Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.Cl.CN([CH:20]=[O:21])C>>[CH:20]([C:10]1[S:6][C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)=[O:21]
Reactant: CN(C)C=O
Reactant: c1csc(-c2cccs2)c1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In a round bottom flask, phosphorus oxychloride (1.83 g) was added at 0° C. to 15 mL of DMF. After 30 minutes, 2,2′-bithiophene (500 mg) was further added and the solution stirred at room temperature for 30 minutes before heating to 50° C. until completion. Diluted hydrochloric acid was added at 0° C., the solution warmed to room temperature and the crude product extracted with ethyl acetate. Purification by flash chromatography (SiO2) yielded the title product as a light brown powder (81%). 1H-NMR (300 MHz, [D] acetone): δ=9.89 (s, 1H), 7.70 (d, 1H, 3J=3.9 Hz), 7.39 (d, 2H, 3J=4.3 Hz), 7.28 (d, 1H, 3J=3.9 Hz), 7.11 (t, 1H, 3J=4.4 Hz). 13C-NMR (50 MHz, [D] acetone): δ=183.0, 147.6, 142.1, 137.8, 136.5, 128.8, 127.5, 126.6, 124.7. EI-MS: m/z ([M]+, 100%).
Reaction SMILES: Cl.[C:2]([NH2:6])(=[NH:5])[CH2:3][CH3:4].C([O:9][C:10](=O)[C:11]#[CH:12])C.[OH-].[K+]>>[CH2:3]([C:2]1[NH:6][C:10](=[O:9])[CH:11]=[CH:12][N:5]=1)[CH3:4]
Reactant: CCC(=N)N
Reactant: C#CC(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCc1nccc(=O)[nH]1
Yield: 22.6 %

Procedure:
To a hot (60° C.) solution of propionamidine hydrochloride prepared in step 2 (54.3 g, 0.5 mol) and propynoic acid ethyl ester (53.9 g, 0.55 mol) in absolute alcohol (1 L) was added dropwise a solution of KOH (70 g, 80%, 1 mol) in absolute alcohol (300 mL) during 3 hours. The temperature was kept between 60° C. and 70° C. during the addition. The solvent was removed in vacuo and the residue was dissolved in water. The aqueous solution was acidified to pH 5 with HCl (6 M), extracted with ethyl acetate for at least 15 times. The organic layer was dried over Na2SO4 and then filtered. The filtrate was evaporated under reduced pressure and the residue was recrystallized with acetonitrile to afford 2-ethyl-3H-pyrimidin-4-one as light yellow crystals (14 g, 23%).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[C:10]1([CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+].CC(O)=O>CO>[C:10]1([CH:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][N:1]2[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)C1CCCNC1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C1CCCN(CC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nipecotic acid (300 mg, 2.38 mmol), diphenylacetaldehyde (1.26 mL, 7.13 mmol), sodium cyanoborohydride (448 mg, 7.13 mmol), and HOAc (204 uL, 3.57 mmol) were dissolved in MeOH (20 mL) and stirred at ambient temperature overnight. The solution was concentrated under reduced pressure, take up in ether and 1N NaOH, extract with ether (3×), acidify the aqueous layer with 1N HCl, and extract with EtOAc (3×). The EtOAc layers were dried (MgSO4) and concentrated to give the title compound without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13](O)=[O:14])[CH2:7]2)([O-:3])=[O:2]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][OH:14])[CH2:7]2)([O-:3])=[O:2]
Reactant: O=C(O)C1Cc2ccc([N+](=O)[O-])cc2C1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CC(CO)C2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
BH3-DMS (10 M, 1.30 mL, 13.0 mmol) was added to a stirred solution of acid 119 (2.07 g, 10.0 mmol) in dry THF (30 mL) at 20° C. under N2 and the mixture was stirred at 20° C. for 30 min. The reaction was quenched with MeOH and the solvent evaporated to give a brown oil which was purified by chromatography, eluting with a gradient (0-20%) of EtOAc/pet. ether, to give alcohol 120 (1.13 g, 59%) as an oil: 1H NMR δ 8.01-8.07 (m, 2H, H-4, H-6), 7.32 (d, J=8.0 Hz, 1H, H-7), 3.68 (d, J=5.8 Hz, 2H, CH2O), 3.09-3.20 (m, 2H, CH2), 2.76-2.91 (m, 3H, CH2, CH); HRMS calcd for C10H11NO3 (M+) m/z 193.0739, found 193.0733.
Reaction SMILES: [F:1][C:2]1[CH:55]=[CH:54][CH:53]=[CH:52][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=3)=[N:9][C:8]=2[N:7]([CH2:26][C:27]2[N:31]=[CH:30][N:29](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:28]=2)[C:6]1=[O:51].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:1][C:2]1[CH:55]=[CH:54][CH:53]=[CH:52][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=3)=[N:9][C:8]=2[N:7]([CH2:26][C:27]2[N:31]=[CH:30][NH:29][N:28]=2)[C:6]1=[O:51]
Reactant: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3Cc2nc[nH]n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A suspension of N-{4-[1-(2-fluoro-benzyl)-2,6-dioxo-3-(1-trityl-1H-[1,2,4]triazol-3-ylmethyl)-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-acetamide (47 mg, 0.06 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with trifluoroacetic acid (1.0 mL). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was treated with triethylsilane (0.01 mL, 0.06 mmol) and then was concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford N-{4-[1-(2-fluoro-benzyl)-2,6-dioxo-3-(1H-[1,2,4]triazol-3-ylmethyl)-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-acetamide (12 mg, 26%) as a white solid: LR-MS for C24H21FN8O3 (M+H)+ at m/z=489.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:15])=[C:5]([OH:14])[C:6]([OH:13])=[N:7]2.N1C2C(=CC=CC=2)C(=O)C(=O)C1=O>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: Oc1nc2cc(Cl)cc(Cl)c2c(O)c1O
Agent: O=C1Nc2ccccc2C(=O)C1=O
Product: O=C1Nc2cc(Cl)cc(Cl)c2C(=O)C1=O

Procedure:
Compound 12b was prepared from 11b similar to 12a as pale-yellow solid, mp 240° C. (dec.). 1H NMR (DMSO-d6), 7.042 (d, 1, J=1.8), 7.312 (d, 1, J=1.8), 7.421 (s, 2), 10.918 (s, 1). 1H NMR (DMSO-d6 +D2O), 7.054 (s, 1), 7.302 (s, 1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](OC1C=CC=CC=1C[Mg]Br)C>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccccc1C[Mg]Br
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: CCOc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using commercially available 2-ethoxybenzylmagnesium bromide (available from Rieke-Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=418.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CN(C=O)C>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cn(-c2nccs2)c2ccccc12
Temperature: 110 °C

Procedure:
To a solution of methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) in NMP (Volume: 1142 μl) were added 2-bromothiazole (206 μl, 2.283 mmol) and cesium carbonate (1116 mg, 3.42 mmol) at RT. The mixture was heated at 110° C. for 2 h, then diluted with DMF, filtered and purified by HPLC to afford the title compound as a brown solid.
Reaction SMILES: [CH:1]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>>[CH:1]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:19]3[CH2:20][O:21]3)=[CH:14][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccc(C2CCc3ccccc32)cc1
Reactant: ClCC1CO1
Product: c1ccc2c(c1)CCC2c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-indan-1-yl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[C:10](=O)([O:13]C)[O:11][CH3:12].[H-].[Na+].CO>C1COCC1>[OH:8][C:5]1[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][C:4]=1[C:10]([O:11][CH3:12])=[O:13]
Reactant: COC(=O)OC
Reactant: CC1(C)CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)CCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a cooled (0° C.) solution of 4,4-dimethylcyclohexanone (21 g, 0.17 mol) and dimethyl carbonate (45 g, 0.50 mol) in THF (400 mL) was added NaH (60% wt/wt in mineral oil, 17 g, 0.43 mol) portionwise over 30 minutes. The resulting slurry was allowed to stir at ambient temperature for 30 minutes followed by two hours at reflux. The reaction mixture was cooled (0° C.) and MeOH (30 mL) was added dropwise over 20 minutes. The resulting slurry was partitioned between 10% aqueous citric acid and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by vacuum distillation provided methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (22.5 g, 75% yield). 1H NMR (400 MHz, CDCl3) δ 12.15 (s, 1H), 3.75 (s, 3H), 2.29 (t, 2H), 2.03 (s, 2H), 1.44 (t, 2H), 0.96 (s, 6H); MS (EI) for C10H16O3: 184 (M+).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:29])([F:30])[F:15])=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)=[O:6]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Example CK was prepared in analogy to Example 123 from 2-Iodo-5-methanesulfonyl-benzoic acid (example BQ) and 1-(4-Trifluoromethyl-phenyl)-piperazine (commercial). MS (m/e): 539.1 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].BrC1C=CC(OC)=C(N[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])C=1.CCCCCCC.C(OCC)(=O)C.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1Br
Reactant: COc1ccc(Br)cc1NC(=O)OC(C)(C)C
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(NC(=O)OC(C)(C)C)ccc1Br

Procedure:
The compound was prepared from 4-bromo-3-methoxyaniline in the manner described for compound (2): 1H NMR (DMSO-d6, 400 MHz) δ 9.46 (s, 1H), 7.4 (d, 1H), 7.35 (s, 1H), 6.95 (d, 1H), 3.78 (s, 3H), 1.48 (s, 9H); TLC (heptane/ethyl acetate 8:2) Rf 0.37; RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=18.60 min.
Reaction SMILES: [Li+].[OH-].O.[CH3:4][N:5]([C@@H:15]([CH2:20][CH:21]=[CH2:22])[C:16]([O:18]C)=[O:17])[C:6](=[O:14])[CH:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10].Cl>C1COCC1>[CH3:4][N:5]([C@@H:15]([CH2:20][CH:21]=[CH2:22])[C:16]([OH:18])=[O:17])[C:6](=[O:14])[CH:7]([CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH3:13]
Reactant: C=CC[C@@H](C(=O)OC)N(C)C(=O)C(CCC)CCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H](C(=O)O)N(C)C(=O)C(CCC)CCC
Reaction time: 72 h
Yield: 94.9 %

Procedure:
Step A (3): A solution of LiOH/H2O (2 M, 1.2 mL) was added to (S)-methyl 2-(N-methyl-2-propylpentanamido)pent-4-enoate (230 mg, 0.85 mmol) from Step A (2) in THF (4.0 mL) at rt. The reaction was stirred for 3 days. The mixture was poured into 1N HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO4, and concentrated in vacuo to give 206 mg (95% yield) of the title compound as a white solid. LC-MS (M+H)+=256.23. 1H NMR (300 MHz, CDCl3) δ 0.78-0.92 (m, 6H) 1.11-1.44 (m, 7H) 1.50-1.69 (m, 2H) 2.47-2.83 (m, 3H) 2.97 (s, 3H) 4.98-5.16 (m, 3H) 5.59-5.78 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:22]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:23]([C:39]([NH:41][C@H:42]([C:47](O)=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C.CCOCC>[NH:22]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[C@H:23]([C:39]([NH:41][C@H:42]([C:47]([NH:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:30]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Yield: 75.1 %

Procedure:
compound A424P. Same procedure as above with Trp-NHPh (67.6 mg, 0.242 mmol), N-Boc-Tyr(Bn)-Leu-OH (117 mg, 0.242 mmol), EDC (49 mg, 0.25 mmol) and HOBt (35 mg, 0.25 mmol) in CH2Cl2/DMF (3.6 mL, 1/1). The crude residue was dissolved in ether and precipitated with heptane to give a beige solid (135.6 mg, 75%). 1H NMR (300 MHz, DMSO-d6) δ 0.83 (d, 3H, J=6.4 Hz, CH3), 0.87 (d, 3H, J=6.4 Hz, CH3), 1.22-1.44 (m, 2H, CH2 Leu), 1.30 (s, 9H, (CH3)3), 1.44 (m, 1H, CH Leu), 2.46-2.89 (m, 2H, CH2), 3.13 (m, 2H, CH2), 4.12 (m, 1H, CHα), 4.38 (m, 1H, CHα), 4.70 (m, 1H, CHα), 5.02 (s, 2H, CH2 (Bn)), 6.87-7.58 (m, 20H, 19 aromatic H and NH Boc), 7.94 (d, J=8.2 Hz, 1H), 8.17 (d, J=7.5 Hz, 1H), 10.0 (s, 1H, NH), 10.83 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6) δ 21.5, 23.1, 23.9 (CH—(CH3)2), 27.7 (CH2 Trp), 28.1 ((CH3)3), 36.2, 40.9 (CH2 Tyr, CH2 Leu), 50.9, 54.1, 55.7 (CHα Tyr, Leu, Tip), 69.0 (CH2 (Bn)), 78.0 (C(CH3)3), 109.6, 111.2, 114.2, 118.2, 118.4, 119.3, 120.8, 123.3, 123.4, 127.3, 127.6, 127.7, 128.3, 128.6, 130.1, 130.3, 135.9, 137.2, 138.8 (25 aromatic C), 155.2, 156.8 (Car-O, CO carbamate), 170, 171.6, 171.9 (3 CO amide). Anal. Calcd. for C44H51N5O6: C, 70.85; H, 6.89; N, 9.39. Found: C, 70.52; H, 7.10; N, 9.33.
Reaction SMILES: Cl[Si](C)(C)C=C[Si](Cl)(C)C.[Cl:11][Si:12]([CH3:20])([CH3:19])[CH:13]=[CH:14][SiH2:15][CH:16]([Cl:18])[Cl:17]>>[Cl:11][Si:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][SiH2:15][CH:16]([Cl:18])[Cl:17]
Reactant: C[Si](C)(Cl)C=C[SiH2]C(Cl)Cl
Agent: C[Si](C)(Cl)C=C[Si](C)(C)Cl
Product: C[Si](C)(Cl)CC[SiH2]C(Cl)Cl

Procedure:
Example 1 was repeated with the modification that, instead of 300.0 g (1.41 mol) of 1,2-bis(chlorodimethylsilyl)ethene, 300.0 g (1.28 mol) of 1-(chlorodimethylsilyl)-2-(dichloromethylsilyl)ethene were used. The results are summarized in Table 1.
Reaction SMILES: [N:1]([CH:4]1[CH:9](O)[CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5]1)=[N+]=[N-].N(C1CCN(C(OCC2C=CC=CC=2)=O)CC1O)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[CH:4]12[NH:1][CH:9]1[CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5]2
Reactant: [N-]=[N+]=NC1CN(C(=O)OCc2ccccc2)CCC1O
Agent: [N-]=[N+]=NC1CCN(C(=O)OCc2ccccc2)CC1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCC2NC2C1
Yield: 25 %

Procedure:
To a solution of benzyl 3-azido-4-hydroxypiperidine-1-carboxylate and benzyl 4-azido-3-hydroxypiperidine-1-carboxylate (1.0 equiv.) in dioxane (0.14M) was added PPh3 (2.0 equiv.) and the reaction was heated to reflux for 1 h. The solution was then concentrated under vacuo and purified via silica gel column chromatography eluting with DCM, 10% MeOH and 1% Et3N to give benzyl 3,7-diazabicyclo[4.1.0]heptane-3-carboxylate as a clear oil in 25% yield. LCMS (m/z): 233.0 (MH+), Rt=1.94 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=2)[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:25].CCN(C(C)C)C(C)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[CH2:18]([N:4]1[C:5]2[C:10](=[N:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)[CH2:11][CH:2]([NH:1][S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:3]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC1Cc2nc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2nc(-c3ccccc3)ccc2N1Cc1ccccc1
Reaction time: 0.08 h
Yield: 69.5 %

Procedure:
To a solution of 2B (63 mg, 0.19 mmol) in CH3CN (2 mL) at RT was added DIPEA (50 μL, 0.285 mmol), followed by benzenesulfonyl chloride (27 μL, 0.21 mmol). After 5 min, white precipitates formed. The reaction was stirred for additional 15 min. The product was collected by filtration and the solid washed with CH3CN (2-3 mL) to give the title compound as a white solid (62 mg, 70%). LC/MS (method A): RT=3.58 min, (M+H)+=470. 1H NMR (CDCl3, 400 MHz): δ 8.41 (d, J=7.4 Hz, 1H), 8.04 (d, J=7.3 Hz, 2H), 7.96 (d, J=7.3 Hz, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.62-7.70 (m, 3H), 7.50 (t, J=7.3 Hz, 2H), 7.44-7.47 (m, 2H), 7.25-7.44 (m, 5H), 5.16 (s, 2H), 4.4-4.55 (m, 1H), 3.25-3.31 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[N:11]=[N:12][C:13]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:17]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2nc(-c3ccc(Cl)nn3)[nH]c2c1
Solvent: CN1CCCC1=O
Product: Clc1ccc2nc(-c3ccc(N4CCNCC4)nn3)[nH]c2c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-chloro-2-(6-chloropyridazin-3-yl)-1H-benzoimidazole (0.212 g, 0.800 mmol) and piperazine (0.260 g, 3.000 mmol) in 1-methyl-2-pyrrolidone (15 mL) was heated at 140° C. and stirred for 30 minutes. The solvent was evaporated in vacuo, the residue was diluted with water (100 mL) and stirred for 15 minutes. A white precipitate was formed which was collected by filtration and dried to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:19][C:20](=[O:33])[CH2:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([SH:31])=[CH:25][C:24]=1[CH3:32]>C(O)(=O)C>[CH3:30][O:29][C:27]1[C:26]([S:31][CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[O:5][N:4]=2)=[CH:25][C:24]([CH3:32])=[C:23]([CH:28]=1)[O:22][CH2:21][C:20]([OH:33])=[O:19]
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Solvent: CC(=O)O
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1cc(-c2ccc(C(F)(F)F)cc2)on1

Procedure:
Preparation of {5-Methoxy-2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 43A) The title compound was prepared in a manner analogous to Example 1F using 42C and 1D. MS m/z 468 (M+1). Step 2. Preparation of {5-Methoxy-2-methyl-4-15-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid (compound 43) The title compound was prepared in a manner analogous to Example 1 using 43A. IR cm−1: 1745, 1322; 400 MHz 1H NMR (DMSO-d6) δ 12.96 (br(s), 1H), 8.01 (d, 2H, J=8.3 Hz), 7.83 (d, 2H, J=8.3 Hz), 7.07 (s, 2H), 6.52 (s, 1H), 4.70 (s, 2H), 4.03 (s, 2H), 3.71 (s, 3H), 1.99 (s, 3H); MS m/z 454 (M+1). Anal. Calc'd for C21H18F3NO3S. 0.1H2O C, 54.46; H, 3.92; N, 3.01 found: C, 54.54; H, 3.74; N, 2.93.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([NH:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:15]=2[C:31]#[N:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:15]=2[CH2:31][NH2:32])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)c2ccccc2)c(C#N)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: B
Solvent: C1CCOC1
Product: COc1cc(NCc2ccccc2)c(CN)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 92 %

Procedure:
To 186 mg (0.39 mmol) of 4-(3-benzoylamino-2-cyano-5-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester dissolved in 10 mL tetrahydrofuran was added 1.57 mM (4 eq., 1.57 mmol) borane (1M in tetrahydrofuran). The mixture was heated to reflux overnight, cooled and quenched with methanol, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduced pressure to provide 153 mg of crude 4-(2-aminomethyl-3-benzylamino-5-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[C:17]([O-])=[O:18]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[CH2:17][OH:18]
Reactant: CC(C)c1nccc(Cl)c1C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1nccc(Cl)c1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium aluminum hydride (226 mg, 5.96 mmol) was stirred in anhydrous THF (30 mL). A solution of 4-chloro-2-(propan-2-yl)pyridine-3-carboxylate (904 mg, 3.97 mmol) in anhydrous THF (5 mL) was added at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with an aqueous solution of sodium hydroxide and extracted 5 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, [4-chloro-2-(propan-2-yl)pyridin-3-yl]methanol was obtained as an oil (735 mg, 100% yield) and used in the next step without further purification.