Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:31]([NH:35][C:36](=[O:45])[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:32]([CH3:34])[CH3:33])([OH:30])=[O:29])[C:17]([O:19]CC1C=CC=CC=1)=[O:18])=O)C1C=CC=CC=1>O1CCOCC1.O.[OH-].[Pd+2].[OH-]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:31]([NH:35][C:36](=[O:45])[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH:32]([CH3:34])[CH3:33])([OH:30])=[O:29])[C:17]([OH:19])=[O:18]
Reactant: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)O[C@@H](CCCCN)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The benzyl (S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoate (85 mg) obtained in the above step (c) was dissolved in a mixed solvent of dioxane (2.4 ml) and water (0.8 ml) and added with palladium hydroxide (45.8 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered with celite and the filtrate was concentrated. The residue was purified with HP-20 (Diaion, 10 cc, methanol:water=1:4 to 1:1) to obtain the title compound: (S)-6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid (25 mg, 45%) (a diastereoisomeric mixture of 1:1).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]1.[NH2:27][C@@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.C(O)C>>[CH:28]1([NH:27][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@H:11]2[C@@H:15]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]3[C@@H:13]([CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(N)(=O)=O)O[C@H]2n1cnc2c(NC3CCc4ccccc43)ncnc21

Procedure:
2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamide (45.0 mg, 0.000111 mol), (S)-(+)-1-aminoindane (20.0 μL, 0.000156 mol) and N,N-diisopropylethylamine (24.0 μL, 0.000138 mol) were dissolved in ethanol (1.25 mL, 0.0214 mol) and reacted in a microwave at 140° C. for 10 minutes. The mixture was then concentrated in vacuo and used crude in the next step.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:13][C@@H:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:15]([F:17])[F:16])[C:10]([OH:12])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:26][C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:30]([C:27]1([NH:26][C:10](=[O:12])[CH:9]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:15]([F:17])[F:16])[CH2:8][S:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)(=[O:7])=[O:6])[CH2:29][CH2:28]1)#[N:31]
Reactant: O=C(O)[C@H](CS(=O)(=O)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)F
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[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: N#CC1(NC(=O)C(CS(=O)(=O)CC2CC2)NC(c2ccc(F)cc2)C(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
To a solution of 3-cyclopropylmethylsulfonyl-2(R)-[2,2,-difluoro-1(S)-(4-fluorophenyl)-ethylamino]propionic acid (0.95 g), 1-aminocyclopropanecarbonitrile HCl salt (400 mg) in DMF (5 mL) at room temperature was added HATU (1.28 g), followed by diisopropylethylamine (1.68 g/2.26 mL). After being stirred at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure and then partitioned between ethyl acetate and brine. The combined organic extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure, and the residue was purified by recrystallization from 2-propanol to yield N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2-[2,2-difluoro-1-(4-fluorophenyl)ethylamino]-propionamide as colorless crystals (250 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=1)[C:5](O)=[O:6].[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][C:25]=12>>[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:5]([C:4]3[CH:8]=[CH:9][C:10]([C:11]4[CH2:16][C:15]([CH3:17])([CH3:18])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=4)=[C:2]([CH3:1])[CH:3]=3)=[O:6])[CH2:26][C:25]=12
Reactant: Cc1cc(C(=O)O)ccc1C1=CC(C)(C)CC(C)(C)C1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CC(C)(C)CC(C)(C)C1
Yield: 80.4 %

Procedure:
3-Methyl-4-(3,3,5,5-tetramethyl-cyclohex-1-en-1-yl)-benzoic acid of Step B (0.100 g, 0.349 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.071 g, 0.384 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.123 g) as white crystals, m.p. 158° C.
Reaction SMILES: [C:1]([N:4]([CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[C:1]([N:4]([CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][N:20]([C:43]([C:42]3[S:41][C:40]4[C:46]([F:51])=[CH:47][CH:48]=[C:49]([F:50])[C:39]=4[C:38]=3[Cl:37])=[O:44])[CH:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(N(C)C(C)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(N(C)C(C)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 106 (420 mg, 0.84 mmol) is treated with acid chloride 8 (249 mg, 0.93 mmol) using Method D to give the title compound.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].C(O)(C)C.Cl>O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 70 °C
Yield: 99.4 %

Procedure:
A mixture of 30 g of 4'-octyloxy-4-formylbiphenyl, 2.0 g of sodium borohydride and 300 ml of isopropanol was stirred on a water bath maintained at 70° C. for 3 hours. 20 ml of 6 N hydrochloric acid and 10 ml of water were added, and the resulting mixture was stirred for 2 hours. The reaction mixture was allowed to cool and filtered to collect solids. These solids were recrystallized from 300 ml of ethanol to obtain 30 g of 4'-octyloxy-4-hydroxymethyl-biphenyl. The total of 4'-octyloxy-4-hydroxymethyl-biphenyl, 100 ml of toluene and 40 g of thionyl chloride were uniformly mixed and allowed to stand overnight at room temperature. Then, the mixture was heated for 30 minutes on a water bath maintained at 70° C. After being allowed to cool, the mixture was poured into ice water and then extracted with 300 ml of toluene. The extract was washed with saturated saline water, with a saturated aqueous sodium hydrogen-carbonate and further with saturated saline water to make it neutral. Then, the extract was dried over anhydrous magnesium sulfate, concentrated and then recrystallized from 300 ml of ethanol to obtain 26 g of 4'-octyloxy-4-chloromethyl-biphenyl having a melting point of 97.3 to 98.0° C. Analysis of the compound by HPLC showed that the purity was 99.6%. (ii) Preparation of Objective Compound
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@H:15]([C:17](=[O:24])[CH2:18][C:19](OCC)=[O:20])[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:31]O.Cl>CO.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@H:15]([C:17]3[O:24][NH:31][C:19](=[O:20])[CH:18]=3)[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(C)(C)C)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
Trans-methyl 2-(4-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.09 g, 2.80 mmol) was dissolved in MeOH (10 mL) and cooled to −40° C. Sodium hydroxide (0.112 g, 2.80 mmol) dissolved in water (1.2 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then, hydroxylamine (50% in water, 0.178 mL, 2.91 mmol) was added over 1 min and stirring continued at −40° C. for 3 h. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(4-tert-butylphenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (910 mg, 90%) was isolated as off-white foam. 1H NMR (400 MHz, cdcl3) δ 1.32 (s, 9H), 1.46-2.23 (m, 3H), 2.46-3.05 (m, 3H), 3.74 (s, 3H), 3.98-4.43 (m, 1H), 5.48-5.72 (m, 2H), 7.10-7.22 (m, 2H), 7.35-7.45 (m, 2H). MS m/z 359 (M+H)+
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1F.O1CCOCC1>O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:18]=1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: c1c[nH]cn1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Br)c(-n2ccnc2)c1
Temperature: 180 °C
Yield: 53.3 %

Procedure:
A microwave vial charged with potassium tert-butoxide (1.108 g, 9.88 mmol), 1H-imidazole (0.672 g, 9.88 mmol), 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.180 ml, 8.23 mmol), and 10 mL dioxane was heated to 180° C. in the microwave for 2 hours. LC/MS showed mostly product, so the reaction mixture was poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography (0 to 100% EtOAc/heptane) yielding 1-(2-bromo-5-(trifluoromethyl)phenyl)-1H-imidazole (1.277 g, 4.39 mmol, 53.3% yield). m/z (ESI) 291.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].CC1C=CC(S(O[CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: Cc1cc(O)c(F)c(C)c1-c1cccc(C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of 3′-fluoro-4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (2.44 g, 10.0 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.51 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol), and the mixture was stirred at 90° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (3.45 g, yield 95%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[N:7]([CH2:14][C:15]#[C:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[OH-].[Na+]>C1COCC1.Cl>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:14][C:15]#[C:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:20])[CH3:21]
Reactant: CCC#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC#CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
To a solution of A7 (0.87 g) in THF (17 ml) is added a solution of SnCl2 dihydrate (2.73 g; 12.1 mmol) in hydrochloric acid (50 ml; 1 N) dropwise. The reaction mixture is stirred at RT for 3 h. After completion 1 N NaOH (until pH 12) is added and the mixture is extracted with CH2Cl2 (2×75 ml). The combined organic layer is washed with brine, dried over MgSO4 and evaporated to give 5,6-diamino-3,3-dimethyl-1-pent-2-ynyl-1,3-dihydro-indol-2-one (0.51 g) which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH:36]1([C:41]([O:43][CH:44](Cl)[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C=O)C>[CH:36]1([C:41]([O:43][CH:44]([N:14]2[C:11]3=[N:12][CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:9]=[C:10]3[C:16]([C:17](=[O:18])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=3[F:33])=[CH:15]2)[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(Cl)OC(=O)C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)C3CCCC3)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 38.2 %

Procedure:
The title compound was prepared according to the procedure as described in Example 12 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL), KOH (69 mg, 1.23 mmol) and a solution of 1-chloroethyl cyclopentanecarboxylate (108 mg, 0.61 mmol) in anhydrous DMF (0.5 mL). The curde product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1) and recrystallized in PE to give the title compound as a white solid (147 mg, 38%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1OB(O)O)[CH2:20][CH3:21].ClCCl>C(N(CC)CC)C>[CH2:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOCc1ccccc1OB(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOCc1ccccc1Oc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Reaction time: 20 h
Yield: 20.9 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g), 2-propoxymethylphenylboric acid (0.80 g), cupric acetate (0.27 g), MS 4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 20 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain methyl 7-(2-propoxymethylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.13 g) as a light yellow, oily substance.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:54][C:55]1[O:59][N:58]=[CH:57][C:56]=1[C:60](Cl)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:60]([C:56]2[CH:57]=[N:58][O:59][C:55]=2[CH3:54])=[O:61])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: Cc1oncc1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oncc1C(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as the starting materials in 40% yield. LCMS for C29H31ClN7O3 (M+H)+: m/z=560.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:12][N:11]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:10]2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]3[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)[CH:19]=1.[OH-].[Li+].Cl.O>CO>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:12][N:11]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:10]2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]3[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)[CH:19]=1
Reactant: CCC(=O)N1CC(Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)OC)c3)c(C)c2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(=O)N1CC(Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)O)c3)c(C)c2)C1
Reaction time: 3 h
Yield: 43.1 %

Procedure:
The crude (S)-methyl 2-(6-((2′,6′-dimethyl-4′-((1-propionylazetidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 14d (45 mg, 0.09 mmol) was dissolved in 3 mL of methanol, followed by addition of 1M aqueous lithium hydroxide solution (0.5 mL, 0.50 mmol). The reaction solution was stirred for 3 hours. To the resulting solution, 1M hydrochloric acid was added dropwise to adjust the pH to 3, 3 mL of water were added, and then the solution was concentrated under reduced pressure and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (S)-2-(6-((2′,6′-dimethyl-4′-((1-propionylazetidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 14 (20 mg, yield 43.0%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][C:11]1[NH:15][C:14]2[CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH2:19][C:13]=2[N:12]=1.[C:23](O)(=[O:26])[C:24]#[CH:25].N1(C(N2C=CN=C2)=O)C=CN=C1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:10]1[CH:25]=[CH:24][C:23](=[O:26])[N:15]2[C:14]3[CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH2:19][C:13]=3[NH:12][C:11]=12)=[O:22]
Reactant: C#CC(=O)O
Reactant: CC1Cc2nc(CC(=O)c3ccc(F)cc3F)[nH]c2CC1C
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC1Cc2[nH]c3c(C(=O)c4ccc(F)cc4F)ccc(=O)n3c2CC1C

Procedure:
The compounds are prepared as described in example 15 with 200 mg (0.66 mmol) of 1-(2,4-Difluorophenyl)-2-(5,6-dimethyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XV), 69 mg (0.99 mmol) of propiolic acid and 192 mg (1.18 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH2:32].O1CCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21][NH:32][CH3:31])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: C1CCOC1
Product: CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C

Procedure:
A solution of (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2(1H)-one (1.5 g, 3.1 mmol) in methylamine/tetrahydrofuran (2.0 M, 16 mL, 32 mmol) was heated in a sealed tube at 100° C. (oil bath) for 3 days. After allowing the mixture to cool to room temperature, it was concentrated and purified via automated flash silica gel chromatography, using a 25 g Silicycle SiliSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound. ES/MS calcd. for C25H35N2O3Si+ 439.2. Found m/z=439.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH2:19]([NH:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)OCC(C(CN)c2ccc(Cl)c(Cl)c2)O1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(C(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a solution of (2RS)-2-(3,4-dichlorophenyl)-2-[(4RS)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamine (10.1 g) in toluene (200 mL) was added benzaldehyde (4.43 g) at room temperature. The mixture was heated under reflux for 1 hr while dehydrating by a Dean-Stark trap, cooled to room temperature, and concentrated under reduced pressure. To the residue was added methanol (60 ml), sodium tetrahydroborate (658 mg) was added under ice-cooling, and the mixture was stirred for 1 hr. The reaction was quenched with water, methanol was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (5%-100%)) to give the title compound (7.96 g) as a yellow oil.