Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]2[C:4]=1[C@@:5]1([CH3:26])[C@H:10]([CH2:11]2)[C@@:9]2([CH3:25])[CH2:18][CH2:19][C@H:20]([OH:24])[C:21]([CH3:23])([CH3:22])[C@@H:8]2[CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]2[C:4]=1[C@@:5]1([CH3:26])[C@H:10]([CH2:11]2)[C@@:9]2([CH3:25])[CH2:18][CH2:19][C:20](=[O:24])[C:21]([CH3:22])([CH3:23])[C@@H:8]2[CH2:7][CH2:6]1
Reactant: COc1cc2c(c(OC)c1)[C@]1(C)CC[C@H]3C(C)(C)[C@@H](O)CC[C@]3(C)[C@H]1C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1)[C@]1(C)CC[C@H]3C(C)(C)C(=O)CC[C@]3(C)[C@H]1C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
To alcohol 5b (600 mg, 1.67 mmol) dissolved in 85 mL of methylene chloride was added Dess-Martin periodinane (DMP, 1.41 g, 3.34 mmol), and the mixture was allowed to stir at room temperature for 1.5 hours. Upon reaction completion, saturated aqueous NaHCO3 (50 mL) was added and the aqueous phase was extracted 3 times with methylene chloride (3×50 mL). The organic extracts were then combined, dried with MgSO4, and concentrated. The crude mixture was purified using flash chromatography (hexanes:ethyl acetate 7:1) to give 6b (476 mg, 1.34 mmol, 80% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 6.27 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 2.71-2.65 (m, 1H), 2.64-2.56 (m, 2H), 2.54-2.41 (m, 2H), 1.87-1.81 (m, 1H), 1.78-1.73 (m, 2H), 1.71-1.48 (m, 4H), 1.13 (s, 3H), 1.11 (s, 6H), 1.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ217.2, 159.5, 155.8, 144.4, 132.9, 101.9, 96.8, 63.4, 55.4, 55.3, 54.9, 47.5, 45.8, 38.8, 37.4, 36.2, 33.9, 29.5, 26.5, 20.7, 20.5, 19.8, 15.5. ESIMS [M+Na]+ calcd for C23H32O3Na 379.2249, found 379.2243. [α]24D=+26.78°.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[O:69][C:70]2[C:76]([C:77]([F:80])([F:79])[F:78])=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=1>>[F:78][C:77]([F:80])([F:79])[C:76]1[C:70]2[O:69][C:68]([S:67][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=4[N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[O:36])[CH2:32][CH2:33]3)=[N:72][C:71]=2[CH:73]=[CH:74][CH:75]=1
Reactant: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Reactant: FC(F)(F)c1cccc2nc(S)oc12
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCSc3nc4cccc(C(F)(F)F)c4o3)CC2)c(N2CCOCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercapto-7-trifluoromethylbenzoxazole, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: [C-:1]#[N:2].[K+].[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[N:15]=NC1C=CC(S([O-])(=O)=O)=CC=1.[Na+]>O>[C:1]([C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH2:15])=[C:5]([OH:4])[CH:14]=1)#[N:2]
Reactant: O=S(=O)([O-])c1ccc(N=Nc2c(O)ccc3ccccc23)cc1
Reactant: [C-]#N
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(O)c(N)c2ccccc12
Reaction time: 48 h
Yield: 55.2 %

Procedure:
30 g (0.46 mol) of potassium cyanide are added to a solution of sodium 4-(2-hydroxy-1-naphthylazo)benzenesulfonate (10 g, 28.5 mmol) in 120 ml of water. After 2 days at 90° C., the mixture is filtered and the filtrate is saturated with carbon dioxide. The yellow precipitate is filtered off to give 2.9 g (55%) of 4-cyano-2-hydroxynaphthylamine (V).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30][CH2:29]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: C1CCN(CCC2CCNCC2)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Product: O=C1Nc2cccnc2N(C(=O)N2CCC(CCN3CCCCC3)CC2)c2ccccc21
Yield: 47 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[2-(1-piperidinyl)ethyl]piperidine in a yield of 47% of theory. Colourless crystals, m.p. 178°-180° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:29])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:21]=[C:20]4[C:16]([C:17]([C:22]5[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=5)=[N:18][NH:19]4)=[CH:15][C:14]=3[F:28])[CH:7]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:29])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:21]=[C:20]4[C:16]([C:17]([C:22]5[CH:27]=[CH:26][N+:25]([O-:38])=[CH:24][CH:23]=5)=[N:18][NH:19]4)=[CH:15][C:14]=3[F:28])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2[nH]nc(-c3ccncc3)c2cc1F
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2[nH]nc(-c3cc[n+]([O-])cc3)c2cc1F
Yield: 56.8 %

Procedure:
A solution of N-cyclopropyl-3-[5-fluoro-3-(4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide (Example 1, 9.3 mg) and m-CPBA (20 mg) in chloroform (2 ml) was stirred under nitrogen at 60° C. for 1 h. The mixture was applied to an Isolute amino cartridge (1 g) and eluted with chloroform/methanol (100:0 and 90:10 to give the title compound as a yellow solid (5.5 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][OH:20])[N:10]=2)=[CH:4][CH:3]=1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccc(CNc2ccc3c(CO)cccc3n2)o1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CNc2ccc3c(COc4ccccc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-methanol (180 mg, 672 mmol) was dissolved in 12 mL tetrahydrofurane. Phenol (70 mg, 0.745 mmol) and triphenylphosphine (200 mg, 0.763 mmol) were added at room temperature. Diisopropyl azodicarboxylate (159 mg, 0.787 mmol) was slowly added at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 50 mL 2N sodium carbonate. The mixture was extracted three times with dichloromethane (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a light brown oil (90 mg, 39%), MS: m/e=345.4 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:3]1.Cl[C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]2[NH:39][N:40]=[CH:41][C:33]=12.C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[NH2:38][C:36]1[N:35]=[C:34]2[NH:39][N:40]=[CH:41][C:33]2=[C:32]([NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH2:3]2)[N:37]=1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: NC1Cc2ccccc2N(S(=O)(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(NC2Cc3ccccc3N(S(=O)(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)C2)c2cn[nH]c2n1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(4-(3-amino-3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl)-3-phenylurea in dimethyl acetamide (1 mL) was added 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (135 mg, 1.0 mmol) and diisopropylethylamine (0.4 mL, 0.30 g, 2.30 mmol). The reaction mixture was stirred at 120° C. for 20 hours. After cooling to room temperature the mixture was poured into water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organics were dried over sodium sulfate and concentrated to give a residue that was purified by reverse phase chromatography on a preparative LC/UV/MS system using a mass triggered fractionation. Compounds were eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95 acetonitrile/water gradient using 0.1% TFA as modifier to yield 1-(4-(3-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl)-3-phenylurea (47.6 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.4 %

Procedure:
In the case of compound 11, the required intermediate for step a) was synthesised as follows: To a stirred solution of 4-bromo-1-methyl-2-trifluoromethylbenzene (10 g) in tetrachloromethane (100 ml) at room temperature is added N-bromosuccinimide (7.5 g) and azobisisobutyronitrile (700 mg). After 15 h of stirring at reflux, the reaction is allowed to cool to room temperature, water is added and the reaction mixture is extracted twice with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (9:1 cyclohexane:ethyl acetate) to yield 4-bromo-1-bromomethyl-2-trifluoromethylbenzene (7.1 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28]>C(#N)C>[N:9]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: COC(=O)Cc1ccccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccccc1OCCCN1CCCCC1

Procedure:
1.51 g of potassium carbonate, 0.3 g of sodium iodide and then 1.0 cm3 of piperidine are successively added to a solution of 2.87 g of methyl [2-(3-bromopropoxy)-phenyl]acetate in 30 cm3 of acetonitrile. The reaction mixture is refluxed for 2 hours and then filtered. The filtrate is concentrated to dryness and the residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 50 cm), eluting under a nitrogen pressure of 0.1 bar with an ethyl acetate and methanol mixture (80/20 by volume) and collecting fractions of 125 cm3. Fractions 9 to 16 are pooled and concentrated to dryness. The residue is triturated in diisopropyl oxide, the suspension is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). 2.0 g of methyl [2-(3-piperidinopropoxy)phenyl]-acetate are obtained in the form of a yellow oil which is used as it in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Cl)=[CH:5][C:3]=1[NH2:4].[C:13]1([OH:19])C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:8]([O:19][CH3:13])=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c([N+](=O)[O-])ccc(N)c1Cl
Temperature: 100 °C
Yield: 51.1 %

Procedure:
A mixture of 2,5-dichloro-4-nitroaniline (7.0 g), phenol (3.2 g), potassium carbonate (9.7 g) and dry dimethylformamide (50 ml) is stirred and heated at 100° C. for 7.5 hours. The mixture is then poured into 500 ml of ice water and stirred. The aqueous mixture is extracted with ethyl acetate (5×200 ml), the extracts are dried and evaporated to dryness. The residual oil is stirred with methylene chloride (20 ml), the resulting solid is collected and dried to yield 3.5 g of title product, m.p. 122°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C(=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)S(C)(=O)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(CO)c1
Yield: 38.7 %

Procedure:
On carrying out the operation according to the procedure of Example 58 starting with 5.1 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidine and 17 cm3 of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol mixture (97/3 by volume) as eluent and collecting 100 cm3 fractions. Fractions 10 to 14 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained is taken up in 2 cm3 of dichloromethane and 10 cm3 of ethyl acetate and then filtered on sintered glass and washed with 2 cm3 of ethyl acetate. 1.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidine are obtained in the form of a white solid melting at 214° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (400 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.50 (2H, d, J=5 Hz, OCH2), 4.80 (1H, s, NCH), 5.25 (1H, t, J=5 Hz, OH), 7.30 (1H, d, J=7 Hz, CH arom.), between 7.35 and 7.45 (7H, m, 7CH arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.)].
Reaction SMILES: C(C1N(CC(OC)=O)C(=O)C(OCCC2C=CC=CC=2)=C(N=C=O)C=1)C1C=CC=CC=1.[K+].[Br-].NC1C(=O)N(C(C)C(OC)=O)C=CC=1.[CH3:48][O:49][C:50](=[O:71])[CH:51]([N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([NH:59][C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[O:61])[C:54]1=[O:70])C>[Pd].CO>[CH2:63]([O:62][C:60]([NH:59][C:55]1[C:54](=[O:70])[N:53]([CH2:51][C:50]([O:49][CH3:48])=[O:71])[CH:58]=[CH:57][CH:56]=1)=[O:61])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: COC(=O)C(C)n1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Agent: COC(=O)C(C)n1cccc(N)c1=O
Agent: COC(=O)Cn1c(Cc2ccccc2)cc(N=C=O)c(OCCc2ccccc2)c1=O
Solvent: CO
Product: COC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
Methyl [6-benzyl-1,2-dihydro-2-oxo-3-(2-phenylethoxy)-carbonylamino-1-pyridyl]acetate (49i), was isolated (88%) as a colorless solid: mp. 130-133° C.; IR (KBr) 3363, 1746, 1732, 1651, 1604, 1515, 1368, 1231, 1212, 1185; 1H NMR (CDCl3) δ 8.00 (1H, d, J=7.0), 7.68 (1H, s), 7.36-7.10 (10H, m), 6.15 (1H, d, J=7.6), 4.7 (2H, s), 4.38 (2H, t, J=7.0), 3.88 (2H, s), 3.67 (3H, s), 2.98 (2H, t, J=7). ##STR132## 2(S) Methyl 2[3-amino-1,2-dihydro-2-oxo-1-pyridyl]propionate (50a). A mixture of 2(S) methyl-2[3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl)propionate (49a) (2.75 g, 8.33 mmol), methanol (100 ml), and 10% palladium on carbon (300 mg) was stirred under an atmosphere of hydrogen for 30 min. The mixture was filtered and concentrated to afford 1.63 g (100%) of a colorless solid: 1H NMR (d6 -DMSO) δ 8.35 (1H, brs), 7.46 (1H, d), 7.22 (1H,d), 6.29 (1H, t), 5.22 (1H, q), 3.63 (3H, s), 1.55 (3H, d).
Reaction SMILES: C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.O[CH:14]([CH:19]([CH:23]([CH3:25])[CH3:24])[CH2:20][CH:21]=[CH2:22])[CH2:15][C:16]([OH:18])=O>>[CH:23]([C:19]1[CH2:20][C@@H:21]2[C@H:15]([CH:14]=1)[C:16](=[O:18])[CH2:22]2)([CH3:25])[CH3:24]
Reactant: C=CCC(C(C)C)C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC(C)C1=C[C@@H]2C(=O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium acetate (14.00 g, 142.7 mmol) was added to an acetic anhydride (67 mL) solution of 3-hydroxy-4-isopropylhept-6-enoic acid (11.10 g, 59.6 mmol), and the mixture was stirred at room temperature for 1 hour and then stirred at 120° C. for 3.5 hours. The mixture was treated with ice water, followed by extraction with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (6.6 g, 74%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[F:25]>CN(C=O)C.C1COCC1>[F:25][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]=1[CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cccc(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1c(F)cccc1[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.6 %

Procedure:
To a suspension of NaH (5.2 g, 130 mmol) in DMF/THF (110 ml/45 ml) was added diethyl malonate (19 ml, 125 mmol) dropwise and the mixture was stirred for 30 min at room temperature. To the mixture was added 2-(Bromomethyl)-1-fluoro-3-nitrobenzene (29 g, 124 mmol) in DMF/THF (40 ml/30 ml) and the resulting mixture was refluxed for 3 h. After cooling, the excess reagent was quenched with brine and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo to afford diethyl 2-(2-Fluoro-6-nitrobenzyl)malonate (48 g) as a brown oil. This crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:39]C)[CH:35]=3)[CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([OH:39])[CH:35]=3)[CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1ccc2cc(OC)ccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate (EXAMPLE 2, Step A, 300 mg, 0.538 mmol) in DCM (10 mL) at 0° C. was slowly added BBr3 (1.0 M in DCM, 2.69 mL, 2.69 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 6 hours. After diluting with DCM, the mixture was washed with water, then saturated NaCl (aq). The organic layer was dried over MgSO4, filtered, then concentrated to afford the title product. LC2 2.65 min. [M+H]+ 544.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Cl[CH2:9][CH2:10][CH:11]1[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C:14]2[CH:20]=[CH:21][CH:22]=[N:23][C:13]=2[O:12]1>CN(C)C=O>[CH3:18][N:16]1[C:15](=[O:19])[C:14]2[CH:20]=[CH:21][CH:22]=[N:23][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[CH2:17]1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(CCn2cccn2)Oc2ncccc2C1=O
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (1.2 g active, 0.05 mole) in dimethylformamide (15 ml) was added dropwise a solution of pyrazole (3.10 g, 0.045 mole) in dimethylformamide (15 ml). The resulting solution was then added to a solution of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one (9.12 g, 0.038 mole) in 30 ml of dimethylformamide. The flask was sealed and stirred overnight. Because the reaction had not yet gone to completion at this point, pyrazole (3.12 g, 0.045 mole) was added to the reaction solution and stirred overnight. The reaction was still not complete and another suspension of sodium hydride (0.5 g active, 0.021 mole) and pyrazole (1.5 g, 0.022 mole) in dimethylformamide (10 ml) was added and the reaction stirred overnight. The reaction appeared to be complete. Dimethylformamide was removed by rotary evaporation (80° C., vacuum pump), and the residue taken up in chloroform (100 ml) which was washed with dilute aqueous sodium hydroxide (1×50 ml), dried over anhydrous sodium sulfate and concentrated by rotary evaporation (70° C., water aspirator). The material was purified by high pressure liquid chromatography, 95:5 by volume ethanol:methanol on a silica gel column. The fractions containing the desired product were concentrated by rotary evaporation (70° C., water aspirator). Crystallization ensued upon cooling. The crystals were collected and recrystallized from ethanol. The yield was 1.5 (14.5%), m.p. 132°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1cccc2ncccc12
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc2ncccc12

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 5-aminoquinoline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.