Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([SH:14])[CH2:11][CH2:12][CH3:13].Br[C:16]1[C:17](=[O:33])[C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](=[O:32])[C:25]=1[NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>C(O)C>[CH2:10]([S:14][C:16]1[C:17](=[O:33])[C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](=[O:32])[C:25]=1[NH:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH2:11][CH2:12][CH3:13]
Reactant: Cc1nc2c(s1)C(=O)C(Br)=C(NCCN(C)C)C2=O
Reactant: CCCCS
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCSC1=C(NCCN(C)C)C(=O)c2nc(C)sc2C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
20 μl (0.115 mmol; 1.2 eq.) of diisopropylethylamine and 16 μl (0.154 mmol; 1.6 eq.) of butanethiol are added to 33 mg (96 μmol) of the compound of Example 35 in solution in 4 ml of anhydrous ethanol. The reaction mixture is maintained under stirring for 24 hours at 60° C., then after concentration under reduced pressure, the residue is purified by chromatography on a silica column (eluent: dichloromethane/methanol 95/5) and the expected product is obtained, after taking up in ethyl ether, in the form of a violet-coloured powder.
Reaction SMILES: [Cr+3:1].[CH3:2][CH:3]([CH2:5][CH3:6])[O-:4].[Al+3:7].[CH3:8][CH:9]([CH2:11][CH3:12])[O-:10].[CH3:13][CH:14]([CH2:16][CH3:17])[O-:15]>ClCCl>[CH3:2][CH:3]([CH2:5][CH3:6])[O-:4].[Al+3:7].[CH3:8][CH:9]([CH2:11][CH3:12])[O-:10].[CH3:13][CH:14]([CH2:16][CH3:17])[O-:15].[Al:7].[Cr:1]
Reactant: [Cr+3]
Agent: CCC(C)[O-]
Agent: [Al+3]
Solvent: ClCCl
Product: [Al]
Product: [Cr]
Yield: 3.7 %

Procedure:
As indicated, in some cases the catalyst was also coated with an aluminum alkoxide. In these cases, dichloromethane is added to a similar flask as used in step B and while maintaining a nitrogen atmosphere stirring is commenced (see U.S. Pat. No. 3,984,351 incorporated herein by reference). To the flask is added a portion of the supported hydrated polymeric chromium (III) of step B. A solution of dichloromethane and aluminum sec-butoxide is prepared in a pressure equalizing dropping funnel and the funnel attached to the stirred flask. The aluminum sec-butoxide solution is gradually added to the flask at the rate of 10 grams of solution per minute. After the addition of the solution is complete the slurry in the flask is stirred for about 1 hour. The supernatant liquid is removed by filtration or distillation at reduced pressure and the coated gel is dried in a rotary evaporator at temperatures up to about 60° C. and 29 inches Hg vacuum. The aluminum sec-butoxide was absorbed to provide about 3.7% aluminum by weight of the support (atomic ratio of aluminum to chromium of 8/1). Where indicated, a portion of the supported hydrated polymeric chromium (III) compound of step B was heat aged in chloroform in the presence of poly(di-μ-diphenylphosphinatotitanium dichloride) with an atomic ratio of titanium to chromium of 1/1; and another portion of the supported anhydrous polymeric chromium (III) of step B was heat aged in chloroform in the presence of aluminum sec-butoxide (atomic ratio of aluminum to chromium of 4/1).
Reaction SMILES: [Br:1]Br.[CH:3]1([C@H:6]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[C:20](=[O:28])[N:19]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C:18]=2[CH3:35])=[O:16])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH2:5][CH2:4]1>ClCCCl>[CH:3]1([C@H:6]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[C:20](=[O:28])[N:19]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C:18]=2[CH2:35][Br:1])=[O:16])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH2:5][CH2:4]1
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(F)c2c(=O)n1-c1cccnc1
Reactant: BrBr
Solvent: ClCCCl
Product: O=C(N[C@H](c1cccc(F)c1)C1CC1)c1c(CBr)n(-c2cccnc2)c(=O)c2c(F)cccc12
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Bromine (220 mg, 1.3 mmol) in 0.5 ml 1,2-dichloroethane was added to 8-fluoro-3-methyl-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (200 mg, 0.450 mmol) in 1,2-dichloroethane (5 mL) at 60° C. The reaction mixture was stirred for 15 minutes at 60° C. The reaction mixture was concentrated in vacuo to give crude 3-bromomethyl-8-fluoro-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide, which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:18]1[CH:23]=[CH:22][C:21]([O:24][C:25](OC2C=CC=CC=2)=[N:26][C:27]#[N:28])=[CH:20][CH:19]=1>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25](=[N:26][C:27]#[N:28])[O:24][C:21]4[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CN=C(Oc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (798 mg, 3.22 mmol) and diphenyl cyanocarbonimidate (853 mg, 3.58 mmol) in THF (10 mL) are stirred at room temp. for 15 h. The reaction mixture is diluted with ether, and the precipitate is filtered off to yield the title product as a colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[CH3:14])=[CH:9][CH:8]=1
Reactant: C=CC(=O)Cl
Reactant: CC(N)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NC(C)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 62a, a mixture of acryloyl chloride (58.2 g) was added to 1-(4-chlorophenyl)ethylamine (100 g) and triethylamine (65.2 g) in dichloromethane (400 ml) to give N-[1-(4-chlorophenyl)ethyl]acrylamide, m.p. 103°-104° C.
Reaction SMILES: S(O)(O)(=O)=O.NC1N=C(O)C(N)=C(O)N=1.NC1N=C(O)C(N)=C(O)N=1.C[N+](C)=C[Cl:29].[Cl-].[Cl:32][C:33]1[C:38]([N:39]=[CH:40][N:41]([CH3:43])[CH3:42])=[C:37]([Cl:44])[N:36]=[C:35]([N:45]=CN(C)C)[N:34]=1>C(O)C>[ClH:29].[NH2:45][C:35]1[N:34]=[C:33]([Cl:32])[C:38]([N:39]=[CH:40][N:41]([CH3:42])[CH3:43])=[C:37]([Cl:44])[N:36]=1
Reactant: C[N+](C)=CCl
Reactant: CN(C)C=Nc1nc(Cl)c(N=CN(C)C)c(Cl)n1
Agent: Nc1nc(O)c(N)c(O)n1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CCO
Product: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Product: Cl

Procedure:
In another experiment, 2,5-diamino-4,6-dihydroxypyrimidine hemisulfate (Sigma, 48.0 g, 0.250 mole) was reacted as in Example 1 with less Vilsmeier reagent (7.2 molar equivalents) and the resulting 4,6-dichloro-2,5-bis-{[(dimethylamino)methylene]amino}pyrimidine (92%), without recrytallizaton, was hydrolyzed in 95% ethanol (1 L) and 6 N aqueous hydrochloric acid (110 mL) to provide the title compound of the same purity (elemental analysis and 1H-NMR) as the characterized sample described above (44.2 g. 76% overall from 2,5-diamino-4,6-dihydroxypyrimidine hemisulfate).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11](O)=[O:12])=[CH:3][CH:2]=1.C(N1CCOCC1)C.ClCCl.[C:35]([NH:39][C:40](=[O:47])[C@H:41]([C@H:43]([CH2:45][CH3:46])[CH3:44])[NH2:42])([CH3:38])([CH3:37])[CH3:36]>C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:39]([C:35]([CH3:37])([CH3:36])[CH3:38])[C:40](=[O:47])[C@H:41]([C@H:43]([CH2:45][CH3:46])[CH3:44])[NH2:42])=[O:12])=[CH:5][CH:6]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)NC(C)(C)C
Reactant: O=C(CN1CCC[C@H]1C(=O)O)c1ccc(-c2ccccc2)cc1
Agent: CCN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(C(=O)[C@@H]1CCCN1CC(=O)c1ccc(-c2ccccc2)cc1)C(C)(C)C
Yield: 15.7 %

Procedure:
A solution of N-[2-(biphenyl-4-yl)-2-oxoethyl] L-proline (50 mg, 0.16 mmol, 1.0 eq), N-ethylmorpholine (125 uL, 0.98 mmol, 6 eq) in acetonitrile (0.5 mL) was cooled to 0° C. and treated with a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (170 uL, 0.27 mmol, 1.6 eq) followed by L-isoleucine tert-butylamide (49 mg, 0.19 mmol, 1.1 eq). Purification by HPLC provided 12 mg (16%) of L-isoleucine, N-[1-(2-(biphenyl-4-yl)-2-oxoethyl)-L-prolyl] tert-butylamide.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:23][CH2:22]3)=[C:17]([CH2:24][C:25]3[CH:34]=[CH:33][C:28]4[O:29][CH2:30][CH2:31][O:32][C:27]=4[CH:26]=3)[CH:16]=2)[O:8][CH:7]([S:35][CH3:36])[C@H:6]1[O:37]C(=O)C)(=O)C.[OH-].[Li+]>CO.C1COCC1.O>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C@H:9]3[C@H:10]([OH:11])[C@@H:5]([OH:4])[C@H:6]([OH:37])[CH:7]([S:35][CH3:36])[O:8]3)=[CH:16][C:17]=2[CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:23][CH2:22]1
Reactant: CSC1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CSC1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Step-XI: To a stirred solution of acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methylsulfanyl-tetrahydro-pyran-3-yl ester (80 mg, 0.14 mmol) in methanol:THF:water (3:2:1 mixture, 6 ml) was added lithium hydroxide (9 mg, 0.4 mmol). After stirring for 2 h at room temperature, volatiles were evaporated under reduced pressure. The resulting residue was taken in ethyl acetate (10 ml) and washed with brine (5 ml), brine containing 1 ml of 5% aqueous KHSO4 (5 ml), brine (5 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish 55 mg of (2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol. 1H NMR (400 MHz, CD3OD): δ 0.52-0.60 (m, 2H), 0.80-0.90 (m, 2H), 1.78-1.88 (m, 1H), 2.15 (s, 3H), 3.32-3.35 (m, 3H), 4.05 (q, J=15.2 Hz, 2H), 4.11 (d, J=8.8 Hz, 1H), 4.17 (s, 4H), 4.38 (d, J=10 Hz, 1H), 6.61 (d, J=8.0 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H). MS (ES) m/z 462.3 (M+18).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2oc(N3CCNCC3)nc2c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
In 200 ml of acetonitrile were dissolved 33.6 g (0.39 mole) of piperazine and 10.0 g (0.065 mole) of 2-chlorobenzoxazole, and 9.0 g (0.065 mole) of potassium carbonate and a catalytic amount of potassium iodide were added thereto. The mixture was refluxed by heating for 11 hours under stirring. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of chloroform : methanol = 9 : 1) to obtain 7.54 g of 1-(2-benzoxazolyl)piperazine as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:15])[CH2:10][CH2:9][CH2:8][CH:7]([N:11]=[N+]=[N-])[CH:6]1[OH:14])=[O:4]>CO.CC(O)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1([CH3:15])[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[CH:6]1[OH:14])=[O:4]
Reactant: COC(=O)C1(C)CCCC(N=[N+]=[N-])C1O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1(C)CCCC(N)C1O

Procedure:
A solution of racemic methyl-3-azido-2-hydroxy-1-methyl-cyclohexane-carboxylate, 66c, (0.90 g, 4.22 mmol) in a mixture of MeOH (50 mL) and AcOH (10 mL) was stirred under a hydrogen atmosphere (balloon) with the presence of palladium (0.50 g, 0.47 mmol) overnight at room temperature. The mixture was filtered through a celite bed and washed with MeOH. The combined filtrates were evaporated to provide methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate as a oil. Et2O was added and the resulted acetic acid salt was stirred for 0.5 hour and was then filtered to give 1.0 g of racemic methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate acetic acid salt as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]([CH2:25][C:26](OCC)=[O:27])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)=O.CCOC(C)=O>[C:1]([N:5]1[C:9]2[NH:10][C:26](=[O:27])[CH:25]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(-c2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1nc(-c2ccccc2)c2c(-c3ccccc3)cc(=O)[nH]c21
Temperature: 110 °C
Yield: 15.7 %

Procedure:
To a stirring solution of crude 2-tert-butyl-5-phenyl-2H-pyrazol-3-ylamine (4.0 g, 18.6 mmol) in AcOH (25 mL) was added ethyl benzoylacetate (6.6 mL, 37.2 mmol). The reaction was then heated to 110° C. for 48 hr, at which time the reaction was cooled to room temperature, diluted with EtOAc, and quenched with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of this material was accomplished by flash chromatography, using an ISCO column (ISCO, Inc., Lincoln, Nebr.), eluting with 15% EtOAc/hexanes. The product-containing fractions were collected and concentrated under reduced pressure to give the title compound (1.0 g, 16% yield) as a tan solid. LRMS m/z (APCl) 344 (M+1).
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][C:7]#[N:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.[CH:15]1([CH2:20][C:21]([CH3:24])([CH3:23])O)[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH2:25]>FC(F)(F)C(O)=O>[C:4]1(=[O:9])[N:5]([CH2:6][C:7]([NH:8][C:21]([CH3:24])([CH3:23])[CH2:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:25])[C:1](=[O:14])[C:2]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:3]12
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Reactant: O
Reactant: CC(C)(O)CC1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC1CCCC1)NC(=O)CN1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
To a solution of 2-phthalimidoacetonitrile (11.2 g, 60 mmol) in trifluoroacetic acid (25 ml) at 0°-5° was added 2-cyclopentyl-1,1-dimethylethanol (8.52 g, 60 mmol) over 20 minutes. The reaction mixture was then stirred at 25° for 2 hours, poured into stirred water (200 ml), and the precipitated solid collected. The crude product was crystallized from ethanol-water (1:1) giving colourless needles m.p. 159°-160°. Found: C, 69.66; H, 7.18; N, 8.22. C19H24N2O3 requires C, 69.51; H, 7.32; N, 8.53.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]=[CH:24][C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=[C:27]([C:41]#[N:42])[CH:26]=3)=[CH:17][C:16]=2[C:43]([F:46])([F:45])[F:44])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:48](=[O:56])[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:48]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:56])[CH2:22][CH:23]=[CH:24][C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=[C:27]([C:41]#[N:42])[CH:26]=3)=[CH:17][C:16]=2[C:43]([F:46])([F:44])[F:45])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: COc1ccc(COc2ccc(C#N)cc2C=CCNc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)N(CC=Cc1cc(C#N)ccc1OCc1ccc(OC)cc1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-((4-methoxybenzyl)oxy)-3-cyanophenyl)prop-2-en-1-yl)benzenamine (1.39 g) in 20 mL of CH2Cl2 was added ethyl 4-chloro-4-oxobutyrate (0.43 g) and pyridine (1 mL) at 0° C. The resulting solution was allowed to warm to ambient temperature for 30 minutes and then diluted with 100 mL CH2Cl2. The organic layer was washed with saturated copper sulfate, dried and concentrated to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-((4-methoxybenzyl)oxy)-3-cyanophenyi)prop-2-en-1-yl)benzenamine as a blue solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH2:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23](O)[CH2:24][CH3:25])[CH:14]=[CH2:15].B(F)(F)F.CCOCC>O1CCOCC1>[CH2:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:24][CH3:25])[CH:14]=[CH2:15]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: C=CCOc1ccccc1C(O)CC
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: C=CCOc1ccccc1C(CC)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a flame-dried flask containing a near-solution of 4-hydroxycoumarin (337mg) and 1-(2-allyloxyphenyl)propanol of Preparation 36 (500 mg) in anhydrous dioxane (10 mL) under nitrogen is added boron trifluoride etherate (1.31 mL). The resulting solution is stirred at RT for 25 hrs. concentrated to remove solvent, diluted with aqueous sodium hydroxide (5%, 20 mL) and extracted with methylene chloride (2×25 mL). The organic phase is discarded and the aqueous phase is adjusted to pH 1 using 6M hydrochloric acid and extracted with methylene chloride (2×25 mL). The organic phase is washed with saline (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a viscous residue which is then chromatographed on silica gel (230400 mesh, 45g), eluting with a gradient of ethyl acetate/hexane (5/95-10/90). Pooling of fractions having an Rf =0.44 by TLC (ethyl acetate/hexane, 25/75) and removal of solvent gives the title compound.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:27]([C:37](O)=[O:38])[CH2:26]1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:40]1([CH2:46][CH2:47][CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54](C([O-])=O)[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[C@H:27]([C:37]([N:54]2[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][CH2:47][CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:52][CH2:53]2)=[O:38])[CH2:26]1)=[O:23])=[O:19])([CH3:15])([CH3:16])[CH3:14]
Reactant: O=C([O-])N1CCN(C(=O)CCCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2CCN(C(=O)CCCc3ccccc3)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.7 %

Procedure:
Triethylamine (72 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98.9 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 144.9 mg), 4-(4-phenylbutanoyl)l-piperazinecarboxylate (B, 100 mg), and 1-hydroxybenzotriazole (65 mg) in dichloromethane at room temperature. After stirring at room temperature for 20 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 20:1) to give the titled compound (220 mg) as a white powder: 1H-NMR(400 MHz, CDCl3) δ 1.46 (s, 18H), 1.99 (t, 2H), 2.33 (m, 2H), 2.69 (t, 2H), 3.39-3.85 (m, 13H), 7.18-7.31(m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)/[C:7](=[O:19])[N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si](C)(C)C)=[CH:4][CH:3]=1.[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[C:31]([O:36][CH:37]([CH3:39])[CH3:38])[C:30]=1[CH:40]=[N:41][C:42]([O:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[CH2:43]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:19])[C:6]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:43][C:42](=[O:44])[NH:41][CH:40]3[C:30]3[C:31]([O:36][CH:37]([CH3:38])[CH3:39])=[CH:32][CH:33]=[C:34]([F:35])[C:29]=3[F:28])[C:5]2=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13]([Si:45]([CH3:46])([CH3:47])[CH3:48])[CH3:14]
Reactant: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1c(OC(C)C)ccc(F)c1F)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(F)c(F)c1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: COC(C)[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 55b, E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one prepared in example 55a (3.4 g, 8.10 mmol) was reacted with 1-(2,3-difluoro-6-isopropoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (16 g, 51.1 mmol) prepared in example 62c in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(Oc2ccccc2)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-3-phenoxybenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.12 min.; [M+H]+: 418.79 g/mol.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25])(=[O:19])[CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:25])(=[O:19])[CH3:18]
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
A mixture of (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (1.50 g, 5.12 mmol, Amine-1, single enantiomer), 2-acetamidoisonicotinic acid (1.01 g, 5.63 mmol), HBTU (2.33 g, 6.14 mmol) and triethylamine (3.57 mL, 25.6 mmol) in dichloromethane (51 mL) is stirred at room temperature for 15 hours. The reaction mixture is poured into water (50 mL) and extracted with dichloromethane (50 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to give 1.30 g (66% yield) of the title compound as a white solid.