue was taken up in methanol (50 mL), the mixture was refluxed overnight The mixture was diluted with 75 mL of 1 N HCl, and the methanol was removed under vacuum. The aqueous solution was washed 3× with diethyl ether (20 mL), and the mixture was treated with the careful addition of saturated sodium bicarbonate to reach pH 8. The aqueous solution was washed 3× with diethyl ether (25 mL), and the mixture was treated with the careful addition of solid sodium hydroxide to reach pH>13. The aqueous phase was extracted 3× with ethyl acetate (50 mL), and the combined organic phases were dried over sodium sulfate and concentrated in vacuo to yield (±)-4-(4-chlorophenyl)-3,3-dimethylpiperidine (2.44 g, 10.91 mmol, 71.3% yield) as a pale yellow oil which solidified upon standing. MS: (ESI+)=224.3, (M+H)+. The enantiomers were separated via chiral super-critical fluid chromatography to yield 1.09 g of isomer A, and 1.05 g of isomer B.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH:24]=[O:25])[CH2:4][CH3:5])[CH3:2].[Li].[CH2:27]1COCC1>>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])[C:8]=1[CH:24]([OH:25])[CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C=O
Reactant: C1CCOC1
Agent: [Li]
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(C)O

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehyde with methylithium lithium in THF at −78° C. The desired product was isolated after silica gel column chromatography to give 60.1% of colorless oil. 1H NMR(CDCl3) d 6.87(s, 2H), 6.06(s, 1H), 5.7(q, 1H), 3.3(m, 1H), 2.29(s, 3H), 2.12(s, 6H), 2.069s, 3H), 1.4-1.7(m, 4H), 1.59(d, 3H), 0.8-1.0(m, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:14][C:15]1[CH:16]=[C:17]([NH:24][C:25]([C:27]2([CH3:30])[CH2:29][O:28]2)=[O:26])[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]>>[OH:28][C:27]([CH3:30])([CH2:29][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1)[C:25]([NH:24][C:17]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([CH3:14])[CH:16]=1)=[O:26]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1C(F)(F)F
Product: COc1ccc(NCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1C(F)(F)F

Procedure:
2-Hydroxy-3-(4-methoxy-3-trifluoromethylphenylamino)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 52 starting from 3-amino-6-methoxybenzotrifluoride and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.5% methanol). 1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.51 (3H, s), 3.12 (1H, dd, J=13.0 Hz, J=4.8 Hz), 3.45 (1H, dd, J=13.0 Hz, J=7.7 Hz), 3.71 (3H, s), 5.42 (1H, m), 6.00 (1H, s), 6.88 (1H, dd, J=8.9 Hz, J=2.7 Hz), 6.92 (1H, d, J=2.7 Hz), 6.97 (1H, d, J=8.9 Hz), 7.78 (1H, dd, J=8.9 Hz, J=2.3 Hz), 7.81 (1H, d, J=1.9 Hz), 8.00 (1H, d, J=8.9 Hz), 9.98 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.CN(C)CCN(C)C.C([Li])CCC.[C:28]1([CH3:36])[C:29]([CH:34]=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH3:36])[OH:35])=[N:11][N:10]=[N:9]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2cnnn2)cc1
Reactant: Cc1ccccc1C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnnc2C(O)c2ccccc2C)cc1
Temperature: -85 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A stirred solution of 1-(4-methoxybenzyl)tetrazole (7.04 g, Tetrahedron Letters, 1995, p1759-1762) in a mixture of dry tetrahydrofuran (120 ml) and N,N,N',N',-tetramethylethylenediamine (12 ml) under a nitrogen atmosphere at -85° C. was treated dropwise with n-butyl lithium (18 ml, 2.5M solution in hexanes) over 10 minutes. After stirring at -85° C. for an additional 5 minutes a solution of o-tolualdehyde (4.45 g) in dry tetrahydrofuran (20 ml) was added dropwise over 10 minutes. The reaction mixture was stirred at -85° C. for 30 minutes, allowed to warm to room temperature, then quenched with saturated ammonium chloride solution (50 ml). The organic phase was separated and the aqueous phase extracted three times with ethyl acetate (100 ml). The combined organic phases were dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and pentane (1:1, v/v) then with a mixture of ethyl acetate and pentane (66:34, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound (9.8 g) as a white solid, m.p. 90-92° C. [Elemental analysis:- C,65.91, H,5.9, N,18.1%. Calculated:- C,65.79, H,5.85, N,18.05%].
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]CC1C=CC=CC=1>[C].[Pd].C(O)(C)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]
Reactant: COc1ccc(CCNCC(O)c2ccccc2OCc2ccccc2)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(CCNCC(O)c2ccccc2O)cc1OC

Procedure:
One g of α-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybenzylalcohol hydrochloride, 0.3 g of 10 % palladium-carbon and 30 ml of 80 % aqueous isopropanol are treated in the same manner as described in Example 1-(c). 0.75 g of α-(3,4-dimethoxyphenethylaminomethyl)-2-hydroxybenzylalcohol hydrochloride are obtained. M.p. 141° - 143° C(decomp.) (recrystallized from a mixture of ethanol and ether).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)=[O:4].Cl[C:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>>[C:15]1([C:14]2([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:11][C:8]3[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][CH3:1])=[CH:6][C:7]=3[O:12]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Product: CCC(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 170 °C

Procedure:
A mixture of 3,4-dihydroxypropiophenone (ICN Biomedicals, Inc., 3300 Hyland Ave., Costa Mesa, Calif., 92626, USA, 5.0 g, 30 mmol) and dichlorodiphenylmethane (10.0 mL, 52.1 mmol) was heated for 7 min at 170° C. The reaction was cooled and poured into 1 N sodium hydroxide. The mixture was extracted with ether (2×) and the combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (2×5 inches packed in hexane) with elution proceeding as follows: 2% ether/hexane (500 mL), 0.84 g of a white solid tentatively identified as 2-chloro-1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one; 5% ether/hexane (250 mL), 1.9 g of an unidentified orange oil; 5% ether/hexane (250 mL), 2.18 g of recovered dichlorodiphenylmethane; 10% ether/hexane (500 mL), 4.82 g (48%) of 1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one as an orange oil which solidified on standing. The product had: mp 69-70.5° C. Analysis calculated for C22H17ClO3 : C, 79.98; H, 5.49. Found: C, 80.05; H, 5.34.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH2:32])[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH:18]([C:26]([NH:28][CH3:29])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4].[CH:36](OC1C=CC([N+]([O-])=O)=CC=1)=[O:37].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(NC(C)=O)C1)=O)CCC>>[CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH:32][CH:36]=[O:37])[CH2:11][C:12]([CH3:30])([CH3:31])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH:18]([C:26]([NH:28][CH3:29])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C(=O)NC)Oc2ccccc21
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(NC(C)=O)Cc2ccccc21)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)NC)Oc2ccccc21)NC=O

Procedure:
140 mg of 5(S)-amino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methylaminocarbonyl-3,4-dihydro-2H-1,4-benzoxazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Example 28)) are reacted with 100 mg of 4-nitrophenyl formate in a manner analogous to that described in Example 17): Rf (S)=0.33; FAB-M S: (M+H)+ =519.