Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=[O:22].[Cl-].C(N=C=NCCC[NH+](C)C)C>C(Cl)Cl>[F:16][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)([F:1])[C:3]([NH:24][NH:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=1[O:18][CH3:17])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)C(=O)O)cc1
Reactant: COc1ccccc1C(=O)NN
Agent: CCN=C=NCCC[NH+](C)C
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(F)(F)C(=O)NNC(=O)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of difluoro[4-(methoxycarbonyl)phenyl]acetic acid (0.12 g, 0.52 mmol) and 2-methoxybenzohydrazide (0.13 g, 0.78 mmol) in methylene chloride (2 mL) was added 3-{[(ethylimino)methylene]amino}-N,N-dimethylpropan-1-aminium chloride (0.2 g, 1.04 mmol). The resulting solution was stirred at ambient temperature for 16 hours. The reaction was purified by flash chromatography (0-4% methanol/methylene chloride) to give methyl 4-{1,1-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoate as a white solid. ESIMS calcd 379.1 (M++H), found 379.1 (M++H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[CH3:22][NH:23][CH:24]([CH3:26])[CH3:25]>>[CH:24]([N:23]([CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[CH2:8][OH:10])[CH3:22])([CH3:26])[CH3:25]
Reactant: CNC(C)C
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Product: CC(C)N(C)Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO

Procedure:
Prepared using intermediate 44 and N-methylisopropylamine. This compound was used directly without collection of analytical data for the preparation of Example 75.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[CH2:5][NH2:6].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: COc1cc(Cl)cc(CN)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NCc1cc(O)cc(Cl)c1
Yield: 66.2 %

Procedure:
A solution of 3-chloro-5-methoxybenzylamine (4.6 mmol, 0.792 g) in DCM (anhydrous, 20 ml) was cooled to −78° C. and BBr3 (1 M in DCM, 9.43 mmol) was added dropwise. The reaction was allowed to reach room temperature over night with stirring. The reaction was quenched by careful addition of methanol (5 ml), solvents were evaporated under reduced pressure and the residue was purified by means of chromatography (silica, DCM/MeOH/NH3 (30% in water) Sep. 1, 2001 v/v/v) to provide the title compound (0.48 g, 66%) as a white solid. (DMSO, 500 MHz) δ 3.61 (s, 2H), 4.57 (br, 1H), 6.62 (s, 1H), 6.80 (s, 1H) and 6.83 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]2[CH2:10][O:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([O:19]C(=O)C)[C:13]=3[CH3:23])=[CH:7][C:6]=1[O:26][CH3:27])(=O)C.N1C=CN=C1.CC1C(O)=CC=C2C=1OCC(C1C=CC(O)=CC=1)=C2>C(O)C>[CH3:27][O:26][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][C:5]=1[OH:4])[C:9]1[CH2:10][O:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=2[CH3:23]
Reactant: COc1cc(C2=Cc3ccc(OC(C)=O)c(C)c3OC2)ccc1OC(C)=O
Agent: Cc1c(O)ccc2c1OCC(c1ccc(O)cc1)=C2
Agent: c1c[nH]cn1
Solvent: CCO
Product: COc1cc(C2=Cc3ccc(O)c(C)c3OC2)ccc1O

Procedure:
3′-Methoxy-8-methylisoflav-3-ene-4′,7-diol was prepared from 4′,7-diacetoxy-3′-methoxy-8-methylisoflav-3-ene (0.21 g, 0.6 mmol) and imidazole (0.52 g) in ethanol (4 ml) as described for 8-methylisoflav-3-ene-4′,7-diol. Yield: (0.1 g, 63%). 1H NMR (CDCl3): δ 2.14 (s, 3H, CH3), 3.94 (s, 3H, OMe), 5.11 (s, 2H, H2), 6.42 (d, 1H, J 8.3 Hz, H6), 6.64 (bs, 1H, ArH), 6.80 (d, 1H, J 7.9 Hz, ArH), 6.94 (m, 2H, ArH), 7.12 (m, 1H, ArH), 7.26, 7.70 (each bs, 1H, OH).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.CN(C=O)C.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([Cl:24])=[O:15]
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)cnn1-c1ccccc1
Temperature: 36 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid from Step B (11B-2) (20.2 g, 0.1 mol) in DCM (200 mL) and DMF (730 mg, 0.01 mol) was added sulfuryl dichloride (8.73 mL, 0.12 mol) at RT. The mixture was stirred at 36° C. for 2 h. The solution was concentrated under reduced pressure and DCM (200 mL) was added to the white solid residue to form a suspension of the above corresponding acyl chloride. Yield: 98%, 1HNMR CDCl3): 8.16 (s, 1H), 7.45-7.59 (m, 5H), 2.53 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10](N(CC)CC)[CH3:11]>CN(C)C=O>[C:10]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])#[CH:11]
Reactant: CCN(CC)CC
Reactant: COc1ccccc1I
Solvent: CN(C)C=O
Product: C#Cc1ccccc1OC
Yield: 51 %

Procedure:
2-Iodoanisole (10.5 g) andtrimethylsilylacetylene (10.3 g) were reacted in dimethylformamide (50 ml), in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml) in nitrogen atmosphere at 50° C. for 12 hr. The resulting reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was dissolved in methanol (100 ml), a 5N aqueous solution of sodium hydroxide (20 ml) was added thereto, and then reacted at 60° C. for 1 hr. The reaction solution was evaporated, and to the resulting residue were added ether and water. The resulting ether layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound as a pale yellow oil (3.02 g, yield; 51%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH:3]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[CH2:4][NH:5][C:6]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:15])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)CNC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of benzyl tert-butyl (3-hydroxypropane-1,2-diyl)biscarbamate (60.0 g, 185 mmol) in DCM (1000 mL) was added methanesulfonylchloride (23 g, 200 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 12 hours, the reaction mixture was concentrated under reduced pressure and purified directly by chromatography on silica gel to give 3-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate. MS ESI calc'd. for C17H27N2O7S [M+H]+ 403. found 403. 1H NMR (400 MHz, CD3OD) δ 7.34-7.32 (m, 5), 5.17-5.07 (m, 2H), 4.18-4.16 (m, 2H), 4.09-3.91 (m, 1H), 3.29-3.28 (m, 2H), 3.05 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[C:4]1[C:5]([O:12]C)=[N:6][C:7]([O:10]C)=[N:8][CH:9]=1.[Na+].[I-]>CC(O)=O>[Br:1]/[CH:2]=[CH:3]/[C:4]1[C:5](=[O:12])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1
Reactant: COc1ncc(/C=C/Br)c(OC)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cc(/C=C/Br)c(=O)[nH]1
Yield: 64.5 %

Procedure:
To a solution of E-5-(2-bromovinyl)-2,4-dimethoxypyrimidine (2.45 g; 10 mmol) in AcOH (10 ml) was added NaI (3.3 g; 2.2 eq.; 22 mmol) and the solution heated under reflux for 3 h. The hot mixture was filtered and diluted with water (15 ml). After cooling, the precipitated product was filtered off, washed with acetone (50 ml) and ether (20 ml) and dried to give a pale yellow powder (1.40 g, 65%). Mp>320° C.; 60 MHz 1H-NMR, DMSO-6d, δ: 7.60 (s, 1H, H-6); 7.30 (d, 1H, J=13 Hz, vinyl H); 6.80 (d, 1H, J=13 Hz, vinyl H).
Reaction SMILES: C[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:13]([OH:15])=[O:14])[N:3]=1.[OH-].[K+]>CCO>[CH3:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[N:3][C:4]([C:13]([OH:15])=[O:14])=[CH:5]2
Reactant: Cc1ccc2c(C)nc(C(=O)O)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2cnc(C(=O)O)cc2c1
Yield: 71.3 %

Procedure:
Methyl 6-methyl-isoquinoline-3-carboxylic acid (0.618 g, 3.07 mmol) is dissolved in 95% EtOH (30 mL). KOH pellets (0.517 g, 9.21 mmol) are added and the reaction is heated at reflux for 1 hour. While heating, a precipitate began to form. Upon cooling, this precipitate (the K+ salt) is filtered and dried at 60° C. in vacuo. The precipitate is dissolved in water and the pH is adjusted to 4–5. The water solution is then loaded onto a column of AGW-×2 resin (H+ form). The resin is rinsed with MeOH, and the desired product is eluted with a solution of 5% TEA in MeOH. The product is concentrated three times from MeOH/MeCN and dried in vacuo. The solid is then dried overnight at 60° C. to yield 6-methyl-isoquinoline-3-carboxylic acid (0.41 g, 71%). HRMS (FAB) calculated for C11H8N O2 K: 188.0711, found 188.0714.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1
Reactant: Brc1cccnc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccnc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromopyridine [CAS 626-55-1; commercially available] (158 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (94 mg, 22%). MS (ISP) 433.3 [(M+H)+]; mp 187-188° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10]([O:12]N1C(=O)CCC1=O)=O.[NH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:85]=[CH:84][C:38]([C:39]([C:41]2[CH:83]=[CH:82][C:44]([O:45][CH2:46][CH2:47][CH2:48][NH:49][C:50](=[O:81])[CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH:65][C:66](=[O:80])[CH2:67][CH2:68][CH2:69][CH2:70][CH:71]3[CH:78]4[CH:74]([NH:75][C:76](=[O:79])[NH:77]4)[CH2:73][S:72]3)=[CH:43][CH:42]=2)=[O:40])=[CH:37][CH:36]=1>C(Cl)Cl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][C:10](=[O:12])[NH:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([C:41]2[CH:83]=[CH:82][C:44]([O:45][CH2:46][CH2:47][CH2:48][NH:49][C:50](=[O:81])[CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH:65][C:66](=[O:80])[CH2:67][CH2:68][CH2:69][CH2:70][CH:71]3[CH:78]4[CH:74]([NH:75][C:76](=[O:79])[NH:77]4)[CH2:73][S:72]3)=[CH:43][CH:42]=2)=[O:40])=[CH:84][CH:85]=1
Reactant: NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Reactant: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCOCCOCCOCCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCCOCCOCCOCCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoate (0.65 g, 2.43 mmol) was added to a solution of crude N-(3-(4-(4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-benzoyl)phenoxy)propyl)-1-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide (2 g, 2.11 mmol) in DCM (20 mL) and the reaction mixture was stirred for 2 hs at room temperature. Upon completion, reaction was then concentrated under reduced pressure, and purified by silica gel chromatography (DCM to DCM:MeOH, gradient) to yield 1.70 g (1.55 mmol, 73%) N-(3-(4-(4-((17-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-15-oxo-4,7,10-trioxa-14-azaheptadecyl)-amino)benzoyl)phenoxy)propyl)-1-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide as yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=2)[NH2:46])[CH2:38][CH2:37]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:46][C:45]5[CH:47]=[CH:48][CH:49]=[C:43]([CH2:42][N:39]6[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]6)[CH:44]=5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Agent: Cl
Product: COc1cc(C(=O)Nc2cccc(CN3CCN(C)CC3)c2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 3-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride with yield 43 mg (33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (br. s., 6H) 1.99 (br. s., 2H) 2.14 (s, 3H) 2.33 (br. s., 8H) 3.43 (s, 2H) 3.94 (s, 3H) 4.09 (t, J=13.89 Hz, 2H) 4.84 (br. s., 1H) 7.01 (d, J=7.58 Hz, 1H) 7.20-7.35 (m, 2H) 7.61 (br. s., 1H) 7.67 (br. s., 1H) 8.10 (s, 1H) 8.23-8.40 (m, 2H) 10.14 (s, 1H). [M+H] calc'd for C33H39F3N8O3, 653. found 653.
Reaction SMILES: [CH3:1][N:2]([CH3:46])[C:3](=[O:45])[CH2:4][NH:5][C@:6]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:38])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.[OH-].[Na+]>O1CCOCC1>[CH3:46][N:2]([CH3:1])[C:3](=[O:45])[CH2:4][NH:5][C@:6]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:38])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C
Yield: 32.2 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.048 mmol) and aqueous 1N sodium hydroxide (0.048 mL, 0.048 mmol) in dioxane (1 mL) was heated up at 78° C. for 3 h. The reaction mixture was filtered and the clear solution was purified by prep HPLC to provide the title compound as a white solid (9.5 mg, 31%). LCMS: m/e 615.56 (M+H)+, 2.52 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.38 (d, J=4.58 Hz, 1H), 4.89 (s, 1H), 4.76 (s, 1H), 4.52 (d, J=16.17 Hz, 1H), 4.04 (d, J=16.17 Hz, 1H), 3.08 (d, J=10.99 Hz, 6H), 3.01-2.86 (m, 1H), 2.37-1.22 (m, 22H), 1.79 (s, 3H), 1.30 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:33]=[CH:32][C:19]4[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][C:18]=4[CH:17]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2].O1CCOCC1.[ClH:40]>>[ClH:40].[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:33]=[CH:32][C:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:18]=4[CH:17]=3)[N:12]=2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1C#N
Yield: 62.7 %

Procedure:
A solution of 1,1-dimethylethyl 7-{5-[3-cyano-4-(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 54) (280 mg, 0.627 mmol) in hydrochloric acid 4M solution in dioxane (5 ml, 20.00 mmol) and 1,4-dioxane (5 ml) was stirred at room temperature overnight. The reaction mixture was filtered and washed with dioxane (˜5 ml), and the solid dried under vacuum to yield the title compound (177 mg, 0.393 mmol, 62.7% yield) as an off white solid. δH (d6DMSO, 400 MHz): 8.99-9.31 (2H, m), 8.53 (1H, s), 8.46 (1H, d), 7.96 (1H, s), 7.93 (1H, d), 7.54 (1H, d), 7.46 (1H, d), 4.07 (3H, s), 3.09-3.31 (7H, m); MS (ES): C20H18N4O2 requires 346; found 347 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][NH:18][CH2:19][CH2:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)=O>O1CCCC1>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH:23][C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1
Reactant: O=C(CCNCC1COc2ccccc2O1)Nc1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)OCC(CNCCCNc1ccc3c(c1)OCO3)O2
Temperature: 50 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
In 50 ml of tetrahydrofuran is suspended 1.5 g of lithium aluminum hydride and a solution of 6.0 g of N-[3-{(1,4-benzodioxan-2-yl}methyl)amino propionyl]-3,4-methylenedioxyaniline prepared according to the procedure described in Example 6 dissolved in 10 ml of tetrahydrofuran is added dropwise to the suspension. After completion of the dropwise addition, the mixture is stirred for 4 hours at 50° C. After completion of the reaction, the reaction mixture is subjected to the post-treatment for lithium aluminum hydride in the conventional manner and the resulting precipitates including aluminum hydroxide are removed by filtration. The filtrate is concentrated and then dissolved in ethyl acetate and the resulting solution is washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Thereafter, 20% hydrogen chloride in ethyl acetate is added and the resulting crystals are collected by filtration and recrystallized from ethanol to give 5.6 g (80%) of N-[3-{(1,4-benzodioxan-2-ylmethyl)amino}propyl]-3,4-methylenedioxyaniline.
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]3[CH:22]=[CH:23][N:24]=[CH:25][C:17]2=3)=[O:15])[O:11][N:10]=1)C1C=CC=CC=1.O.C(=O)([O-])O.[Na+]>Br.C(O)(=O)C>[O:19]1[CH2:20][CH2:21][N:16]([C:14]([C:12]2[O:11][N:10]=[C:9]([OH:8])[CH:13]=2)=[O:15])[C:17]2[CH:25]=[N:24][CH:23]=[CH:22][C:18]1=2
Reactant: O=C(c1cc(OCc2ccccc2)no1)N1CCOc2ccncc21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1cc(O)no1)N1CCOc2ccncc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 3 ml of 33% hydrobromic acid in acetic acid solution, (3-benzyloxy -isoxazol-5-yl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (45 mg, 0.13 mmol) was dissolved and then stirred at room temperature for 24 hours. After completion of the reaction by adding water dropwise, the mixture was adjusted to weak acidic condition (pH=6) by using saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The aqueous layer was evaporated under reduced pressure and the residue was purified by using preparative TLC plate to obtain the target compound 44, i.e., (2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-(3-hydroxy-isoxazol-5-yl)-methanone, as white solid (8 mg, 24%).
Reaction SMILES: COP([CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(OC)=O.[Mg+2].[Br-].[Br-].[Cl:17][C:18]1[C:19]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)=[N:20][CH:21]=[C:22]([CH:24]=O)[CH:23]=1.Cl>C1COCC1.CCOC(C)=O.CCN(CC)CC>[Cl:17][C:18]1[C:19]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)=[N:20][CH:21]=[C:22](/[CH:24]=[C:7](\[F:13])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:23]=1
Reactant: CCOC(=O)C(F)P(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Agent: Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
The mixture of ethyl (dimethoxyphosphoryl)(fluoro)acetate (2.51 mL), MgBr2 (2.73 g), Et3N (1.89 mL) in THF (45 mL) was stirred at 3-5° C. for 1 hr and to the mixture was dropwise added a solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-piperidinecarboxylate (3.0 g) in THF (21 mL) at 3-5° C. The reaction mixture was stirred at same temperature for 2.5 hrs. The reaction mixture was poured into a mixture of AcOEt and ice-water and the mixture was adjusted to pH 3.5 with 1N-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of AcOEt and hexane (1:2 v/v) as an eluant. The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.38 g).
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:23]([NH:25][N:26]1[C:30](=[O:31])[N:29]([CH3:32])[NH:28][C:27]1=[O:33])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:23]([NH:25][N:26]1[C:30](=[O:31])[N:29]([CH3:32])[NH:28][C:27]1=[O:33])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11]
Reactant: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]n(C)c1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]n(C)c1=O)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 71.6 %

Procedure:
A solution of 0.229 g of 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)valeramide in 20 ml of methanol was hydrogenated in the presence of 0.02 g of 10% palladium-on-carbon for 5 hours. Filtration and evaporation gave a residue which was triturated with diethyl ether to give 0.135 g of 2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)valeramide in the form of a white solid.