Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[N:25]1([C:2]2[N:7]=[C:6](/[CH:8]=[C:9]3/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/3)[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: O=C1NC(=O)/C(=C/c2cccc(Br)n2)S1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)/C(=C/c2cccc(N3CCCCC3)n2)S1
Temperature: 110 °C
Reaction time: 24 h
Yield: 13 %

Procedure:
A 2 dram round-bottomed vial was charged with (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (60 mg, 0.210 mmol, 1 equiv.), DMSO (1 mL, 0.08 M), diisopropylethylamine (34 μL, 0.2 mmol, 1 equiv.), and piperidine (21 μL, 0.21 mmol, 1 equiv.), and the reaction was heated with shaking at 110° C. for 24 h. The solvent was removed under reduced pressure (Genvac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide (Z)-5-((6-(piperidin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (7.9 mg, 60.9 mg theoretical, 12.9%). LC-MS m/z 290.1 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10](=[O:33])[NH:11][CH2:12][C:13]1[N:22]=[C:21]([N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:9])(C)(C)C.NCC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=CC=2)N=1.N(C(OC(C)(C)C)=O)[C@@H](C(O)=O)C.CCN=C=NCCCN(C)C.C(N(C(C)C)C(C)C)C>CN(C=O)C>[NH2:7][C@H:8]([CH3:9])[C:10]([NH:11][CH2:12][C:13]1[N:22]=[C:21]([N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:33]
Reactant: COc1ccc(N(C)c2nc(CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C)nc3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Agent: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(CNC(=O)[C@@H](C)N)nc3ccccc23)cc1

Procedure:
[(R)-1-({4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-carbamoyl)-ethyl]-carbamic acid tert-butyl ester: The title compound was prepared from (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg, 0.37 mmol), Boc-D-Ala-OH (70 mg, 0.37 mmol), EDCI (86 mg, 0.45 mmol), HOBt-hydrate (68 mg, 0.82 mmol) and ethyl-diisopropyl-amine (191 μL, 1.1 mmol) in DMF (1.2 mL) by a procedure similar to the preparation of Example 238a and was isolated as a yellow solid, 114 mg (67%). 1H NMR (MeOH-d4) δ 7.7 (d, 1H), 7.62-7.57 (m, 1H), 7.18 (d, 2H), 7.06-6.98 (m, 4H), 4.55 (m, 2H), 4.2 (q, 1H), 3.82 (s, 3H), 3.62 (s, 3H), 1.49 (s, 9H), 1.48 (d, 3H); LC-MS (ESI+; 466 ([M+H]+)).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN([C:29]([O:33][N:34]1N=NC2C=CC=C[C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CONC>C(#N)C>[CH3:29][O:33][N:34]([CH3:35])[C:14]([C:11]1[N:10]=[CH:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]=1[CH3:13])=[O:16]
Reactant: Cc1c(C(=O)O)ncn1Cc1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CON(C)C(=O)c1ncn(Cc2ccccc2)c1C
Yield: 134 %

Procedure:
Part B: To a magnetically stirred solution of N-benzyl-5-methyl-1H-imidazole-4-carboxylic acid (6.77 gram, 0.031 mol) in anhydrous acetonitrile (35 ml) was successively added diisopropylethylamine (DIPEA) (17.2 ml, 0.0992 mol), HBTU (14.098 gram, 0.0372 mol) and methoxy-methylamine (3.63 gram, 0.0372 mol). The resulting mixture was reacted at 20° C. for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in ethylacetate and successively washed with 5% aqueous NaHCO3 solution and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting oily residue (18.45 gram) was purified by flash chromatography (ethyl acetate/acetone=7/3 (v/v)) to give N-methoxy-N-methyl-5-methyl-1-benzyl-1H-imidazole-4-carboxamide (10.77 gram, 82% yield). MH+=260. 1H-NMR (400 MHz, CDCl3): 2.34 (s, 3H), 3.47 (s, 3H), 3.77 (s, 3H), (s, 2H), 7.05-7.10 (m, 2H), 7.18-7.28 (m, 3H), 7.48 (s, 1H).
Reaction SMILES: [CH2:1]([Mg:3][Br:4])[CH3:2].[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9]C#C>>[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9][C:2]#[C:1][Mg:3][Br:4]
Reactant: C#CCCC(OC)OC
Reactant: CC[Mg]Br
Product: COC(CCC#C[Mg]Br)OC

Procedure:
1,1-dimethoxy-pent-4-yn-5-yl magnesium bromide was prepared in situ from ethyl magnesium bromide and 1,1-dimethoxy-4-pentyne. The latter was prepared as follows:
Reaction SMILES: [P:1]([O-])([O:4]C)[O:2][CH3:3].O.[CH2:8]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:9][CH2:10][CH3:11]>CO>[CH3:3][O:2][P:1]=[O:4].[CH2:8]([O:12][CH2:13][CH2:14][CH2:15][NH3+:16])[CH2:9][CH2:10][CH3:11]
Reactant: COP([O-])OC
Reactant: CCCCOCCCN
Solvent: CO
Solvent: O
Product: CCCCOCCC[NH3+]
Product: COP=O
Yield: 89.4 %

Procedure:
A mixture of 11 g. (0.1 moles) of dimethyl phosphite, 20 ml. of water and 20 ml. of methanol is reacted with a mixture of 13.12 g. (0.1 moles) of 3-butyloxypropyl amine and 30 ml. of methanol as described in Example 1. 22.6 g. of 3-butyloxypropyl-ammoniummethyl phosphanate are obtained. Yield: 89.4%. nD30 =1.4420
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]([O:20][CH3:21])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>>[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH:26][CH2:18][C:16]1[CH:15]=[C:14]([O:20][CH3:21])[C:3]([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=2)=[C:2]([F:1])[CH:17]=1
Reactant: CC(C)(C)CCN
Reactant: COc1cc(C=O)cc(F)c1Oc1ccc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(CNCCC(C)(C)C)cc(F)c1Oc1ccc(C(N)=O)cn1
Yield: 80.1 %

Procedure:
Using a method similar to Example 710, Step 4, using 6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinamide (250 mg, 0.861 mmol), 3,3-dimethyl-butylamine (104 mg, 1.03 mmol), and NaBH4 (49 mg, 1.29 mmol) gave the title compound (259 mg) as a white solid. Mass spectrum (ion spray): m/z=376 (M+1); 1HNMR (DMSO-d6): 8.50 (s, 1H), 8.23 (d, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.13 (d, 1H), 6.96 (s, 1H), 6.89 (d, 1H), 3.71 (s, 3H), 3.68 (s, 2H), 2.51 (t, 2H), 1.37 (t, 2H), 0.86 (s, 9H).
Reaction SMILES: B.[F:2][C:3]1[CH:4]=[C:5]([C@H:9]([OH:24])[C@H:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]2=O)[CH:6]=[CH:7][CH:8]=1.[F:25][C:26]1[CH:27]=[C:28]([C@@H:32]([OH:47])[C@@H:33]2[O:38][CH2:37][CH2:36][N:35]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]2=O)[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[F:2][C:3]1[CH:4]=[C:5]([C@H:9]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11]2)[OH:24])[CH:6]=[CH:7][CH:8]=1.[F:25][C:26]1[CH:27]=[C:28]([C@@H:32]([C@H:33]2[O:38][CH2:37][CH2:36][N:35]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:34]2)[OH:47])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C1[C@@H]([C@@H](O)c2cccc(F)c2)OCCN1Cc1ccccc1
Reactant: O=C1[C@H]([C@H](O)c2cccc(F)c2)OCCN1Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: O[C@@H](c1cccc(F)c1)[C@@H]1CN(Cc2ccccc2)CCO1
Product: O[C@H](c1cccc(F)c1)[C@H]1CN(Cc2ccccc2)CCO1
Temperature: 60 °C

Procedure:
A solution of borane in tetrahydrofuran (1M, 30.7 ml) was added dropwise to a stirred solution of diastereomer 1 (2R)-2-[(S)-(3-fluorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one and (2S)-2-[(R)-(3-fluorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one (2.42 g 7.68 mmol) in dried tetrahydrofuran (30 ml) at room temperature under nitrogen causing effervesence. The solution was heated to 60° C. for 2 h, allowed to cool to room temperature and excess borane quenched by adding methanol (15 ml) slowly. Aqueous hydrochloric acid (1M, 15 ml) was added, heated to 60° C. for 1 h and then evaporated to a white solid. Added saturated aqueous sodium carbonate (50 ml) and diethyl ether (50 ml) to dissolve the solid and extracted with diethyl ether (2×50 ml). The extracts were washed with brine solution, dried, filtered and evaporated to a colourless oil (2.38 g). The oil was purified by chromatography on silica eluting with diethyl ether:hexane 75:25 to give (R)-[3-fluorophenyl][(2R)-4-benzylmorpholin-2-yl]methanol and (S)-[3-fluorophenyl][(2S)-4-benzylmorpholin-2-yl]methanol as a colourless oil (2.23 g)
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C:14]2([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(#N)C.C(N(CC)C)C>C(=O)=O>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=NC2(c3cccs3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Agent: CCN(C)CC
Agent: O=C=O
Solvent: CC#N
Solvent: CO
Product: O=C(NC1=N[C@@]2(c3cccs3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Yield: 46.5 %

Procedure:
Racemic benzyl 2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (34 g, 63 mmol) is chirally purified by SFC (Column: Chiralpak IC (5 j), 2×250 mm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% diethylmethyl amine) in CO2; flow: 65 mL/min at UV 260 nm). The second eluting isomer is the title compound (14 g, 42%, >98% ee): [α]D20=−30 (C=1.0, methanol), ES/MS (m/e) 478 (M+H).
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[C:5]([C:9]1[CH:10]=[C:11]([C:20]2[C:21]([OH:34])=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)[C:12]([OH:19])=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]1([Cl:4])[O:34][C:21]2[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:25][C:20]=2[C:11]2[CH:10]=[C:9]([C:5]([CH3:6])([CH3:7])[CH3:8])[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]=2[O:19]1
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: ClP(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c2op(Cl)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
45.21 grams of phosphorous trichloride in 50 ml of toluene was added dropwise over 85 minutes to a solution of 123.0 grams of 4,4',6,6'-tetra-tert.-butyl-2,2'-biphenol and 60.6 grams of triethylamine in about 600 ml of toluene and stirred at room temperature overnight (about 20 hours). The reaction product was filtered free of triethylamine hydrochloride, the desired product being isolated by removal of the solvent at reduced pressure to yield a solid m.p. 168°-174°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH:3]1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CC1NC(=O)c2ccccc21
Reaction time: 3.5 h

Procedure:
A solution of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid (described by F. M. Rowe et al., cited above, 130 g, 0.682 mol) in methanol (1300 ml) containing 6.5 g of p-toluenesulfonic acid is refluxed with stirring for 3.5 hr. Most of the methanol is evaporated and the residue is dissolved in chloroform. The solution is washed with 5% aqueous sodium bicarbonate and water, dried and evaporated. The residue (125 g) is crystallized from isopropanol to give methyl 1,3-dihydro-3-oxo-2H-isoindole-1-acetate, mp 136°-138° C.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])[CH3:2].[ClH:16].[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][C:25](=[O:28])[CH:24]=[CH:23]2>>[ClH:16].[O:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:17][C:4]([N:3]([CH2:1][CH3:2])[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[NH:5])[CH:23]=[CH:24][C:25]1=[O:28]
Reactant: CCN(C#N)c1cccc2ccccc12
Reactant: Nc1cccc2ccc(=O)oc12
Agent: Cl
Product: CCN(C(=N)Nc1cccc2ccc(=O)oc12)c1cccc2ccccc12
Reaction time: 9 h

Procedure:
In a 5 ml round bottom flask was placed N-ethyl-N-1-naphthylcyanamide (766 mg, 3.91 mmol), 8-aminocoumarin hydrochloride (818 mg, 4.15 mmol; Clayton, J., Chem. Soc. 97: 1350 (1910)) and a stir bar. The flask was evacuated via aspirator and flushed with N2. This was immediately placed in a preheated 160° C. oil bath where it was allowed to stir under N2 for 9 h. The resulting greenish brown melt was dissolved in methanol (5 ml) and diluted with hot distilled water (20 ml). This solution was basified with 0.1N NaOH (10 ml) and extracted with CHCl3 (4×15 ml) to yield a yellowish brown oil upon drying (910 mg). A TLC of this oil showed a mixture of reactants and product. Reactants were eluted by column chromatography with benzene. The product was eluted with benzene/ethanol 8:1 (TLC Rf 0.44, CHCl3 :EtOH, 1:1), 0.64 g (46%). This pale yellow oil was dissolved in methanol (5 ml), then methanol (5 ml) saturated with HCl gas was added dropwise to yield a light tan foam of the HCl salt after drying. This tan foam was dissolved into ethanol (1 ml) and placed in an ether diffusion chamber for 5 days to afford white prisms, 0.28 g (29%), m.p. 193°-194° C. IR (KBr) 3343, 3303 (--NH), 1712 (carbonyl), 1653 (--C=NH). 1H-NMR (CD3OD) δ1.12 (t, 3H, J=7.2), 3.55 (q, 2H, J=7.2), 6.47 (d, 1H, J=9.3), 7.30-8.12 (m, 11H, H-aromat and one olefinic). 13C-NMR (CD3OD) CO, 161.4; CN3, 157.6; Ar, 145.7, 136.6, 136.1, 132.5, 131.7, 131.5, 131.16, 130.12, 130.0, 129.5, 129.4, 129.4, 127.3, 126.2, 124.1, 123.2, 121.9, 117.8; CH2, 58.4; CH3, 18.5. Mass Spec. m/e calcd for C22H19N3O2, 357.1477; Found, 357.1453.
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[O:50]1[CH2:55][CH2:54][N:53]([C@H:56]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:57](O)=[O:58])[CH2:52][CH2:51]1>>[CH3:46][O:45][C:44]([NH:43][C@H:3]([C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[C@@H:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:57](=[O:58])[C@H:56]([N:53]3[CH2:54][CH2:55][O:50][CH2:51][CH2:52]3)[C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[CH:23][CH:22]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:16][CH:17]=1)=[O:41])=[O:42])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:47]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccccc2)cc1)C(C)(C)C
Reactant: O=C(O)[C@@H](c1ccccc1)N1CCOCC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCOCC3)cc2)c2ccccc2)cc1)C(C)(C)C
Yield: 66.9 %

Procedure:
The product from Example 10A (40 mg, 0.060 mmol) and the product of Example 57A (19.9 mg, 0.090 mmol) were processed using the method described in Example 43 to afford 35 mg (67%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.80 (s, 1H), 9.78 (s, 1H), 7.35 (m, 3H), 7.28 (m, 2H), 7.14 (m, 3H), 6.97 (m, 4H), 6.88 (m, 3H), 6.46 (d, J=8.1 Hz, 2H), 6.37 (t, J=7.2 Hz, 1H), 4.40 (bs, 4H), 4.22 (m, 1H), 4.11 (m, 1H), 4.05 (m, 2H), 3.67 (m, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.34 (s, 3H), 3.30 (m, 3H), 3.24 (m, 2H), 2.49 (s, 8H), 2.22 (m, 2H), 2.12 (m, 2H), 1.92 (m, 1H), 1.79 (m, 3H), 1.62 (m, 4H), 0.77 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:42]=[CH:41][C:12]([C:13]([NH:15][NH:16][C:17](=O)[C@H:18]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([Cl:38])[C:31]=2[CH3:39])[C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[O:14])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[Si](O[C@@H](C)[C@@H](NC1C=CC(C#N)=C(Cl)C=1C)C1OC(C2C=CC=C(O[Si](C(C)(C)C)(C)C)C=2)=NN=1)(C(C)(C)C)(C)C>>[Si:22]([O:21][C@H:19]([CH3:20])[C@@H:18]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([Cl:38])[C:31]=1[CH3:39])[C:17]1[O:14][C:13]([C:12]2[CH:41]=[CH:42][C:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])=[CH:10][CH:11]=2)=[N:15][N:16]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
4-(tert-butyldimethylsilyloxy)-N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)benzohydrazide (intermediate 10b) (202 mg, 0.3 mmol) was cyclized with PS-PPh3 (3.0 mmol/g, 209 mg, 0.63 mmol), I2 (152 mg, 0.6 mmol), and TEA (0.33 mL, 2.4 mmol) as described for the preparation of intermediate 7c. After column chromatography (20% EtOAc/hexanes) the title compound was isolated as a white solid (147 mg, 75%). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.86 (AA′XX′, J=8.7 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 6.91 (AA′XX′, J=8.7 Hz, 2H), 6.62 (d, J=8.7 Hz, 1H), 5.11 (d, J=8.8 Hz, 1H), 4.81 (dd, J=3.9, 8.8 Hz, 1H), 4.43 (m, 1H), 2.32 (s, 3H), 1.28 (d, J=6.3 Hz, 3H), 0.98 (s, 9H), 0.93 (s, 9H), 0.22 (s, 6H), 0.13 (s, 3H), 0.10 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][C:4]=1[C:9]([O:11]C)=[O:10].[OH-].[Li+].Cl>C1COCC1.CO.O>[OH:1][CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][C:4]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1scc(C)c1CO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc(C(=O)O)c1CO
Temperature: 100 °C

Procedure:
In a 15 mL microwave tube, methyl 3-(hydroxymethyl)-4-methylthiophene-2-carboxylate (440 mg, 2.36 mmol, 1.0 eq) was dissolved in THF/MeOH/water (2:1:1, 2 mL). To above solution was added Lithium hydroxide (68 mg, 2.84 mmol). The mixture was heated at 100° C. for 30 min in microwave reactor, neutralized with 1 N HCl, extracted with dichloromethane, washed with brine and water. The organic phase was dried over MgSO4, filtered and concentrated. LC-MS (IE, m/z): 195.3 [M+Na]+; 1H NMR (500 MHz, CD3OD, δ in ppm): 7.25 (114, s), 4.86 (2H, m), 2.28 (3H, s);
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])[CH2:2][CH3:3].[C:15](OC(=O)C)(=[O:17])[CH3:16].[CH3:22][CH2:23][O:24][C:25](OCC)(OCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C.C1CCCCC1.CO>[C:15]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:13][CH:12]=2)[C:8](=[C:25]([O:24][CH2:23][CH3:22])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:14])(=[O:17])[CH3:16]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCCCC1
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccc(C(=O)CC)cc21)c1ccccc1

Procedure:
Prepared from 5-propionyl-2-indolinone, acetic anhydride and triethyl orthobenzoate Rf=0.79 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
Reaction SMILES: [C:1](#[N:3])[CH3:2].F[C:5](F)(F)[C:6](O)=O.[Br:11][C:12]1[C:20]2[NH:19][C:18]3[CH:21]4CCN([CH2:25][C:17]=3[C:16]=2[CH:15]=[CH:14][CH:13]=1)CC4>O>[Br:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]1[CH2:21][N:3]3[CH2:6][CH2:5][CH:25]([C:17]2=1)[CH2:2][CH2:1]3
Reactant: O=C(O)C(F)(F)F
Reactant: CC#N
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Solvent: O
Product: Brc1cccc2c3c([nH]c12)CN1CCC3CC1

Procedure:
Crude reaction mixture was obtained as described in Example 1B. Analytical HPLC analysis [Phenomenex® Luna® Combi-HTS C8 (2) 5 μm 100 Å (2.1×30 mm), a gradient of 10-100% acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 2.0 mL/minute over 3 minutes (0-0.1 minute 10% A, 0.1-2.6 minutes 10-100% A)] identified the product of Example 1B as the major product (retention time 1.77 minutes) and the title compound as the minor product (retention time 1.95 minutes). The crude reaction mixture was dissolved in dimethyl sulfoxide and then was purified by reverse-phase HPLC (Waters XBridge™ C18 5 μm OBD 30×100 mm column, flow rate 40 mL/minute, 20-99% gradient of methanol in water with 0.1% trifluoroacetic acid over 20 minutes) to afford a major fraction containing the product of Example 1B and a minor fraction containing the title compound. The fractions containing the title compound were combined and partitioned between CHCl3/2-propanol (4:1, 2×200 mL) and 1.0 M sodium carbonate (200 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under vacuum to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.92-2.13 (m, 4 H), 2.99-3.10 (m, 2 H), 3.19-3.28 (m, 3 H), 4.28 (s, 2 H), 6.88 (t, J=7.8 Hz, 1 H), 7.17 (dd, J=7.6, 0.6 Hz, 1 H), 7.38 (d, J=7.9 Hz, 1 H); MS (APCI) m/z 291/293 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10]2.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25]>O1CCCC1>[CH3:18][O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:24]([C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=3)[OH:25])[CH:8]=2)[N:13]=1
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)c3cccc(C(F)(F)F)c3)ccc2n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 66.1 %

Procedure:
Butyllithium (12.5 ml) was added dropwise at -78° C. to a solution of 6-bromo-2-methoxyquinoline (4 g) in tetrahydrofuran (160 ml). After complete addition the mixture was stirred at -78° C. for 15 minutes. A solution of 3-(trifluoromethyl)-benzaldehyde (3.51 g) in tetrahydrofuran (40 ml) was added dropwise and the mixture was stirred at -78° C. for 30 minutes, then quenched with water (50 ml) and extracted with ethylacetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 3.7 g (66%) of (±)-2-methoxy-α-[3-(trifluoromethyl)phenyl]-6- quinoline methanol (intermediate 28).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].N1CCCCC1.Cl>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[NH:10][C:11](=[O:12])[NH:13][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)N1
Temperature: 130 °C
Yield: 87.9 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (100 g, 0.819 M), hydantoin (90 g, 0.9 M) and piperidine (165 ml) was heated to 130° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 60° C. and 3.2 l water was added. The reaction mixture was acidified with 12N HCl. The precipitated solid was filtered and washed with cold water to yield the title compound of the formula (18) (147 g, 88%), (Org. Syn. Vol. V., pp627).