Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[Cu][C:17]#[N:18].CCOC(C)=O>CN1C(=O)CCC1>[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:18]
Reactant: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c[nH]c2ccc(C#N)cc12
Yield: 46.7 %

Procedure:
Step H (2): To a solution of methyl 2-(5-bromo-1H-indol-3-yl)acetate (134 mg, 0.5 mmol) in NMP (1.0 mL) was added copper(I) cyanide (54 mg, 0.6 mmol). The reaction mixture was microwaved at 180° C. for 1.5 h. More copper (I) cyanide (54 mg, 0.6 mmol) was added, and the mixture was microwaved again at 180° C. for 2 h. 100 mL of EtOAc was added, and the reaction mixture was washed with 1.0 N HCl and H2O. The organic layer was dried and the residue was purified by flash chromatography to give 50 mg of the methyl 2-(5-cyano-1H-indol-3-yl)acetate (yield 47%). MS (ESI) (M+H)+=215.16. 1H NMR (500 MHz, CDCl3) δ ppm 3.73 (s, 3 H) 3.77 (s, 2 H) 7.26 (d, J=2.14 Hz, 1 H) 7.37 (d, J=8.24 Hz, 1 H) 7.40 (dd, J=8.24, 1.22 Hz, 1 H) 7.95 (s, 1 H) 8.54 (s, 1 H).
Reaction SMILES: C[C:2]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[K+].Cl>C(O)C.O>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([O:22][CH:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[CH:28][CH:27]=1
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)(C(=O)O)c1ccc(OCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Yield: 81.3 %

Procedure:
To a solution of 8.5 g of methyl(α,α,α-trifluoro-p-tolyloxy){p-[(p-chlorophenoxy)methoxy]phenyl}acetic acid in 50 ml of ethanol is added a solution of 6 g of potassium hydroxide in 50 ml of water. The mixture is refluxed for 4 hours and while hot, is acidified with 10 ml of concentrated HCl. The mixture is chilled immediately and extracted with dichloromethane. The extract is washed with a solution of sodium chloride, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is triturated with hexane containing small amounts of ether and dichloromethane and chilled to give 6.7 g of product as white crystals. The product is recrystallized by dissolving in 50 ml of benzene, filtering the solution and diluting the filtrate with 75 ml of hexane. Chilling and filtering gives 6.1 g of white crystals, mp 88°-89° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:8]([C:10]1[N:14]2[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=[CH:18][C:13]2=[CH:12][N:11]=1)=[O:9]>O1CCOCC1.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:8]([C:10]1[N:14]2[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]2=[CH:12][N:11]=1)=[O:9]
Reactant: COC(=O)c1ccc2cnc(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2ncc3ccc(C(=O)O)cn23)ccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
1.64 ml (1.64 mmol) of a 1N aqueous sodium hydroxide solution are added to 530 mg (1.49 mmol) of methyl 3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylate obtained in example 4 in a mixture of 20 ml of dioxane and 10 ml of methanol. The reaction medium is heated at 60° C. for 3 hours and then concentrated under reduced pressure. The residue is taken up in water and the aqueous phase obtained is washed with dichloromethane and then neutralized by addition of 1.64 ml of 1N hydrochloric acid. The precipitate formed is filtered off, washed with water and then dried. 405 mg of a yellow solid are collected. Melting point: 313° C.; 1H NMR (d6-DMSO): 4.01 (3H, s), 7.78 (1H, d), 7.98 (1H, s), 8.06-8.10 (3H, m), 8.15 (1H, s), 10.28 (1H, s)
Reaction SMILES: CO.[OH-].[Na+].[NH2:5][C:6]1[C:11]([C:12]2[O:16][N:15]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.Cl[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1>CN(C)C=O>[CH3:26][C:27]1[N:28]=[C:29]([CH2:33][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:14]3[CH:13]=[C:12]([C:11]4[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=4)[O:16][N:15]=3)=[CH:19][CH:20]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Cc1cccc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)n1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
Methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.18 mL) were added to 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (50 mg, 0.19 mmol) described in Manufacturing Example 5-1-1, which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue were added 2-chloromethyl-6-methyl-pyridine (31.8 mg, 0.22 mmol) described in Manufacturing Example 10-1-1 and N,N-dimethylformamide (2 mL), which was stirred for 20 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (36 mg, 51.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[C:4]=1[N+:14]([O-:16])=[O:15].[Br-].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+]>ClCCl>[N+:11]([C:5]1[C:4]([N+:14]([O-:16])=[O:15])=[C:3]([O:2][CH3:1])[CH:10]=[CH:9][C:6]=1/[CH:7]=[CH:23]\[C:22]1[CH:43]=[C:44]([O:48][CH3:49])[C:45]([O:46][CH3:47])=[C:20]([O:19][CH3:18])[CH:21]=1)([O-:13])=[O:12]
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(/C=C\c2ccc(OC)c([N+](=O)[O-])c2[N+](=O)[O-])cc(OC)c1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 50.3 %

Procedure:
4-methoxy-2,3-dinitrobenzaldehyde (2.94 mmol) and 3,4,5-trimethoxybenzyltriphenyl phosphonium bromide (1.54 g, 2.94 mmol, 1.0 equiv) in anhydrous dichloromethane (25 mL) was added NaH (0.424 g, 17.67 mmol, 6.0 equiv). The reaction mixture was stirred at room temperature for about 7 hours and monitored by TLC. The reaction was quenched by adding water, the organic layer was separated and the aqueous layer was extracted with dichloromethane (3×25 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to orange colored slush. To this was added about 15 mL of dichloromethane and refrigerated overnight. The crude mixture was subjected to flash chromatography to isolate 2′,3′-Dinitro-3,4,4′,5-tetramethoxy-(Z)-stilbene (0.581 g, 1.48 mmol, 51%, solid)
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH2:7][NH:8][C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])C>C(#N)C>[CH3:17][O:16][C:14](=[O:15])[C@@H:9]([N:8]1[CH2:7][C:6]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:5][C:4]1=[O:3])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CCOC(=O)C=C(CN[C@@H](CCSC)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Product: COC(=O)[C@H](CCSC)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 140 °C
Yield: 34.5 %

Procedure:
A solution of 3-(2-chloro-phenoxy)-4-((S)-1-methoxycarbonyl-3-methylsulfanyl-propylamino)-but-2-enoic acid ethyl ester (1.56 g, 3.88 mmol) in acetonitrile (4 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 140° C. for 3 h. After this time, the mixture was cooled to room temperature and concentrated in vacuo with silica gel (4 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylsulfanyl-butyric acid methyl ester (477 mg, 24% over two steps) as a golden oil: HR-ES-MS m/z calculated for C16H18NO4ClS [M+Na]+ 378.0537, observed 378.0538.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[O:12][C:13]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:14]=3[C:15]=2[C:16](=[O:29])[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH:8]=[N:7]1)C.[OH-].[Na+:38]>C1COCC1.O>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:14]2[C:15]([C:16](=[O:29])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[C:11]([C:9]3[CH:8]=[N:7][N:6]([CH2:5][C:4]([O-:36])=[O:3])[CH:10]=3)[O:12][C:13]=2[CH:33]=1.[Na+:38]
Reactant: CCOC(=O)Cn1cc(-c2oc3cc(OC)ccc3c2C(=O)c2cc(OC)c(OC)c(OC)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cnn(CC(=O)[O-])c3)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a stirred solution of {4-[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-yl]-pyrazol-1-yl}-acetic acid ethyl ester (25 mg, 0.051 mmol) in a mixture of THF (1 mL) and water (1 mL) was added sodium hydroxide (70 mg, 1.75 mmol) and the reaction allowed to stir overnight at ambient temperature. After this time the reaction was concentrated under vacuum and the residue dissolved in water (20 mL) and washed with diethyl ether (5 mL). The aqueous layer was acidified to pH 1-2 with concentrated hydrochloric acid and extracted with ethyl acetate (2×15 mL). The combined organic layers were concentrated under vacuum, the residue was dissolved in methanol (2 mL) and the resulting solution was treated with a methanolic solution of sodium methoxide until a pH of 9 was obtained. The solvent was removed under vacuum and the resulting yellow solid was washed with small portions of cold diethyl ether and isopropanol to provide the title compound (22 mg, 89%). 1H-NMR (D2O) δ 7.48 (s, 1H), 7.28 (s, 1H), 6.68-6.60 (m, 2H), 6.60 (s, 2H), 6.28 (d, J=7.6 Hz, 1H), 4.49 (s, 2H), 3.61 (s, 3H), 3.49 (s, 3H), 3.39 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:15][C:16]1[CH2:20][CH:19]=[C:18]([CH3:21])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].Cl.C([O-])(O)=O.[Na+]>>[CH3:21][C:18]1[CH2:19][CH:20]=[C:16]([CH3:15])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=CCC(C)=C1c1ccccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC1=CCC(C)=C1c1ccccc1NC(=O)C(C)(C)C
Yield: 102.2 %

Procedure:
0.130 g (1.29 mmol) of triethylamine and 0.155 g (1.29 mmol) of pivaloyl chloride were added to 0.263 g (1.42 mmol) of 2-(2,5-dimethylcyclopenta-1,4-dienyl)phenylamine solution melted in 10 mL of MC solvent, and then reacted at room temperature for 1 hour. 5 mL of 2N HCl was added to the reaction product and strongly stirred for a few minutes. The organic layer was neutralized using 5 mL of NaHCO3, and the product was filtered using a column chromatography with a hexane/ethyl acetate (v/v, 10:1) solvent. The refined product was dried in vacuum to remove the solvent therein, thereby obtaining while solid (0.355 g, 93%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([S:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C@H:31]4[CH2:35][CH2:34][O:33][CH2:32]4)=[O:29])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].ClC1C=C(C=CC=1)C(OO)=[O:45]>ClCCl.CO>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([S:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C@H:31]4[CH2:35][CH2:34][O:33][CH2:32]4)=[O:29])=[CH:23][CH:22]=3)=[O:45])[CH2:18][CH2:19]2)=[CH:11][CH:10]=1)([OH:8])[C:2]([F:38])([F:1])[F:39]
Reactant: O=C(Nc1ccc(SC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)N[C@H]1CCOC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc(S(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)N[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(S)-1-(4-(1-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidin-4-ylthio)phenyl)-3-(tetrahydrofuran-3-yl)urea (0.246 mmol, 142 mg) was dissolved in dichloromethane (5 mL) and the solution cooled to 0° C. 3-Chlorobenzoperoxoic acid (0.246 mmol, 42.4 mg) was added and the reaction mixture stirred for 2 hours. The reaction mixture was diluted with methanol and dichloromethane. The reaction mixture was washed with water and the organic layer separated, dried, and concentrated under vacuum. The residue was purified by silica column chromatography (eluting with a dichloromethane/methanol/ammonia gradient) to afford the title compound. MS m/z 594.5 [M+H]+
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([C:14](Cl)=[O:15])[O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[NH3:27]>>[C:14]([C:12]1[O:13][C:8]2[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:9]=2[C:10](=[O:17])[CH:11]=1)(=[O:15])[NH2:27]
Reactant: N
Reactant: CS(=O)(=O)Nc1cc2oc(C(=O)Cl)cc(=O)c2cc1Oc1ccccc1
Product: CS(=O)(=O)Nc1cc2oc(C(N)=O)cc(=O)c2cc1Oc1ccccc1

Procedure:
7-Methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one-2-carboxylic acid chloride was reacted with ammonia to obtain 2-carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH:25]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([C:26]3[CH:25]=[C:24]([C:23]([F:38])([F:37])[F:22])[CH:29]=[CH:28][N:27]=3)[CH2:31][CH2:32]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2cc(C(F)(F)F)ccn2)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3cc(C(F)(F)F)ccn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 38 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 1-[4-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine dihydrochloride (0.220 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.112 g, 38%). 1H NMR (500 MHz, CDCl3): δ 8.28-8.23 (m, 1H), 7.59-7.52 (m, 2H), 7.51-7.44 (m, 3H), 6.79-6.74 (m, 1H), 6.74-6.70 (m, 1H), 5.27-5.17 (m, 1H), 4.17-4.07 (m, 2H), 3.24-3.13 (m, 1H), 2.57-2.48 (m, 2H), 1.83-1.69 (m, 2H), 1.75 (s, 9H), 1.42-1.31 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 149.3, 134.1, 131.9, 130.2, 129.0, 125.3, 108.5, 107.4, 102.9, 61.9, 50.5, 43.9, 32.0, 27.8; Mass Spectrum: M−H+ 509.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[C:24](Cl)(=[O:26])[CH3:25]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(OC2CCNCC2)c2cc(F)ccc2c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(OC2CCN(C(C)=O)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of [6-fluoro-4-(piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (the intermediate for example 4-1, 1st step, 80 mg, 0.25 mmol) and acetyl chloride (39 mg, 0.5 mmol) in tetrahydrofuran (2 mL) was added a solution of 4-dimethylaminopyridine (76 mg, 0.63 mmol) in tetrahydrofuran (1 mL) dropwise. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 10-50% ethyl acetate in petroleum ether) to afford [4-(1-acetyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (72 mg, 79%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[CH3:29].O>C(O)CCC>[CH3:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[NH:18][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: Clc1nc(-c2ccccc2)c2ccccc2n1
Solvent: O
Solvent: CCCCO
Product: COC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)c(C)c1
Temperature: 160 °C
Yield: 79.6 %

Procedure:
A mixture of 2-chloro-4-phenylquinazoline (200 mg, 0.83 mmol) and methyl 4-amino-3-methylbenzoate (137 mg, 0.83 mmol) in n-butanol was heated to 160° C. for 1 h and then cooled to rt. Water (10 mL) was added and the product collected by filtration to give the methyl 3-methyl-4-(4-phenylquinazolin-2-ylamino)benzoate (244 mg, 79%), which was dissolved in a 1:1 mixture of water and methanol (10 mL) containing sodium hydroxide (100 mg, 2.5 mmol). The mixture was heated to 60° C. overnight. Ethyl acetate (100 mL) was added and the phases were separated. The aqueous layer was acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator to give 3-methyl-4-(4-phenylquinazolin-2-ylamino)benzoic acid (188 mg, 80%).
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=O)C1C=CC=CC=1.[CH3:19]C(C)(CC(OC)=O)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:11]([C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([O:16][CH3:19])=[O:15])=[C:9]=[O:8]
Reactant: COC(=O)CC(C)(C)C(=O)O
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC(C)(C)N=C=O
Temperature: 5 °C

Procedure:
3-(Benzyloxycarbonylamino)-3-methylbutanoic Acid. A solution of 2,2-dimethyl-3-carbomethoxypropionic acid (LeMaul, Bull. Soc. Chim. Fr., 828 (1965), 20 g, 0.125 mol), diphenylphosphorylazide (34.3 g, 0.125 mol) and triethylamine was heated in toluene (150 ml) at 100° C. for 2 h After cooling to 5° C., the toluene solution was washed successively with 0.5M HCl, aqueous NaHCO3 and brine. Evaporation of the dried solution gave a residue which was chromatographed on silica gel eluting with 60/40 hexane-ether. There was obtained 13 g of methyl 3-isocyanato-3-methylbutanoate as a mobile liquid. A solution of this material in toluene (20 ml) was treated with benzyl alcohol (13 ml) and the resulting mixture heated at reflux for 40 h. Evaporation of the toluene left a residue which was dissolved in methanol (125 ml) and then treated with a solution of NaOH (6.6 g, 0.165 mol) in 22 ml of water. After 5 h, the reaction mixture was partially evaporated, washed with ether and acidified with 6N HCl. Extraction with methylene chloride and evaporation gave 21 g of the desired product. NMR (300 MHz, CDCl3): 1.42 (s,6H), 2.78 (s,2H), 5.08 (s,2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:25])[CH:11]=[CH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:6][CH2:5]1.[F:26][C:27]1[CH:28]=[C:29]2[C@:36]3([C:40](=[O:41])[NH:39][C:38](=[O:42])[NH:37]3)[CH2:35][C@@H:34]([C:43](Cl)=[O:44])[O:33][C:30]2=[CH:31][CH:32]=1>>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22])[CH:12]=[CH:11][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:43]([C@@H:34]2[CH2:35][C@@:36]3([C:40](=[O:41])[NH:39][C:38](=[O:42])[NH:37]3)[C:29]3[C:30](=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=3)[O:33]2)=[O:44])[CH2:5][CH2:6]1)=[O:25]
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Reactant: COc1cc(C=CC(=O)N2CCN(CCN)CC2)cc(OC)c1OC
Product: COc1cc(C=CC(=O)N2CCN(CCNC(=O)[C@@H]3C[C@]4(NC(=O)NC4=O)c4cc(F)ccc4O3)CC2)cc(OC)c1OC
Yield: 72 %

Procedure:
The procedure similar to that described in Example 8 was carried out with the use of the compound of 4-(2-aminoethyl)-1-(3,4,5-trimethoxycinnamoyl)piperazine and (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1) to give the desired compound with yield of 72.0%.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14]C)=[O:13].O>[OH-].[Na+].CC(O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)CCc1cc(F)cc(F)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)CCc1cc(F)cc(F)c1Br

Procedure:
Methyl 3-(2-bromo-3,5-difluorophenyl)propanoate (prepared as described in Step 1, 4.3 g) in aqueous NaOH (4 M, 13.5 mL) and 2-propanol (30 mL) is heated at 50° C. for 2 hours. Water is added, the mixture washed with diethyl ether, acidified to ca. pH 5 by adding concentrated aqueous HCl, and extracted twice with diethyl ether. The combined extracts of the acidified mixture are washed with brine and volatiles evaporated under reduced pressure. The resulting material (Yield 3.6 g) is used in the next step without further purification. LC (METHOD 7): tR=0.99 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH2:16][CH2:17][CH3:18])[N:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=1)[C:8]2=[O:56])(=[O:3])[CH3:2].[NH4+].[OH-].C(O)(=O)C>CO.Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH2:16][CH2:17][CH3:18])[N:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:33][N:34]=[N:35][N:36]=3)=[CH:22][CH:21]=1)[C:8]2=[O:56])(=[O:3])[CH3:2]
Reactant: CCCCc1nc2ccc(NC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc2ccc(NC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a solution of 0.073 g (0.099 mmol) of the product from Example 42 in 2 mL of MeOH was added 4 drops of conc. HCl. The reaction mixture was stirred for 5 minutes and then made basic by addition of conc. NH4OH. The pH of the solution was adjusted to 5.0 by addition of acetic acid. The reaction mixture was concentrated in vacuo and the residue was taken up in 20 ml of EtOAc. The solution was washed with water (2×5 mL) and brine (1×5 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo. The crude product was very insoluble and was consequently purified by trituration with CHCl3, EtOAc and hexanes to give 32 mg of an off white solid, 65% yield. 1H-NMR (CD3OD 300 MHz): 0.83 (t, 3H, J=7.3 Hz), 1.32 (m, 2H), 1.62 (2H, m), 2.09 (s, 2H), 2.68 (3 line m, 2H, J=8.1 Hz), 5.37 (bs, 2H), 7.00-7.10 (m, 4H), 7.42-7.61 (m, 5H), 7.89 (dd, 1H, J=2.4, 8.8 Hz), 8.39 (d, J=2.5 Hz). FABMS m/e: 494(M+ +1) calc. for C28H27N7O2.