Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23](OC)=[O:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH3:27][NH:28][O:29][CH3:30].C([Mg]Cl)(C)C>C1COCC1>[CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]([N:28]([O:29][CH3:30])[CH3:27])=[O:24])[CH2:19][CH2:18]2)(=[O:15])=[O:16])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)OC)CC2)s1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)N(C)OC)CC2)s1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
327a (390 mg, 1 mmol) and N,O-dimethylhydroxylamine (148 mg, 1.52 mmol) were stirred at −20° C. in anhydrous THF, while Isopropylmagnesium chloride in THF (2M, 1.65 mL, 3.23 mmol) were slowly added. The reaction mixture was allowed to warm to r.t. during 30′, followed by an additional stirring at r.t. for 30′. The reaction is quenched with ammoniumchloride solution (20%). The aqueous layer is extracted with t-butylmethylether, and the combined organic layers are washed with brine, dried over MgSO4 and evaporated to dryness. The crude is purified by flash chromatography on silica gel using cyclohexan/EtOAc 1:1 as eluent. 327b (380 mg, 90%) was obtained as a colourless solid: H1 NMR (DMSO d6) δ7.53 (d, J=3.7 Hz, 1H), 7.16 (d, J=3.6 1H), 5.89 (m, 2H), 5.24 (m, 4H), 3.86 (s, 2H), 3.62 (m, 5H), 3.15 (m, 7H), 2.74 (m, 1H), 2.50 (m, 2H), 2.25 (m, 2H), 1.84 (m, 2H), 1.63 (m, 2H). M/Z APCI: 428.1 (M+1).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C:15]1([CH3:42])[NH:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[CH:30][C:29]=2[F:41])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:34][C:33]1[CH:32]=[C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:29]([F:41])[C:28]=1[CH:26]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][C:15]([CH3:14])([CH3:42])[N:27]1[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)/C=C/c1cc(F)c(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1cc(F)c(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Reaction time: 24 h
Yield: 56.5 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (0.339 g, 1.51 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate (0.3 g, 0.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.458 ml, 2.65 mmol) in 1,4-dioxane (2 ml). The stirring was continued for 24 hours then the volatiles were removed under vacuum and the crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in heptane. Pre fractions were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (0.202 g, 36%) as a white solid. The material was combined with another batch (0.36 g) and purified by preparative HPLC (Chiralpak IA column, 20 μm silica, 20 mm diameter, 250 mm length), Heptane:IPA 70:30 at 80 ml/min (4 injections). Fractions containing the desired compounds were evaporated to yield (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1, first eluted, 217 mg) and (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 2, second eluted, 165 mg). Analysis was done on Chiralpak IA column, 5 μm silica, 4.6 mm diameter, 50 mm length, Heptane:IPA 70:30 at 2 ml/min. 1H NMR (400 MHz, DMSO, 30° C.) δ 0.50 (3H, d), 1.02 (3H, s), 1.30 (3H, s), 2.11 (1H, dd), 2.62 (2H, d), 2.80 (1H, d), 2.99 (1H, dd), 3.74 (3H, s), 4.09-4.23 (1H, m), 4.29 (1H, d), 5.09 (1H, s), 6.81 (1H, d), 6.97 (2H, dt), 7.16 (1H, d), 7.39 (1H, d), 7.53 (2H, d), 7.64 (1H, d), 10.44 (1H, s). m/z: ES+ [M+H]+ 471.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:13][CH2:14][CH2:15][NH2:16])[C:5]2[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][C:6]=2[N:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>O1CCOCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[N:3]=[C:4]([CH2:13][CH2:14][CH2:15][NH2:16])[C:5]4[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: NCCCc1nc(Cl)nc2c1S(=O)(=O)CC2
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Product: NCCCc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)(=O)CC2
Temperature: 150 °C
Yield: 69.9 %

Procedure:
0.262 g (1.00 mmol) of (2-chloro-5,5-dioxo-6,7-dihydro-5H-5λ6-thieno[3,2-d]pyrimidin-4-yl)propylamine (II) and 0.433 g (2.20 mmol) of 1-(4-chlorophenyl)piperazine are placed in 4.50 mL of dioxane, then heated to 150° C. in the microwave for 0.75 hours. Then the reaction mixture is concentrated by evaporation, the residue is treated with water. It is suction filtered, washed with water, and dried. The product which is not yet clean is purified by chromatography (column: 10 g Chromabond SiOH cartridge, solvent: petroleum ether/ether 1:1). Corresponding fractions are combined and concentrated by evaporation. 0.295 g of product III (70%) is obtained as a powder (m.p. 243° C.-245° C.).
Reaction SMILES: C([O:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])C.[Se](=O)=O.[O:16]1CCO[CH2:18][CH2:17]1>O.C(OCC)(=O)C>[CH2:17]([O:16][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:5]([CH:4]=[O:3])=[O:6])[CH3:18]
Reactant: CCOCC(=O)c1ccccc1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccccc1C(=O)C=O

Procedure:
2 g of 2-ethoxyacetophenone are dissolved in 20 ml of dioxane, and a solution of 2 g of selenium dioxide in one ml of water is added thereto. The solution is refluxed for 10 hours. After the reaction, insoluble materials are removed by filtration, and the filtrate is concentrated. The residue thus obtained is dissolved in ethyl acetate. The ethyl acetate solution is washed with water and then with an aqueous sodium bicarbonate solution and water. Then, said solution is dried and evaporated to remove solvent. 2.1 g of 2-ethoxyphenylglyoxal are obtained as a crude oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:24])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:29](Cl)(=[O:32])[CH2:30][CH3:31].Cl>[N+](C)([O-])=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:29](=[O:32])[CH2:30][CH3:31])[O:10][C:6]=2[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: CCC(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3ccoc23)c1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCC(=O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
1.3 g (1.4 mmol) of 3-(4-chloro-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 1.9 g (1.4 mmol) of aluminum chloride, were dissolved in 20 ml of nitromethane, and 0.5 g (1.4 mmol) of propionyl chloride was dropwise added thereto under cooling with ice. After completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into a mixture of dilute hydrochloric acid and ice and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated s odium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.33 g (yield: 56%) of the desired product as a yellow glassy substance. Refractive index: unmeasurable, 1H-NMR (solvent, CDCl3): 1.20(3H,m), 2.91(2H,q), 3.56(3H,s), 6.38(1H,s), 7.28(1H,d), 7.58(1H,s)ppm
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:8]2[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=2[C:10]([NH:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([N:19]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4/[C:23](=[CH:30]/[C:31](O)=[O:32])/[C:22]([F:35])([F:34])[CH2:21][CH2:20]3)=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:5]=[CH:6][N:7]=1)[CH3:2].[CH:42]1([NH2:45])[CH2:44][CH2:43]1>>[CH:42]1([NH:45][C:31](/[CH:30]=[C:23]2\[C:22]([F:34])([F:35])[CH2:21][CH2:20][N:19]([C:17]([C:16]3[CH:36]=[CH:37][C:13]([NH:12][C:10](=[O:11])[C:9]4[CH:38]=[CH:39][CH:40]=[CH:41][C:8]=4[N:4]4[CH:5]=[CH:6][N:7]=[C:3]4[CH2:1][CH3:2])=[CH:14][CH:15]=3)=[O:18])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]\2=3)=[O:32])[CH2:44][CH2:43]1
Reactant: NC1CC1
Reactant: CCc1nccn1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(F)(F)/C(=C\C(=O)O)c3ccccc32)cc1
Product: CCc1nccn1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(F)(F)/C(=C\C(=O)NC3CC3)c3ccccc32)cc1

Procedure:
Using 0.5 g of (Z)-[1-[4-[2-(2-ethyl-1H-imidazol-1-yl)benzoylamino]benzoyl]-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetic acid and 0.074 ml of cylopropylamine, a similar procedure as in Example 11 was repeated to obtain 325 mg of (Z)-4'-[[5-[(N-cyclopropylcarbamoyl)methylene]-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-(2-ethyl-1H-imidazol-1-yl) benzanilide.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Br[C:43]1[C:44]([CH:57]2[CH2:59][CH2:58]2)=[CH:45][C:46]([O:53][CH:54]([CH3:56])[CH3:55])=[C:47]([CH:52]=1)[C:48]([O:50][CH3:51])=[O:49]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:57]1([C:44]2[C:43]([CH:1]3[CH2:3][CH2:2]3)=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[C:46]([O:53][CH:54]([CH3:56])[CH3:55])[CH:45]=2)[CH2:59][CH2:58]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Br)c(C2CC2)cc1OC(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(C2CC2)c(C2CC2)cc1OC(C)C
Temperature: 100 °C
Reaction time: 15 h
Yield: 97.8 %

Procedure:
Cyclopropylboronic acid (2.83 g), a 2 M aqueous sodium carbonate solution (33 mL), tris(dibenzylideneacetone)dipalladium(0) (1.41 g), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.36 g) were added at room temperature to a toluene (100 mL) solution of methyl 5-bromo-4-cyclopropyl-2-isopropoxybenzoate (6.89 g), and the mixture was stirred at 100° C. for 15 hours in an argon atmosphere. Water was added to the reaction mixture at room temperature. The mixture was filtered through celite, and then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.90 g).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:33][CH:34]([F:36])[F:35])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:27])=[CH:24][CH:25]=1)=[C:8]2[O:33][CH:34]([F:35])[F:36]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of {8-chloro-4-difluoromethoxy-2-ethyl-3-[4-(pyrrolidine-1-carbonyl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.037 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.0 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, acidified by the addition of sodium dihydrogenphosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to afford title compound, 0.034 g.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[N:9]=[CH:10][N:11]2[CH:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:13][C:12]=12.[O:21]=[C:22]1[C:27]2[CH:28]=[C:29]([C:32](Cl)=[O:33])[CH:30]=[CH:31][C:26]=2[N:25]=C(C2C=CC=CC=2)[O:23]1.[OH-].[K+].Cl>ClCCCl.CN1C(=O)CCC1.O>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:10]2[N:11]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:12]3=[CH:8][N:9]=2)=[O:33])=[CH:28][C:27]=1[C:22]([OH:23])=[O:21]
Reactant: O=C(Cl)c1ccc2nc(-c3ccccc3)oc(=O)c2c1
Reactant: COC(=O)c1ccc2cncn2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)c2ncc3ccc(C(=O)O)cn23)cc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 197.1 %

Procedure:
3.68 ml (0.026 mol) of triethylamine and then, under a nitrogen atmosphere at ambient temperature, 1.5 g (8.5 mmol) of methyl imidazo[1,5-a]pyridine-6-carboxylate [described in WO 06/097625] are added to 4.02 g (0.014 mol) of 4-oxo-2-phenyl-4H-3,1-benzoxazin-6-carbonyl chloride in 60 ml of 1,2-dichloroethane. After stirring for 24 hours at ambient temperature, the reaction medium is filtered, and washed with 1,2-dichloroethane, then with a 1N aqueous solution of hydrochloric acid and then with water. After drying overnight under reduced pressure at 40° C., the product obtained is dissolved in 60 ml of NMP. 3.59 g (6.4 mmol) of potassium hydroxide dissolved in 11 ml of water are added. The reaction medium is heated at 100° C. for 4 hours and then poured into a 1N aqueous solution of hydrochloric acid. After filtration, the solid obtained is rinsed with water and then dried overnight in an oven under reduced pressure at 40° C. 5.45 g of a yellow solid are obtained.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][C:27]1([C:31](O)=[O:32])[CH2:30][O:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31]([C:27]5([CH3:26])[CH2:30][O:29][CH2:28]5)=[O:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CC1(C(=O)O)COC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC1(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)COC1

Procedure:
The title compound, white solid (13.6 mg, 37.3%), MS (ISP) m/z=429.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (31.2 mg, 0.085 mmol) and 3-methyl-oxetane-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]([CH:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=2)[CH2:16][CH3:17])[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11].[CH3:28][O:29][P:30]([O:50][CH3:51])([C:32]([P:44]([O:48][CH3:49])([O:46][CH3:47])=[O:45])([O:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[O:31]>>[CH3:49][O:48][P:44]([O:46][CH3:47])([C:32]([P:30]([O:29][CH3:28])([O:50][CH3:51])=[O:31])([O:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[CH2:33][CH2:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:22][CH:23]=2)[CH2:16][CH3:17])[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11])=[O:37])=[O:45]
Reactant: CCC(c1ccc(OCOC)cc1)C(CC)c1ccc(OCOC)c(N)c1
Reactant: COP(=O)(OC)C(CCCC(=O)O)(O[Si](C)(C)C)P(=O)(OC)OC
Product: CCC(c1ccc(OCOC)cc1)C(CC)c1ccc(OCOC)c(NC(=O)CCCC(O[Si](C)(C)C)(P(=O)(OC)OC)P(=O)(OC)OC)c1

Procedure:
Erythro 3-(3-(5,5-bis(dimethoxyphosphinoyl)-5-trimethylsilyloxybutyrylamino)-4-methoxymethoxyphenyl)-4-(4-methoxymethoxyphenyl)hexane (1.17 g, quantitative yield) was obtained in the same manner as in Example 4 except for using erythro 3-(3-amino-4-methoxymethoxyphenyl)-4-(4-methoxymethoxyphenyl)hexane (560 mg) obtained by the process described in Reference Example 4 and 5,5-bis(dimethoxyphosphinoyl)-5-trimethylsilyloxyvaleric acid (1 equivalent per equivalent of the former) obtained by the process described in Reference Example 31.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]([C:29]([O:31]CC)=[O:30])=[C:27]([C:34]([OH:37])([CH3:36])[CH3:35])[N:26]=[C:25]2[CH2:38][CH2:39][CH3:40])=[CH:19][CH:18]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.O1CCOCC1>[C:4]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]([C:29]([OH:31])=[O:30])=[C:27]([C:34]([OH:37])([CH3:36])[CH3:35])[N:26]=[C:25]2[CH2:38][CH2:39][CH3:40])=[CH:19][CH:18]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A solution of 4.8 g of lithium hydroxide monohydrate in 100 ml of water was added to a solution of 11.6 g of ethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] in 60 ml of dioxane, and the resulting mixture was stirred at room temperature for 16 hours. The dioxane was removed by distillation under reduced pressure, and then the concentrate was mixed with ice-water and with ethyl acetate, after which 114 ml of 1N aqueous hydrochloric acid were added. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The crystalline residue was triturated in diisopropyl ether and collected by filtration to give 9.09 g of the title compound, melting at 155°-157° C.
Reaction SMILES: C(OC(N[C@H](C(O)=O)C)=O)(C)(C)C.[N+](=C)=[N-].COC(=O)[C@H](C)NC(OC(C)(C)C)=O.[H-].C([Al+]CC(C)C)C(C)C.C(OC(N[C@H](C=O)C)=O)(C)(C)C.C(=C1C=CC=CC1[PH+](C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.[ClH:79].C(OC([NH:87][C@@H:88]([CH3:97])[CH2:89][CH2:90][C:91]1[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1)=O)(C)(C)C>[Pd].O1CCOCC1.CO>[ClH:79].[CH3:97][C@H:88]([NH2:87])[CH2:89][CH2:90][C:91]1[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1
Reactant: C[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: C1=CC(=Cc2ccccc2)C([PH+](c2ccccc2)c2ccccc2)C=C1
Agent: C=[N+]=[N-]
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)CCc1ccccc1

Procedure:
(S)-1-Methyl-3-phenylpropanamine hydrochloride was prepared by first esterifying N-(tert-butyloxycarbonyl)-L-alanine with diazomethane, then reducing the resulting N-(tert-butyloxycarbonyl)-L-alanine methyl ester with diisobutylaluminum hydride, then condensing the resulting N-(tert -butyloxycarbonyl)-L-alaninal with benzylidenetriphenylphosphonium ylide, then hydrogenating over palladium catalyst the resulting [S-(E)]-N-(tert-butyloxycarbonyl)-1-methyl-3-phenyl-2-propenamine having m.r. 86°-88° C. and [α]D25 (c=1, methanol) -50.9°, and finally deprotecting with hydrogen chloride in dioxane the resulting (S)-N-(tert-butyloxycarbonyl)-1-methyl-3-phenylpropanamine having m.r. 78°-80° C. and [α]D25 -7.1° (c=1, methanol). ##STR13##
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1nc2ccccc2o1

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloro-1,3-benzooxazole as starting materials and by operations similar to those of Example 303-3 and 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Oc1cc(Br)cc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Br)cc(F)c2F)cc1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
To a solution of 5-bromo-2,3-difluorophenol (1.0 g) in tetrahydrofuran (10 ml) under nitrogen was added sodium hydride, 60% dispersion in mineral oil (0.20 g). The solution was stirred at room temperature. After 30 minutes a solution of 4-methoxybenzylbromide (0.96 g) was added in tetrahydrofuran (7 ml). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was partitioned between dichloromethane and brine, then dried (MgSO4), the solvents were removed in vacuo to give a crude residue. This crude residue was purified using flash chromatography to give 5-bromo-1,2-difluoro-3-(4-methoxy-benzyloxy)-benzene (0.76 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].N1CCCCC1.Cl[C:20]([CH:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21]>O1CCCC1>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:20]([CH:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Yield: 110.6 %

Procedure:
5-Fluoro-6-amino-1,3-dihydro-indol-2-one 3d (450 mg, 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring at room temperature. The mixture was cooled down to −45° C. in a dry ice-acetone bath and added with 364 μl of piperidine. A solution of acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added dropwise to the above reaction system. Upon completion of the addition, the ice-acetone bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was washed with water, and the resulting solid was dried to obtain the title compound acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester 8a (840 mg) as a white solid to be used directly in the next step.