Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([NH:15][C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:32][CH3:33])[C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@H](C)C1
Temperature: 23 °C
Reaction time: 7 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoate (278 mg, 0.640 mmol) in CH2Cl2 (5 mL) and AcOH (500 uL) was added acetaldehyde (359 mg, 6.40 mmol) and sodium triacetoxyborohydride (428 mg, 1.92 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 7 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The content was extracted with ethylacetate, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (236 mg, 80% yield.). 1H-NMR (400 MHz, CDCl3) δppm; 7.79 (s, 1H), 7.43 (s, 1H), 7.21-7.36 (m, 5H), 3.92 (s, 3H), 3.87 (d, J=14.0 Hz, 1H), 3.38 (d, J=14.0 Hz, 1H), 3.04-3.15 (m, 4H), 2.73-2.80 (m, 1H), 2.53 (s, 3H), 1.76-1.82 (m, 1H), 1.51-1.63 (m, 2H), 1.34-1.42 (m, 1H), 1.06 (d, J=6.0 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 0.86 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][CH:6]=1)=[O:4])[NH2:2].[NH2:21][C:22]1[C:27]([C:28](O)=[O:29])=C[C:25]([Br:31])=[CH:24][N:23]=1.C([N:34](CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.O>[NH2:21][C:22]1[C:27]([C:28]([NH:2][NH:1][C:3]([C:5]2[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:9][CH:10]=2)=[O:4])=[O:29])=[N:34][C:25]([Br:31])=[CH:24][N:23]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CCN(CC)CC
Reactant: CN(Cc1ccc(C(=O)NN)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(=O)NNC(=O)c2nc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl N-[[4-(hydrazinecarbonyl)phenyl]methyl]-N-methyl-carbamate (1 g, 3.580 mmol) in DMF (7.769 mL) and 2-amino-5-bromo-pyridine-3-carboxylic acid (776.9 mg, 3.580 mmol) was added triethylamine (724.5 mg, 997.9 μL, 7.160 mmol) followed by TBTU (1.724 g, 5.370 mmol). The resulting mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×20 mL) and combined organic extracts washed with saturated aqueous sodium hydrogen carbonate solution (1×20 mL), brine (1×20 mL), dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2 to give the product as a white solid (1.71 g, 58% yield); 1H NMR (400.0 MHz, DMSO) d 1.39-1.45 (m, 9H), 2.80 (s, 3H), 4.45 (s, 2H), 4.45 (s, 2H), 7.28 (s, 2H), 7.35 (d, 2H), 7.90 (d, 2H), 8.20 (d, 2H), 8.24 (d, 1H), 10.50 (s, 1H) and 10.54 (s, 1H) ppm; MS (ES+) 480.16
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:21][CH3:22])=[C:11]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=2)[CH:7]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH3:32])[CH:25]=1)=[O:5])[CH3:2].[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:21][CH3:22])=[C:11]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:33](=[O:35])[CH3:34])[CH:12]=2)[CH:7]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH3:32])[CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C=Cc2cc(OCCCO)c(OC)cc2C1Cc1cccc(OCC)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)N1C=Cc2cc(OCCCOC(C)=O)c(OC)cc2C1Cc1cccc(OCC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a stirred solution of 6-(3-hydroxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (160 mg, 0.59 mmol) in pyridine (4.2 mL) was added acetic anhydride (2.1 mL). The reaction mixture was stirred at room temperature for 15 hrs. The mixture was concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (285 mg, 99% yield). The crude product was used without further purification.
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:11]=2)([CH3:6])[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.CC(=O)OCC>C1COCC1>[NH2:1][C:2]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:11]=2)([CH3:6])[CH2:3][OH:4]
Reactant: CCCCCCCOc1ccc2cc(C(C)(N)C(=O)O)cnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCOc1ccc2cc(C(C)(N)CO)cnc2c1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a solution of crude 2-amino-2-(7-(heptyloxy)quinolin-3-yl)propanoic acid (600 mg, 1.8 mmol) in dry THF (30 mL) was added LAH (138 mg, 3.6 mmol, 2 eq.) at 0° C. under N2. Then, the mixture was warmed to room temperature for 3 h. Then the reaction mixture was added water (1 mL), diluted (EA), filtered and dried (Na2SO4), evaporated to dryness to give the crude product, which was purified by prep-HPLC to give 2-amino-2-(7-(heptyloxy)quinolin-3-yl)propan-1-ol as white solid (200 mg, yield 35%). ESI-MS: 317 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCC[CH:17]1CCC2.[OH-].[Na+].O.Br[C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9](=[O:15])[NH:10][CH:11]([CH3:17])[CH2:12][CH2:13][CH2:14][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCNC(=O)OCc1ccccc1
Reactant: B1C2CCCC1CCC2
Reactant: FC(F)(F)c1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CCCc1cc(C(F)(F)F)ccn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
A solution of but-3-enyl-carbamic acid benzyl ester (3.06 g, 14.0 mmol, 1 eq) in anhydrous toluene (40 mL) was cooled under argon to 0-5° C. 9-BBN (0.50 M, solution in THF; 30.8 mL, 1504 mmol, 1.1 eq.) was added dropwise, the mixture was stirred and allowed to reach room temperature. After 24 h, 1N NaOH/H2O (23.8 mL, 23.8 mmol, 1.7 eq.) was added, followed by 2-bromo-4-trifluoromethyl-pyridine (3.16 g, 14.0 mmol, 1 eq.) and toluene (25 mL). The resulting mixture was degassed and Pd(PPh3)4 (0.89 g, 0.70 mmol, 0.05 eq.) was added. The mixture was rapidly stirred under argon at 60° C. for 24 h, and then it was cooled to room temperature. Afterwards, the mixture was partitioned between EtOAc (100 mL) and brine (100 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc in Heptane) to afford 2 as colorless oil (5.1 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C@H:9]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([F:19])([F:18])[F:17])[C:10]([O:12]C)=[O:11]>CO.C1COCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C@H:9]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([F:17])([F:18])[F:19])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)[C@H](Cc1ccccc1Cl)NC(c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@H](Cc1ccccc1Cl)NC(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 3-(2-chlorophenyl)-2(S)-(2,2,2-trifluoro-1(RS)-phenylethylamino)-propionate was dissolved in a mixture of MeOH (2 mL) and THF (5 mL) and IN NaOH (4 mL) was added and the reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated using a rotavap and the pH was adjusted to 6 using 1N HCl. The precipitated yellow solid was filtered and dried to give 3-(2-chlorophenyl)-2(S)-(2,2,2-trifluoro-1(RS)-phenylethylamino)propionic acid (500 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:41]C)C=C4)N(CC2)C1.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+].[OH2:142]>C(O)(C)(C)C>[CH2:1]([C:3]1([CH2:13][C:14]([OH:41])([C:16]([F:17])([F:18])[F:19])[CH2:15][OH:142])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: O
Reactant: C=C(CC1(CC)CCCc2ccccc21)C(F)(F)F
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCC1(CC(O)(CO)C(F)(F)F)CCCc2ccccc21
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
1-Ethyl-1-[2-(trifluoromethyl)-2-propen-1-yl]-1,2,3,4-tetrahydronaphthalene (Intermediate 12) (100 mg, 0.373 mmole), AD-MIX-α (300 mg) and AD-MIX-β (300 mg) in t-butanol (2 ml) and water (2 ml) were stirred at room temperature. After 1 hour further AD-MIX-α (600 mg) and AD-MIX-β (600 mg) were added and the mixture was heated to 30° C. for 18 h. Sodium sulphite (2 g) was added together with water (5 ml) then stirred for 10 min. Extraction of the mixture with ethyl acetate (3×20 ml) followed by washing of the extract with 2M HCl (x2), 2M NaOH and evaporation of volatiles in vacuo gave a crude product. After purification (silica SPE, 85:15 cyclohexane:ethyl acetate) the title compound was obtained (30 mg, 27%).
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[Cl:23]N1C(=O)CCC1=O>C(O)(=O)C.C(#N)C.O>[Cl:23][C:12]1[S:13][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][C:11]=1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C:2]([F:1])([F:22])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1csc(-c2ccccc2)c1)N1CCCC(F)(F)CC1
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C(c1cc(-c2ccccc2)sc1Cl)N1CCCC(F)(F)CC1
Yield: 25.5 %

Procedure:
(4,4-Difluoro-azepan-1-yl)-(5-phenyl-thiophen-3-yl)-methanone (0.104 g, 0.33 mmol) and N-chlorosuccinimide (0.445 g, 0.33 mmol) in acetic acid (2 mL) were heated by microwave irradiation to 140° C. for 4 minutes. The mixture was diluted with acetonitrile and water and purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were evaporated to give the title compound as a gum (0.03 g). LCMS m/z 356.13 [M+H]+ R.T.=12.26 min (Analytical Method 2).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([F:52])[CH:48]=[CH:47][C:46]=1[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([F:53])=[CH:47][CH:48]=[C:49]([F:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Fc1ccc(F)c(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(F)ccc(F)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3-chloro-1,4-difluorobenzene and isolated as white solid (8.0 mg, 44%). MS (m/e): 443.4 (MH+).
Reaction SMILES: C(N(CC)CC)C.F[B-](F)(F)F.[C:13]([C:15](=NOC(N(C)C)=[N+](C)C)[C:16](OCC)=O)#[N:14].[CH2:30]([O:32][C:33]([C:35]([CH3:46])=[CH:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([OH:41])=O)=[O:34])[CH3:31].C(N)CC>CN(C)C=O>[CH3:46][C:35](=[CH:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](=[O:41])[NH:14][CH2:13][CH2:15][CH3:16])[C:33]([O:32][CH2:30][CH3:31])=[O:34]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCN
Product: CCCNC(=O)c1ccccc1C=C(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of 0.69 cm3 (5.0 mmol) of triethylamine and 1.64 g (5.0 mmol) of O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide is added at 0° C. to a solution of 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide. After stirring for 30 minutes at 0° C. and then for 30 minutes at a temperature in the region of 20° C., this solution is introduced dropwise into a second solution consisting of 296 mg (5.0 mmol) of n-propylamine and 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide, and the mixture is stirred for a further 6 hours at a temperature in the region of 20° C. After leaving the solution to stand overnight, the solvent is removed under vacuum and the residue is dissolved in ethyl acetate. After washing twice with sodium bicarbonate solution and then once with sodium chloride solution, the organic phase is dried over sodium sulfate and then concentrated. 1.10 g of ethyl 2-methyl-3-(2-propylcarbamoylphenyl)acrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: [C:1]([O:10]N1C(=O)CCC1=O)([O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])=O.[Si:18]([O:25][CH:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][NH:35][CH3:36])[CH2:28][CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O.C(Cl)Cl>[Si:18]([O:25][CH:26]1[CH2:27][CH2:28][CH:29]([CH2:32][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][N:35]([CH3:36])[C:1]([O:3][CH2:4][CH2:5][Si:6]([CH3:7])([CH3:8])[CH3:9])=[O:10])[CH2:30][CH2:31]1)([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CNC[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Solid Teoc-OSu (1.35 g, 5.25 mmol) was added to a two-phase solution of (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamate (2.0 g, 5.0 mmol), K2CO3 (0.75 g, 9.0 mmol) in H2O (6 ml) and CH2Cl2 (12 mL). The mixture was vigorously stirred for 2 h at rt. The product was extracted with CH2Cl2. The combined organic layers were washed with sat'd aq NaHCO3 and brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to provide (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (1.9 g, 3.49 mmol, 70% yield). 1H NMR (400 MHz, CD3OD): 0.05 (s, 15H), 0.87 (s, 9H), 1.40 (s, 9H), 1.69 (s, 3H), 2.96 (m, 3H), 3.40-3.52 (m, 1H), 3.81-3.92 (m, 1H), 4.12-4.29 (m, 2H). MS (E/Z): 545 (M+H+)
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.CN1CCOCC1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([N:25]=[C:2]=[O:4])=[CH:23][C:22]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 161.2 %

Procedure:
With a waste gas absorption device, triphosgen (167 g, 0.56 mol, 0.5 eq) was dissolved in chloroform (500 mL). A solution of N-methyl morpholine (11.4 g, 0.11 mol, 0.1 eq) in chlorofrom (100 mL) was added dropwise into the above mixture at 5° C. After addition, a solution of 4-chloro-3-(trifluoromethyl)aniline (220 g, 1.13 mol, 1.0 eq) in chloroform (700 mL) was added dropwise at 10° C. The mixture was warmed to 40° C. and stirred for 15 hours, and then warmed to 50° C. and stirred for 5 hours, and then heated to 60-65° C. and refluxed for 5 hours. The solvent was removed under atmospheric pressure. The residue was distilled under vacumm (oil temperature 110-120° C., vacuum 200 Pa) and the fractions at 95-100° C. were collected to give the title compound (200 g, purity 98.7%, yield 84%) as a colorless liquid.
Reaction SMILES: [N:1]1[C:10]2C(=CC=CC=2)C=C[CH:2]=1.C[NH:12]N.[Cl:14][C:15]1[CH:20]=[C:19]([CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:26][CH:25]=2)=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]2[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)=[CH:26][CH:25]=3)=[N:12][N:1]([CH3:10])[CH:2]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CNN
Reactant: c1ccc2ncccc2c1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: Cn1cc(-c2ccnc(Cl)c2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline but substituting methyl hydrazine and 2-(2-Chloro-pyridin-4-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.19 (m, 2 H), 8.07 (d, J=8.3 Hz, 1 H), 7.83 (d, J=8.3 Hz, 1 H), 7.74 (t, J=8.3 Hz, 1H), 7.67 (d, J=8.3 Hz, 1 H), 7.58 (s, 1H), 7.55 (t, J=8.3 Hz, 1 H), 7.36 (d, J=8.7 Hz, 2H), 7.20 (s, 1H), 7.03 (m, 3H), 5.40 (s, 2H) 3.95 (s, 3H); MS: (M+H m/z=427.0).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:4]=1[C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([O:13]CC2C=CC=CC=2)[C:9]1=[O:21])=[O:6].C1CC=CCC=1>C(O)C.[Pd]>[CH3:27][O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([OH:13])[C:9]1=[O:21])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@H]1C
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: COc1cccc(OC)c1C(=O)N[C@@H]1C(=O)N(O)[C@H]1C

Procedure:
To a stirred solution of (3S-trans)-3-[(2,6-dimethoxybenzoyl)amino]-4-methyl-1-[(phenylmethyl)oxy]-2-azetidinone (0.848 g) in absolute ethanol (20 ml) under nitrogen is added 1,4-cyclohexadiene (8 ml) and freshly prepared palladium black (approximately 0.85 g). After one hour the reaction mixture is filtered and evaporated to a solid (0.605 g).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[C:3]([CH3:5])[CH3:4].Cl.[NH2:8][C@H:9]([C:12](O)=O)[CH2:10][SH:11].C([O-])([O-])=O.[Na+].[Na+].[OH2:21]>C(O)C>[NH2:8][CH:9]([CH2:12][CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])[C:10]([OH:21])=[S:11]
Reactant: N[C@@H](CS)C(=O)O
Reactant: O
Reactant: CC(C)=CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)=CCCC(N)C(O)=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 18 %

Procedure:
A solution of prenyl chloride (6.31 g; 0.06 m) in ethanol (40 ml) was slowly added to a stirred solution of cysteine hydrochloride (7.9 g, 0.05 m) and Na2CO3. 10 H2O (28.6 g, 0.10 m) in water (130 ml) at 15° C. The mixture was stirred for three hours at room temperature, carefully heated to 80° C., kept at this temperature for half an hour and allowed to stand overnight at room temperature. The white precipitate was filtered, washed with ethanol followed by a water wash and dried. 1.6 g (18%) of a white crystalline solid of the above composition was obtained m.p. 190°-4° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[CH2:29][C@H:16]([NH:15][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (257 mg, 0.93 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (476 mg, 0.81 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (535 mg, 1.14 mmol) in Chloroform (15 mL). DIEA (0.808 mL, 4.63 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (225 mg, 34%): LC-MS (ES) m/z=507 (M+H)+