Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:30](Br)[CH:31]=[CH2:32]>O1CCCC1>[CH2:32]([C@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:16]([O:18][CH3:19])=[O:17])[CH:31]=[CH2:30]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)C(=O)OC
Temperature: -70 °C
Reaction time: 2 h

Procedure:
11.01 g (40 mmol) of dimethyl Boc-glutamate (Advanced Chemtech) were dissolved in 160 ml of tetrahydrofuran and cooled to −70° C. 88 ml (88 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise at this temperature over a period of one hour, and the mixture was stirred at −70° C. for another 2 hours. 14.52 g (120 mmol) of allylbromide were then added dropwise, and after 2 h at this temperature, the cooling bath was removed and 200 ml of 2N aqueous hydrochloric acid and 400 ml of ethyl acetate were added. The organic phase was separated off, washed with water until neutral, dried over sodium sulphate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed in silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([F:12])[CH:6]=1
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(OCc2ccccc2)c(F)c1
Temperature: 60 °C
Yield: 86.6 %

Procedure:
To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (15 g, 54.3 mmol) and benzyl bromide (9.28 g, 54.3 mmol) in DMF (50 mL), was K2CO3 (7.24 g, 54.3 mmol) added at an ambient temperature. The reaction mixture was heated to 60° C. and maintained for 2 hours. The reaction was cooled to room temperature and poured into H2O (150 mL). The organic compound was extracted with ether (150 mL) and washed with sat NaHCO3 (100 mL). The ether layer was dried over MgSO4, and concentrated under vacuum to afford the desired compound (12.9 g, 87.9%) as a white crystal. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 7.41-7.49 (m, 5H), 7.15-7.23 (m, 2H), 7.02-7.04 (m, 1H), 5.19 (s, 2H), 3.65 (s, 2H), 3.63 (s, 3H). LCMS 273.4 [MH+].
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([O:13][C@@H:22]2[CH:23]3[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]3)[CH2:21]2)=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)C(Nc1ccc(F)cc1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38 %

Procedure:
2-(4-Fluorophenylamino)-2-phenylacetic acid hydrochloride (I38) (2.00 g, 8.15 mmol) was dissolved in THF (25 ml), and (R)-quinuclidin-3-ol (1.14 g, 8.97 mmol) was added. To the resulting solution, HOBt (1.10 g, 8.15 mmol) and DCC (0.841 g, 4.08 mmol) were added, and the mixture was stirred at room temperature for three days. Then a second portion of HOBt (0.55 g, 4.08 mmol), DCC (0.84 g, 4.08 mmol) and (R)-quinuclidin-3-ol (0.52 g, 4.08 mmol) were added, and the mixture was stirred at room temperature overnight. THF was removed under vacuum, and the residue was treated with H2O and extracted twice with EtOAc. The combined organic phases were washed with saturated Na2CO3 and dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The crude was purified by flash chromatography (EtOAc/MeOH=9/1 to 75/25) to afford (R)-quinuclidin-3-yl 2-(4-fluorophenylamino)-2-phenylacetate (1.1 g, 3.10 mmol, 38.1% yield, mixture of diasteromers).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:18](CC)([O-])=O.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:18]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)cc1O
Yield: 52.4 %

Procedure:
A mixture of 226 g (1.00 mol) of 2-hydroxy-4(phenylmethoxy)benzaldehyde in 287 ml (3.83 mol) of nitroethane and of 313 g (2.3 mol) of sodium acetate in 570 ml of acetic acid is heated at 104° C. for 8 hours and is then poured into 3 l of a mixture of water and ice. The precipitate is then filtered off, rinsed with diisopropyl ether and dried. 118 g of product are obtained. Moreover, the filtrate is extracted with diethyl ether, the organic phase is washed with an aqueous sodium hydrogencarbonate solution and then with water, dried over sodium sulphate and concentrated under reduced pressure and the residue is then triturated in diisopropyl ether. 67 additional g of product are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2[CH:14]=O)[CH:6]=[CH:5][CH:4]=1.[CH3:16][C:17]([CH3:19])=[O:18].[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2/[CH:14]=[CH:16]/[C:17](=[O:18])[CH3:19])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2ccsc2C=O)n1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2ccsc2/C=C/C(C)=O)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a 500 mL recovery flask was added 3-(6-methoxypyridin-2-yl)thiophene-2-carbaldehyde (30C, 6.2 g, 28.3 mmol, 1.0 eq.), acetone (16.6 mL, 226 mmol, 8.0 eq.), and H2O (130 mL). Upon cooling to 0° C. in an ice bath, aqueous NaOH (5N, 6.2 mL, 31.1 mmol, 1.1 eq.) was added. The reaction mixture was stirred overnight while warming to room temperature. LC/MS monitoring showed the reaction to be ˜60% complete, so additional aqueous NaOH (5N, 1 mL, 5.0 mmol, 0.18 eq.) was added. After stirring for an additional 6 h the reaction was complete by LC/MS. The reaction mixture was neutralized with 3N aqueous HCl to a pH ˜8. The mixture was extracted with EtOAc (3×100 mL). The organic phases were combined and washed with saturated aqueous NaCl (100 mL). The combined aqueous phases were extracted with EtOAc (100 mL). The organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated to give a black solid. The residue was purified via flash chromatography (60% CH2Cl2/Hex to 100% CH2Cl2) to give a yellow solid 30D (4.8 g, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H) 3.96 (s, 3H) 6.59 (d, J=15.92 Hz, 1H) 6.84 (d, J=8.34 Hz, 1H) 7.41 (d, J=7.58 Hz, 1H) 7.60 (d, J=5.31 Hz, 1H) 7.75-7.88 (m, 2H) 8.71 (d, J=15.92 Hz, 1H). ESI-MS: m/z 260.3 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][S:9]([C:12]1[CH:38]=[CH:37][C:15]([O:16][C:17]2[C:31]([CH:32]3[CH2:36][CH2:35][CH2:34][NH:33]3)=[CH:30][C:20]3[NH:21][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:23][C:19]=3[CH:18]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:31]([CH:32]3[CH2:36][CH2:35][CH2:34][N:33]3[C:1](=[O:3])[CH3:2])=[CH:30][C:20]3[NH:21][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:23][C:19]=3[CH:18]=2)=[CH:37][CH:38]=1)(=[O:10])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Solvent: ClCCl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.003 ml of acetic anhydride was added to a methylene chloride (1 ml) solution of 10 mg of 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole, and the reaction liquid was stirred at room temperature for 1 hour. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([OH:18])=[CH:13][C:12]=2[OH:19])=[O:10])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=O)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][C:14]([OH:18])=[C:15]([Cl:17])[CH:16]=3)[O:19][C:20]=2[CH3:21])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccc(Br)cc1)c1cc(Cl)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(Br)cc1

Procedure:
This compounds was synthesised in the same manner as described above. 2-(4-Bromo-phenyl)-1-(5-chloro-2,4-dihydroxy-phenyl)-ethanone (1.5 g, 4.4 mmol), Acetic anhydride (2.0 ml), Potassium carbonate (2.1 g 15.2 mmol). 3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-2-methyl-chromen-4-one was obtained an off white solid (1.2 g, 74.5%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:25]=1[C:30](=[O:29])[N:1]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])[C:27]2=[O:28])(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 43.3 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid was prepared by the procedure of Example 4 from 3-amino-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (2.7 g, 13 mmol), 3-acetamido-phthalic anhydride (4.0 g, 14.5 mmol) and sodium acetate (1.2 g, 14.5 mmol) in acetic acid (50 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (2.6 g, 45%) as yellowish solid. mp 89-91° C.; 1H NMR (CDCl3): δ 1.42 (t, J=7.5 Hz, 3H, OCH2CH3), 2.51 (s, 3H, CH3CO), 3.19 (dd, J=5.8, 15.5 Hz, 1H, CH2), 3.79 (dd, J=8.4, 15.5 Hz, 1H, CH2), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 5.65-5.71 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, CF2H), 7.03-7.11 (m, 3H, Ar), 7.45 (d, J=7.5 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.72 (d, J=8.3 Hz, 1H, Ar), 9.46 (s, 1H, NHCO). 13C NMR (CDCl3): δ 14.6, 24.8, 35.6, 50.3, 64.7, 98.4, 99.1, 111.8, 113.5, 115.2, 115.9, 118.2, 120.1, 120.2, 122.7, 125.0, 131.0, 136.0, 136.5, 137.4, 138.1, 140.0, 140.1, 140.2, 150.6, 167.4, 169.5, 169.7, 175.1; Anal. Calcd. for C22H20F2N2O7+0.17H2O: C, 56.77; H, 4.40; N, 6.06, H2O, 0.66; Found: C, 56.60; H, 4.43; N, 6.02; H2O, 0.66.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=2[CH:26]([CH3:28])[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:26]([C:18]1[CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C(C)C)cc2C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
2-(2,4-diisopropyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (211 mg, 0.54 mmol) is dissolved in EtOH (8 mL), and solid KOH (823 mg, 14 mmol) and water (0.8 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with concentrated HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (250) as white solid (188 mg, 95%).
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH:7]=[CH:8][C:9]([Cl:15])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C=CC1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=CC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-cyclohexyl-acrylic acid (5.0 g, 32.5 mmol) and oxalyl chloride (3.4 ml, 34.0 mmol) in anhydrous DCM (50 ml) was treated with one drop of dimethylformamide. The resulting solution was stirred at room temperature for 18 h, concentrated and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:31][CH3:32])=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[C:3]([O:31][CH3:32])=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:15])[CH3:16]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1c(/C(C)=C(F)\C=C\C(C)=C\C(=O)O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, a solution of ethyl 7-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-octa-2E,4E,6E-trienoate (Compound 164, 38 mg, 0.082 mmol) in ethanol and THF was hydrolyzed with 1M NaOH to give rise to the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2].I[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(C(F)(F)F)cc2)cc1C

Procedure:
In analogy to the procedure described in example 13B], 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]) and 1-iodo-4-trifluoromethyl-benzene gave the title compound as a light yellow viscous oil.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)[C@@H:26]([NH2:28])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.[NH2:37][C:38](=[O:42])[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)[C@@H:26]([NH:28][C:39]([C:38]([NH2:37])=[O:42])=[O:40])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:13][CH:14]=1
Reactant: NC(=O)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
N,N-Diisopropylamine (0.049 mL, 0.30 mmol) was added to a suspension of (1R,2S)-1-(1-(4-fluorophenyl)indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (53 mg, 0.14 mmol), 2-amino-2-oxoacetic acid (12 mg, 0.14 mmol) and HBTU (62 mg, 0.16 mmoL) in dichloromethane (2 mL). The mixture was stirred at r.t. overnight. The clear solution was concentrated and purified by HPLC to give the title compound (43 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH:5]=[C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([O:11][C:12](=O)[CH:7]12)=[O:10].C(N(CC)CC)C>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][CH2:6][C:7]1[CH:12]=[CH:16][CH:15]=[CH:14][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1ccccc1C=C1C=CC=C2C(=O)OC(=O)C12
Agent: [Ni]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccccc1CCc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
10 g (0.0397 mol) of 2-methoxybenzylidene phthalic anhydride (compound 1) is placed in a 500 ml autoclave. 230 ml of ethanol, 4.02 g (1 eq.) of triethylamine and 20 g of Raney nickel freshly prepared from 40 g of 50% Raney nickel alloy by a conventional method are added. The reaction mixture is stirred under an H2 pressure of 4 kg/cm2 at room temperature for 2 days. After the catalyst is filtered off and washed with ethanol, the filtrate is evaporated. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give 6.548 g (yield 64%) of colorless acicular crystals having a melting point of 118° to 119° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].Cl.[C:18]([NH2:26])(=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>CN(C)C(=O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:26]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:25]=1
Reactant: N=C(N)c1ccccc1
Reactant: N#Cc1c(F)cccc1Oc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1nc(-c2ccccc2)nc2cccc(Oc3ccccc3)c12
Temperature: 150 °C
Yield: 12.3 %

Procedure:
A mixture of 2-fluoro-6--phenoxybenzonitrile (2.7 g, 13 mmol, Maybridge), benzamidine hydrochloride (3.0 g, 19 mmol, Aldrich) and sodium acetate (1.6 g, 19 mmol) in 60 mL of N,N-dimethylacetamide was heated at 150° C. under nitrogen for 6.5 hours. After cooling to room temperature the reaction mixture was evaporated under reduced pressure. The product was suspended in a mixture of 20 mL of ethanol and 100 mL of water, and 10 mL of concentrated ammonium hydroxide was added. The solid was collected by vacuum filtration, washed with water, dried, recrystallized twice from 60 mL of 2-propanol at 4° C., and dried at 50° C. under vacuum to give 0.5 g (12% yield) of 4-amino-2-phenyl-5-phenoxyquinazoline, m.p. 190-191° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].FC(F)(F)C(O)=O.[O:72]=[C:73]1[CH:77]=[CH:76][C:75](=[O:78])[N:74]1[CH2:79][CH2:80][C:81]([CH3:87])([CH3:86])[C:82]([NH:84][NH2:85])=[O:83]>>[O:78]=[C:75]1[CH:76]=[CH:77][C:73](=[O:72])[N:74]1[CH2:79][CH2:80][C:81]([CH3:87])([CH3:86])[C:82]([NH:84][NH:85][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:83]
Reactant: CC(C)(CCN1C(=O)C=CC1=O)C(=O)NN
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)C(C)(C)CCN1C(=O)C=CC1=O)C(C)C

Procedure:
6 mg (6.7 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 61) were reacted with 3 mg (8.7 μmol) of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2,2-dimethylbutanehydrazide trifluoroacetate in analogy to Intermediate 142 to give 2 mg (27% of theory) of the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.CCN=C=NCCCN(C)C.[C:31]12([C:41](O)=[O:42])[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2>C(Cl)Cl>[C:31]12([C:41]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:42])[CH2:38][CH:37]3[CH2:36][CH:35]([CH2:34][CH:33]([CH2:39]3)[CH2:32]1)[CH2:40]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)C13CC4CC(CC(C4)C1)C3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.096 ml was added in a methylene chloride 5 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 100 mg, and stirred at 0° C. for 30 min. WSC 0.13 g and 1-adamantanecarboxylic acid 0.11 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 15 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(1-adamantyl carbonyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 10 ml solution of lithium aluminum hydride 24.0 mg and refluxed under heating for 1.5 hour. The reaction mixture was cooled, then added water, and removed the insoluble material by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform) to obtain the product.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[N+:9]([O-])[CH:10]=1)[CH3:3].CO.[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:12][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:10][N:9]=1)(=[O:17])[CH3:16]
Reactant: Cc1ccc(OC(C)C)c[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)OCc1ccc(OC(C)C)cn1
Yield: 71 %

Procedure:
5-(1-Methylethoxy)-2-methylpyridine 1-oxide (234 mg, 1.40 mmol) was dissolved in acetic anhydride (3.0 mL) and the resultant mixture was stirred at 140° C. for 1 hour. The reaction solution was added with methanol at room temperature, stirred, then concentrated in vacuo, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and [5-(1-methylethoxy)pyridin-2-yl]methyl acetate (209 mg, yield 71%) was obtained as a yellow oil.