Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.O[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=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>[CH3:11][O:10][C:8]([C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)=[O:9]
Reactant: COC(=O)[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reaction time: 18 h

Procedure:
1.1 g of methyl trans-4-hydroxycyclohexanecarboxylate (6.95 mmol, 1.35 eq.), 1 g of tert-butyl 4-hydroxybenzoate (5.15 mmol, 1 eq.) and 2.03 g of triphenylphosphine (7.72 mmol, 1.5 eq.) are placed in 10 mL of tetrahydrofuran at room temperature. 1.5 mL of diisopropyl azodicarboxylate (7.72 mmol, 1.5 eq.) are added dropwise to the reaction medium with stirring. After 18 hours at room temperature, the medium is concentrated to dryness and taken up in diethyl ether. The triphenylphosphine oxide is filtered off. The organic phase is washed with sodium hydroxide solution, dried over sodium sulfate, filtered and evaporated to give a residue. This residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 0% to 50%. 1.23 g of tert-butyl cis-4-(4-methoxycarbonylcyclohexyloxy)-benzoate are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:3]1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:3]1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CN1CCC(Oc2ccc(N)cc2)C1

Procedure:
A solution of 1-methyl-3-(4-nitro-phenoxy)-pyrrolidine•TFA (0.34 g, 1.0 mmol) in ethanol (10 mL) is hydrogenated for one hour at atmospheric pressure over 10% Pd/C. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 4-(1-methyl-pyrrolidin-3-yloxy)-phenylamine•TFA as a black solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][NH:10][C@@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][C:21]1[CH:28]=[C:27]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)[CH:26]=[C:25]([CH3:35])[C:22]=1[C:23]#[N:24].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:23]([C:22]1[C:25]([CH3:35])=[CH:26][C:27]([C:29]2[CH2:34][CH2:33][N:32]([C:16]([C@@H:9]3[C@@H:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:12]([F:14])([F:15])[CH2:11][NH:10]3)=[O:18])[CH2:31][CH:30]=2)=[CH:28][C:21]=1[CH3:20])#[N:24]
Reactant: Cc1cc(C2=CCNCC2)cc(C)c1C#N
Reactant: CC(C)(C)OC(=O)[C@H]1CC(F)(F)CN[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=CCN(C(=O)[C@H]3NCC(F)(F)C[C@@H]3C(=O)OC(C)(C)C)CC2)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2S,3S)-3-(tert-butoxycarbonyl)-5,5-difluoropiperidine-2-carboxylic acid (48 mg, 0.00018 mol) and 2,6-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride (84.7 mg, 0.000217 mol) TFA salt in N,N-dimethylformamide (0.406 mL, 0.00524 mol) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (96.0 mg, 0.000217 mol), followed by N,N-diisopropylethylamine (0.0756 mL, 0.000434 mol). The mixture was stirred at rt overnight, then quenched with aq. sodium bicarbonate. The mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried, and evaporated to dry. The residue was used directly in next step without further purification. LCMS (M+H) 460.2.
Reaction SMILES: [CH3:1][Mg]Br.[NH2:4][C:5]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O>CCOCC>[NH2:4][C:5]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:6]=1[C:7]([CH3:1])([OH:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[Mg]Br
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(O)(c1ccccc1)c1cc(Cl)ccc1N
Reaction time: 8 h
Yield: 75 %

Procedure:
Methylmagnesium bromide (267 ml of 3M ether-solution; 0.8 mole) is added during 45 minutes to a solution of 2-amino-5-chlorobenzophenone (46.3 g; 0.2 mole) in 1 liter of ether. The mixture is refluxed for 5 hours and allowed to stand overnight. It is then cooled in ice and decomposed with 400 ml of water. The ether layer is decanted, washed with saturated salt solution dried (MgSO4) and evaporated. The residue is crystallized from ether-Skellysolve B to give 37.1 g (75% yield), mp 93°-94° C., unchanged on recrystallization. Spectral data support the product structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Product: COc1cc2ncnc(Cl)c2cc1OC

Procedure:
The key starting material, 4-chloro-6,7-dimethoxyquinazoline, was prepared according to published procedures (Nomoto, et al., 1990, Chem. Pharm. Bull., 38:1591-1595; Thomas, C. L., 1970, IN:Catalytic Processes and Proven Catalysts, Academic Press, New York, N.Y.) as outlined below in Scheme 1. Specifically, 4,5-dimethoxy-2-nitrobenzoic acid (compound 1) was treated with thionyl chloride to form acid chloride, followed by reacting with ammonia to yield 4,5-dimethoxy-2-nitrobenzamide (compound 2). Compound 2 was reduced with sodium borohydride in the presence of catalytic amounts of copper sulphate to give 4,5-dimethoxy-2-aminobenzamide (compound 3), which was directly refluxed with formic acid to yield 6,7-dimethoxyquinazoline-4(3H)-one (compound 4). Compound 4 was refluxed with phosphorus oxytrichloride to give 4-chloro-6,7-dimethoxyquinazoline (compound 5) in good yield.
Reaction SMILES: C([NH:4][C:5]1[CH:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:6]=1[C:7]#[N:8])(=O)C.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].[OH-].[K+]>O>[NH2:4][C:5]1[CH:12]=[C:11]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: COCCOCCO
Reactant: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOCCOc1cc(N)c(C#N)cc1[N+](=O)[O-]

Procedure:
20 g of 2-acetylamino-4-chloro-5-nitrobenzonitrile obtained in Step (4) above was mixed with 110 ml of diethyleneglycol monomethyl ether, 11.4 g of potassium hydroxide was added thereto, and the mixture was reacted at 80° C. for 4 hours. After the completion of the reaction, the reaction mixture was cooled, then 250 ml of water was added thereto with stirring. The crystals thus-deposited were collected by filtration, washed with a mixture of water and methanol (1:1) and dried. Yield: 14.5 g (53.7%). Melting point: 106° to 108° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:21]([O:20][C:18]([NH:17][C:13]1([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][CH2:15][CH2:16]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1(C2CCN(Cc3ccccc3)C2)CCC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C2CCNC2)CCC1
Reaction time: 3 h

Procedure:
A 525 mg (1.59 mmol) portion of 1-benzyl-3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine (fr. 2) was dissolved in 50.0 ml of ethanol, mixed with 500 mg of 10% palladium-carbon and stirred for 3 hours under a hydrogen pressure of 4 atm with warming by an infrared lamp. After removing the catalyst by filtration, the solvent was evaporated to yield quantitative amount of the title compound.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: C1CCNC1
Reactant: O=C(c1ccc(F)cc1)C1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(c1ccc(N2CCCC2)cc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 4.1 g of 1-carbobenzoxy-4-(4-fluorobenzoyl)piperidine and 8 ml of pyrrolidine was stirred at 100° C. for 24 hours and the reaction mixtures was then worked up in the same manner as Example 2 to give 3.2 g of the title compound as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C=Cc1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)CCc1cccc(Cl)c1
Yield: 54.8 %

Procedure:
1-(3-Chlorophenyl)-1-buten-3-one (20.0 g, 111 mmol) was subjected to hydrogen catalytic reduction in ethanol (200 ml) at room temperature by using platinum oxide (PtO2; 0.30 g) as a catalyst. The catalyst was filtered off and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 11.1 g of 1-(3-chlorophenyl)butan-3-one.
Reaction SMILES: [CH3:1][NH:2]N.Cl.[CH2:5]([O:7][C:8](=[O:21])[C:9](=[CH:17][N:18](C)C)[C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:6]>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[N:2]([CH3:1])[N:18]=[CH:17][C:9]=1[C:8]([O:7][CH2:5][CH3:6])=[O:21])=[O:12])[CH3:15]
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Reactant: CNN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C)c1C(=O)OCC
Temperature: 60 °C
Yield: 36 %

Procedure:
Under an atmosphere of argon, methylhydrazine (1.15 g, 25 mmol) and HCl (36.5% in water, 2.5 ml) were added to a solution of 2-dimethylaminomethylene-3-oxo-succinic acid diethyl ester (6.07 g, 25 mmol, obtained by the method of Hanzlowsky et al., J. Heterocyclic Chem. 2003, 40(3), 487-498) in ethanol (200 ml). The mixture was heated to 60° C. until HPLC analysis indicated the disappearance of the starting material (2 h). The solvent was evaporated, and the residue was taken up in dichloromethane and washed (water). The organic layer was dried (Na2SO4), the solvent was evaporated and the title compound (2.06 mg, 36%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). (The regioisomeric 1-methyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester can also be isolated, and can be distinguished from the desired product by NOE-1H-NMR.) MS (m/e)=227.2 [M+H+].
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32]Cl)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17].C(Cl)Cl>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32][N:7]4[CH2:8][CH2:9][N:4]5[CH:3]=[N:2][N:1]=[C:5]5[CH2:6]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: c1nnc2n1CCNC2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCn2cnnc2C1
Temperature: 80 °C
Yield: 31.2 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.18 g) in DMF (8 mL) was added Ag2CO3 (1.12 g, 5 eq). The mixture was then added into a solution of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.21 g) in DMF (2 mL) at rt under stirring. The reaction mixture was heated at 80° C. for 36 h under N2, and cooled to room temperature. To the reaction mixture was added CH2Cl2 (100 mL), and the reaction mixture was washed with brine (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound (80.00 mg, 17.62%), HPLC: 88.57%. The title compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 484.2 (M+1); and 1H NMR (400 MHz, CDCl3) δ: 22.02-2.08 (m, 2H), 2.75 (t, J=13.20 Hz, 2H), 2.89 (t, J=10.80 Hz, 2H), 3.73 (s, 2H), 3.94 (s, 3H), 4.01 (t, J=10.80 Hz, 2H), 4.12 (t, J=12.40 Hz, 2H), 7.10 (m, 1H), 7.24 (s, 1H), 7.27 (t, J=6.00 Hz, 1H), 7.43 (s, 1H), 7.54-7.58 (m, 1H), 7.82-7.84 (m, 1H), 8.05 (s, 1H), 8.44 (s, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[S:20])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:22][CH:23](Br)[CH3:24]>CN(C)C=O>[CH2:22]([S:20][C:10]1[NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)[CH:23]([S:20][C:10]1[NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)[CH3:24]
Reactant: CC(Br)CBr
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Product: CC(CSc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)Sc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1

Procedure:
A solution of 4,5-bis(4-fluorophenyl)-1H-imidazole-2-thione (10 g, 0.035 mol) and 1,2-dibromopropane (3.5 g, 0.017 mol) in N,N-dimethylformamide (25 ml) was refluxed for two hours, then cooled. The precipitate was collected, treated with hot chloroform and recrystallized from isopropanol to give the title compound as its dihydrobromide salt, m.p. 243°-245°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a 1000 mL RB flask fitted with magnetic stirrer was charged 250 mL of DMF, 3-(4-Hydroxy-phenyl)-propanoic acid (25.0 g, 150.43 mmol) and K2CO3 (41.58 g, 300.87 mmol). The resulting mixture was stirred at RT for 30 minutes. Methyl Iodide (25.627 g, 180.51 mmol) was added to the resulting mixture which was precooled to 0° C. The resulting mixture was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), the solvent was removed under reduced pressure and the crude mass was dissolved in ethyl acetate (250 mL). The organic layer was washed with water (250 mL), saturated sodium bicarbonate solution (250 mL×2), and saturated brine solution (250 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as yellow color oil (26 g, Yield: 95.9%): MS (ESI, 120 eV): m/z=178.9 (M−H)+; 1H NMR (300 MHz, CDCl3): δ 6.97-7.00 (d, 2H), 6.66-6.69 (d, 2H), 4.94 (s, 1H), 3.59 (s, 3H), 2.78-2.83 (t, 2H), 2.50-2.55 (t, 2H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[N:22]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[N:25][CH:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]1[C:3]([N:29]2[CH2:30][CH2:31][CH:27]([N:22]3[CH:26]=[N:25][CH:24]=[N:23]3)[CH2:28]2)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: c1ncn(C2CCNC2)n1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1COc2c(N3CCC(n4cncn4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
A suspension of 70.25 mg (0.25 mmol) of (-) -9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 87 mg (0.5 mmol) of 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride in 3 ml of acetonitrile in the presence of 76 mg (0.5 mmol) DBU was stirred under nitrogen at reflux condition overnight. The yellow solution was then evaporated to dryness and to the residue, water was added and solid collected. The off-white solid was dissolved in chloroform and the small amounts of the suspension were filtered off. The supernatant was evaporated and to the residue, water was added and solid collected (60 mg), m.p. 229°-231° C. 1H NMR (CDCl3) δ: 8.59 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.7 (d, 13.5Hz, 1H), 5.17-5.00 (m, 1H), 4.6-3.73 (m, 7H), 2.67-2.4 (m, 2H), 1.61 (d, 6.7Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]([CH2:32][C:33](Cl)=[O:34])#[N:31]>ClCCl>[C:30]([CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:34])#[N:31]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: N#CCC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 98.9 %

Procedure:
Using the method for the preparation of the side chain acid in Example 3, 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 500 ml of dichloromethane, 21.0 ml (150 mmol) of triethylamine, 20 ml (158 mmol) of chlorotrimethylsilane, and 5.67 g (55 mmol) of cyanoacetyl chloride [Org. Syn. Col. Vol. V p. 171] gives 14.7 g of 6-[4-(cyanoacetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>280°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:16]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([CH2:12][NH2:16])([OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A stirred solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol (60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1csc2ccc(O)cc12
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc2scc(C(=O)O)c2c1
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A solution of 1,140 mg of the above obtained 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1) in 2 ml of acetic anhydride and 4 ml of pyridine was allowed to stand for 3 hours. After addition of water, the mixture was stirred for 1.5 hours under ice-cooling, and the precipitated crystals were filtered, washed with water, and dried to give 1,349 mg of 5-acetoxybenzo[b]thiophene-3-carboxylic acid (4). Yield 97.3%. mp 239-240° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=2)[CH2:7][C:6]=1[CH3:16].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.O>N1C=CC=CC=1>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[F:15])[C:7](=[CH:23][C:22]1[CH:21]=[C:20]([O:19][CH3:18])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=1)[C:6]([CH3:16])=[C:5]2[CH2:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)CC1=C(C)Cc2cc(F)c(F)cc21
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C=C2C(C)=C(CC(=O)O)c3cc(F)c(F)cc32)cc(OC)c1OC
Reaction time: 8 h

Procedure:
1.19 g (5.0 mmol) of 5,6-difluoro-2-methylindene-3-acetic acid methyl ester is dissolved in 10 ml of dry pyridine followed by 0.98 g (5.0 mmol) of 3,4,5-trimethoxy-benzaldehyde. The flask is placed under nitrogen, and 5.0 g (5.1 mol) of Triton B is added. The deeply colored solution is allowed to stand overnight. Water (2 ml) is added. After standing for 15 minutes, the mixture is poured into an excess of water. The organics are extracted with ether (2×50 ml). The aqueous phase is added to 10% HCl-ice. The orange, gummy solid that precipitates is extracted into methylene chloride and dried (MgSO4). The solvent is removed to leave an orange solid. The solid is filtered to give a crude product which is recrystallized to give 5,6-difluoro-2-methyl-1-(3,4,5-trimethoxy-benzylidene)-indene-3-acetic acid. When 2,4,6-trimethoxybenzaldehyde or 2,4,5-trimethoxybenzdehyde is used in the above procedure, instead of 3,4,5-trimethoxy-benzaldehyde, the corresponding indene acetic acid is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:11]1[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:39]([C:36]1[CH:35]=[CH:34][C:33]([S:32][CH3:31])=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: CSc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(SC)cc2)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.626 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate was dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 0.593 g of 4-methylsulphanylbenzenesulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 4-(2-methoxy-phenoxy)-3-(4-methylsulphanyl-benzenesulphonylamino)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a yellow oil.