Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:15])[C:13]=1F)[C:5]([O:7][CH2:8][C:9]#[CH:10])=[O:6].[CH2:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].O>CN(C=O)C>[F:15][C:12]1[CH:11]=[C:4]([CH:3]=[C:2]([F:1])[C:13]=1[O:19][CH2:16][C:17]#[CH:18])[C:5]([O:7][CH2:8][C:9]#[CH:10])=[O:6]
Reactant: C#CCOC(=O)c1cc(F)c(F)c(F)c1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC(=O)c1cc(F)c(OCC#C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a solution of 5.0 g of 2-propynyl 3,4,5-trifluorobenzoate and 1.7 g of propargyl alcohol in 20 ml of DMF was added 1.1 g of 60% sodium hydride (oily) at 0° C. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.9 g of 2-propynyl 3,5-difluoro-4-(2-propynyloxy)benzoate represented by the formula:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH:15]=[CH2:16].C([C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([CH3:40])[CH:31]=1)=C>CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru-4](Cl)(Cl)=CC1C=C(S(N(C)C)(=O)=O)C=CC=1OC(C)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:13][CH2:14]/[CH:15]=[CH:16]/[C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[C:32]([CH3:40])[CH:31]=1
Reactant: C=Cc1cc(C)cc(C(F)(F)F)c1
Reactant: C=CCC[C@H](NC(=O)OCc1ccccc1)c1cc(C(F)(F)F)ccc1Br
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru-4](Cl)(Cl)=Cc2cc(S(=O)(=O)N(C)C)ccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: Cc1cc(/C=C/CC[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 73.7 %

Procedure:
To a 100 mL RBF equipped with a reflux condenser was added benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (0.5 g, 1.13 mmol), 1-ethenyl-3-methyl-5-(trifluoromethyl)benzene (421 mg, 2.26 mmol) and dichloromethane (10 mL). The system was flushed with nitrogen and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (41 mg, 0.57 mmol) (Zhan catalyst-1B) was added before heating at 60° C. for 20 min. The reaction was cooled to room temperature and was directly purified by column chromatography to yield benzyl {(1R,4E)-1-[2-bromo-5-(trifluoromethyl)phenyl]-5-[3-methyl-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (500 mg, 0.833 mmol). 1H NMR (500 MHz, CDCl3) δ7.72 (m, 1H), 7.58 (s, 1H), 7.39 (b, 5H), 6.4 (d, J=8.2 Hz, 1H), 6.25 (m, 1H), 5.35 (m, 1H), 5.20 (m, 1H), 5.10 (s, 2H), 2.40 (s, 3H), 2.19 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
MsCl (15.8 mL. 204 mmol) was added to a solution of 2-(2-(benzyloxy)ethoxy)ethanol (46) (25 g, 127 mmol) and Et3N (36 mL, 255 mmol) in DCM (180 mL) at 0° C., the reaction mixture was allowed to warm up to RT and stirred for 16 h. The reaction mixture was diluted with DCM (50 mL) and washed with water (2×50 mL), 1M HCl (aq.) (2×50 mL), the organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 2-(2-(benzyloxy)ethoxy)ethyl methanesulfonate (47) (35 g, 100%) as an orange oil: m/z 275 (M+H)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.37-7.27 (m, 5H), 4.55 (s, 2H), 4.40-4.37 (m, 2H), 3.78-3.76 (m, 2H), 3.71-3.68 (m, 2H), 3.64-3.62 (m, 2H), 3.02 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]([OH:21])[C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:21])[C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1C(O)C#C[Si](C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(Br)cc1C(=O)C#C[Si](C)(C)C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a solution of [4-bromo-2-(1-hydroxy-3-trimethylsilanylprop-2-ynyl)phenoxy]acetic acid ethyl ester (0.95 g, 2.46 mmol) in CH2Cl2 (10 mL) was added activated MnO2 in 2 portions (1.5 g+1 g), and the reaction was stirred for 90 min. The solid was filtered off through a celite pad and the filtrate was concentrated in vacuo to give the title compound as yellow oil (0.83 g, 2.16 mmol, 87%). LC/MS (an 10p8) Rt 4.70 min, m/z 383 [M+H]+; 1H NMR (CDCl3): δ 0.30 (s, 9H), 1.30 (t, 3H), 4.27 (q, 2H), 4.72 (s, 2H), 6.81 (d, 1H), 7.58 (dd, 1H), 8.10 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:36][NH2:37]>C1COCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33]([NH:37][CH3:36])[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(Cl)ncn5)ccc43)cc2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(NC)ncn5)ccc43)cc2)CC1

Procedure:
A solution of 134 mg (0.27 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amide in 5 ml THF and 1.2 ml methylamin solution (2 M in THF) is stirred for 3 d in a sealed tube at rt. The reaction mixture is concentrated and the residue chromatographed by reversed phase MPLC (Gilson system), yielding the title compound: MS: [M+1]+=488; HPLC: BtRet=11.5.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1.ClC1N=C(NC2C=CC=CC=2C(NC)=O)C(C(F)(F)[F:60])=CN=1.NC1C(OC)=CC(CP(=O)(OCC)OCC)=CC=1F>>[F:60][C:34]1[CH:33]=[C:23]([CH:22]=[C:21]([O:35][CH3:36])[C:20]=1[NH:19][C:11]1[N:10]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:37](=[O:40])[NH:38][CH3:39])[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=1)[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1cc(F)c(N)c(OC)c1)OCC
Product: CCOP(=O)(Cc1cc(F)c(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) with 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A) and Diethyl (4-amino-3-fluoro-5-methoxybenzyl)phosphonate (Compound 146A). 1H NMR (CD3OD, 400 MHz): δ=1.30 (t, J=7.07 Hz, 6H), 2.90 (s, 3H), 3.33-3.40 (m, 2H), 3.85 (s, 3H), 4.06-4.18 (m, 4H), 6.88 (dt, J=10.11, 2.02 Hz, 1H), 6.95 (s, 1H), 7.17 (br. s., 1H), 7.37 (br. s., 1H), 7.64 (d, J=6.82 Hz, 1H), 8.29 (br. s., 2H). MS (ES+): m/z 586.21 [MH+] (TOF, polar).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl.[CH2:13](O)[CH3:14]>>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:13][CH3:14])=[O:8])=[CH:10][CH:11]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(CN)cc1

Procedure:
3 g (19.9 mmol) of 4-aminomethylbenzoic acid was suspended in 100 ml of ethanol. 10 ml of ethanol containing 25% of hydrogen chloride was added to the suspension, and they were heated under reflux for 8 hours. The solvent was evaporated, and the title compound was obtained by the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH2:27]1[C:30]2([CH2:35][NH:34][CH2:33][CH2:32][O:31]2)[CH2:29][N:28]1[CH2:36][CH2:37][C:38]1[CH:39]=[C:40]([CH2:44][CH2:45][OH:46])[CH:41]=[CH:42][CH:43]=1.[CH:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[OH:46][CH2:45][CH2:44][C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[CH2:37][CH2:36][N:28]1[CH2:29][C:30]2([CH2:35][N:34]([C:55]([C:53]3[N:54]=[C:50]([CH:47]([CH3:49])[CH3:48])[S:51][CH:52]=3)=[O:56])[CH2:33][CH2:32][O:31]2)[CH2:27]1
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: OCCc1cccc(CCN2CC3(CNCCO3)C2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCO)c4)C3)C2)cs1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
HATU (0.792 g) was added in one portion to a stirred solution at 0° C. of 2-(3-(2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethyl)phenyl)ethanol 2HCl (0.56 g) (example 176 step e), 2-isopropylthiazole-4-carboxylic acid (0.275 g) and triethylamine (1.117 ml) in DMF (7 mL). The mixture was stirred at 20° C. for 3 hours and then partitioned between ethyl acetate and brine, the organic layer was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, 5% methanol in ethyl acetate with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.475 g
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:7])[C:4](O)=[O:5].[OH-].[Na+].[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.Cl>O1CCCC1>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][NH:1][CH2:2][CH:3]([CH3:7])[CH2:4][OH:5])=[CH:14][CH:13]=1
Reactant: CC(CN)C(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CNCC(C)CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution of 3-amino-2-methyl-propionic acid (5.00 g, 48.4 mmol) in tetrahydrofuran (107 ml) and 1N sodium hydroxide (107 ml, 107 mmol) was added 4-methoxybenzoyl chloride (8.69 g, 50.9 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours and partitioned between water and ethyl acetate. The water phase was washed with ethyl acetate and acidified with 1N hydrochloric acid. The product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, and concentrated in vacuo. To the residue dissolved into tetrahydrofuran (20 ml) was added 1M borane-tetrahydrofuran complex (6.40 ml, 6.40 mmol) at 0° C. The mixture was stirred at room temperature. After 30 minutes, the mixture was refluxed for 5 hours and acidified with 3N hydrochloric acid. The acidic aqueous solution was stirred at 60° C. for 2 hours. The organic solvent was evaporated under reduced pressure, then the residue was partitioned between water and ethyl acetate. The water phase was washed with ethyl acetate and basified with 3N sodium hydroxide. The product was extracted with chloroform. The organic phase was dried over sodium sulfate, and concentrated in vacuo to afford 3-(4-methoxy-benzylamino)-2-methyl-propan-1-ol as colorless oil (8.28 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Br:14][C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[Br:14])=[O:6]
Reactant: Brc1ccc[nH]1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Product: COc1ccc(C(=O)n2cccc2Br)c(OC)c1
Yield: 299.4 %

Procedure:
Following the procedure of Example B, 2,4-dimethoxybenzoyl chloride (6.74 g, 3.36 mmol) and 2-bromopyrrole (22.4 mmol) gave 3.12 g of the title compound: mp 81-82° C.; 1H NMR (CDCl3) δ: 7.42 (1 H, t, J=8.4), 6.99 (1 H, t, J=1.8), 6.70-6.45 (2 H, m), 6.42-6.25 (1 H, m), 6.16 (1 H, t, J=3.5), 3.87 (3 H, s), 3.77 (3 H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:17]([C:19]3[O:20][C:21](=[O:35])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:18])[N:9]=[C:10](C3C=NC=CN=3)[C:3]=12.NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)C)N=C(I)C=12.C[Sn](C)(C)[C:68]1[CH:76]=[CH:75][CH:74]=[C:73]2[C:69]=1[CH:70]=[N:71][NH:72]2>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:17]([C:19]3[O:20][C:21](=[O:35])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:18])[N:9]=[C:10]([C:68]3[CH:76]=[CH:75][CH:74]=[C:73]4[C:69]=3[CH:70]=[N:71][NH:72]4)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnccn2)c2c(N)ncnc21
Reactant: C[Sn](C)(C)c1cccc2[nH]ncc12
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cccc3[nH]ncc23)c2c(N)ncnc21
Yield: 39 %

Procedure:
The title compound was made in a similar way as that of the compound of example 52 from 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 50 mg, 0.098 mmol), and 4-(trimethylstannyl)-1H-indazole (Intermediate G19, 41.4 mg, 0,147 mmol) to give the title compound (19 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH3:12])[N:10]=2)[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc2ccc(Cl)nn2c1=O
Temperature: 25 °C
Yield: 67.2 %

Procedure:
0.853 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was dissolved in 5 ml of N,N-dimethylformamide; 0.83 g of potassium carbonate was added; with stirring at room temperature, 0.5 ml of methyl iodide was added. After stirring at room temperature for 15 hours, ice water and saline were added; the reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the crystal obtained was collected by filtration, washed with diethyl ether, and dried, to yield 0.62 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][O:8]C(C)(C)[O:6]1)=[O:4].Cl.O1CCOCC1.N1C=CN=C1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C@H:5]([OH:6])[CH2:9][O:8][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
To a solution of (R)-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid methyl ester (2.5 g, 15.6 mmol) in methanol (15 mL) was added HCl in dioxane (4N, 5 mL, 20 mmol) and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated in vacuo, the resultant residue dissolved in THF (20 mL) and imidazole (1.28 g, 18.7 mmol) and tert-butylchlorodimethylsilane (2.47 g, 16.4 mmol) added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2 gradient 0-50% EtOAc in cyclohexane) to yield (R)-3-(tert-butyl-dimethyl-silanyloxy)-2-hydroxy-propionic acid methyl ester as a colorless oil (2.29 g, 63%). 1H NMR (400 MHz, CDCl3) 4.26-4.20 (1H, m), 3.93 (1H, dd, J=10.1, 3.4 Hz), 3.86 (1H, dd, J=10.1, 2.8 Hz), 3.79 (3H, s), 3.01 (1H, d, J=7.8 Hz), 0.88 (9H, s), 0.06 (3H, s), 0.04 (3H, s)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][CH3:17])[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[CH2:16]([C:12]1[N:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:8]=2)[CH:15]=[CH:14][N:13]=1)[CH3:17]
Reactant: CCc1nccn1-c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCc1nccn1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(2-Ethyl-imidazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (750 mg) was dissolved in THF (14 mL) and water (8 mL), and LiOH hydrate (128 mg, 3.1 mmol) was added as one portion. The reaction mixture was stirred at room temperature for 3 hours, then THF was removed under reduced pressure. Concentrated HCl was added into the remaining aqueous solution to adjust the pH to ˜6. The solution was extracted with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(2-ethyl-imidazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1[C:46](=O)[CH3:47]>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]=[C:46]([C:37]2[CH:38]=[CH:39][C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:36]=2)[CH3:47])=[CH:29][CH:30]=1
Reactant: COc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)c1ccc2ccccc2c1
Agent: [Br-]
Agent: [Li]CCCC
Product: COc1ccc(CC=C(C)c2ccc3ccccc3c2)cc1
Yield: 48.3 %

Procedure:
Starting from p-methoxyphenethyltriphenylphosphonium bromide (3.15 g, 6.60 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.2 mL, 6.60 mmol, 1.0 equiv.) and 1-(naphthalen-2-yl)ethanone (1.69 g, 9.90 mmol, 1.5 equiv.), 0.92 g (48%) of the title compound as a yellow oil was obtained after purification by flash chromatography on SiO2 (hexanes/EtOAc 995:5→99:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].[H-].[Na+].[C:17]([S:20][CH2:21][C@H:22]([CH3:26])[C:23](Cl)=[O:24])(=[O:19])[CH3:18].C(SC[C@@H](C)C(O)=O)(=O)C.S(Cl)(Cl)=O>O1CCCC1>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([C:23](=[O:24])[C@H:22]([CH3:26])[CH2:21][S:20][C:17](=[O:19])[CH3:18])[C:3]1=[O:14]
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Agent: CC(=O)SC[C@@H](C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)SC[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Yield: 44.7 %

Procedure:
1.3 g of tert.-butyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 15 ml of tetrahydro-furan, and 0.35 g of sodium hydride (62% oil dispersion) is added thereto under ice-cooling and stirring. A solution of (2S)-3-acetylthio-2-methylpropionyl chloride (prepared by heating a mixture of 1.5 g of (2S)-3-acetylthio-2-methylpropionic acid and 6 ml of thionyl chloride at 50° C. for 3 hours and then evaporting excess thionyl chloride under reduced pressure) in 5 ml of tetrahydrofuran is added dropwise to the mixture. Then, the mixture is treated in the same manner as described in Example 1-(4). 1.0 g of tert.-butyl (4S)-1-methyl-3-[(2S)-3-acetylthio-2-methylpropionyl]-2-oxoimidazolidine-4-carboxylate is obtained as colorless crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=2[NH:9][CH:8]=1>C1COCC1.C(Cl)Cl.CO.[O-2].[Mn+4].[O-2]>[NH:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.9 %

Procedure:
LiAlH4 (1.0 m in THF, 10 mL, 10 mmol) was added dropwise to a suspension of 5-benzimidazolecarboxylic acid (500 mg, 3.08 mmol) in THF (20 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 24 h followed by heating at 50° C. for an addition 24 h. MeOH (4×5 mL) was added and the solution was concentrated between each addition. The resulting brown syrup was dried in vacuo for 3 h. The syrup was dissolved in 100:1—CH2Cl2:MeOH, filtered through celite and concentrated to a light brown foam (300 mg, 66%). To a stirred solution of the crude alcohol (300 mg, 2.0 mmol) in CH2Cl2 (10 mL) and MeOH (0.8 mL) was added manganese (IV) oxide (85%, 2.05 g, 20 mmol). The suspension was heated to 40° C. for 18 h, cooled to room temperature and filtered through celite. The filtrant was concentrated to a light yellow foam (260 mg). Purification of the crude material by column chromatography on silica gel (200:1:1—EtOAc:MeOH: NH4OH) gave the title compound as a white powder (139 mg, 60%). 1H NMR (300 MHz, CD3OD) δ 10.0 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 7.87 (d, 1H, J=9.0 Hz), 7.75 (d, 1H, J=9.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([NH:14][C:15]2[C:16]([CH3:26])=[C:17]([CH:22]=[CH:23][C:24]=2[CH3:25])[C:18]([O:20][CH3:21])=[O:19])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:27]([Si:31]([CH3:40])([CH3:39])[O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.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]>[Si:31]([O:32][CH:33]1[CH2:34][CH2:35][N:36]([C:2]2[CH:3]=[C:4]([C:12]([NH:14][C:15]3[C:16]([CH3:26])=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([O:20][CH3:21])=[O:19])=[O:13])[C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:37][CH2:38]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)cc3ccccc23)c1C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)cc3ccccc23)c1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
To a solution of methyl 3-(3-bromo-1-naphthamido)-2,4-dimethylbenzoate (0.48 g, 0.0011 mol), tert-butyl-dimethyl-(4-piperidyloxy)silane (0.75 g, 0.0034 mol, see preparation 3) and Cs2CO3 (1.00 g, 0.0033 mol) in 1,4-dioxane (8 ml) is added Pd2(dba)3 (0.10 g, 0.00011 mol) followed by S-Phos (0.045 g, 0.00011 mol). The reaction mixture is purged with nitrogen for 5 minutes and then stirred at 80° C. After 16 hours, the reaction is cooled to ambient temperature, filtered through Celite™ and washed with EtOAc. The organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a black semi-solid (0.52 g, crude). Mass spectrum (m/z): 547.5 (M+1).