Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:33])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[OH:33][CH:25]([CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: NCC(O)CN1CCOCC1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (72.2 mg, 0.2 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (38 mg, 0.24 mmol) to precipitate 5-[5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (55 mg, 55%). 1H NMR (DMSO-d6) δ2.27 (m, 1H), 2.32 (m, 1H), 2.39(m, 4H), 2.41, 2.42 (2×s, 6H, 2×CH3), 3.13 (s, 1H), 3.35 (m, 1H), 3.55 (m, 4H), 3.77 (m, 1H), 4.74 (d, J=4.4 Hz, 1H, OH), 6.80 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.0, 8.0 Hz, 1H), 7.51 (t, J=5.6 Hz, 1H), 7.76 (s, 1H), 8.09 (d, J=2.0 Hz, 1H) (aromatic and vinyl), 10.99 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 503.4 (M−1).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.[Cl-].[OH:12][NH3+:13]>N1C=CC=CC=1>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[N:13][OH:12])[C:4]=2[CH:3]=[CH:2]1
Reactant: [NH3+]O
Reactant: O=C1CCCc2[nH]ccc21
Agent: [Cl-]
Solvent: c1ccncc1
Product: ON=C1CCCc2[nH]ccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 1,5,6,7-tetrahydro-indol-4-one (5.4 g) in pyridine (40 mL) was added hydroxyammonium chloride (2 eq.) at rt. After 2 hours, the solvent was removed and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried and concentrated to give 5.5 g of 1,5,6,7-tetrahydro-indol-4-one oxime as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1>>[O:12]1[CH2:13][CH2:14][CH:10]([O:9][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11]1
Reactant: OC1CCOC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OC2CCOC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and 3-hydroxytetrahydrofuran by the method of Example 10 (b). 1H NMR (DMSO-D6) 2.0 (m, 1H), 2.2 (m, 1H), 3.8 (m, 4H), 5.4 (m, 1H), 6.8 (d, 1H), 7.8 (m, 1H), 8.2 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6](=[O:25])[C:5]=1O)(=O)[CH3:2].[NH:27]([C:29]1[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1)[NH2:28]>CCCCCC.CCOC(C)=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:28][N:27]([C:29]4[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:5]=3[C:6](=[O:25])[N:7]2[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:10][CH:11]=1
Reactant: COc1ncccc1NN
Reactant: COc1ccc(CN2C(=O)C(O)=C(C(C)=O)C2c2ccc(Cl)cc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)c3c(c(C)nn3-c3cccnc3OC)C2c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-3-hydroxy-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (Step 71.2) and 3-hydrazinyl-2-methoxypyridine (Step 71.1). tR: 5.79 min (HPLC 1); tR: 1.29 min (LC-MS 2); ESI-MS: 475 [M+H]+ (LC-MS 2); Rf=0.60 (hexane/EtOAc 1:1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)[C:2]1C=CC=CC=1.ICC>CN(C)C=O>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH3:2])[CH2:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: OC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCC(O)(c2cccc(Cl)c2F)C1
Temperature: 80 °C
Yield: 53.2 %

Procedure:
In a sealed tube a mixture of (+)-1-benzyl-3-(3-chloro-2-fluorophenyl)pyrrolidin-3-ol (0.31 g, 1.01 mmol), dimethyl formamide (3 mL) and iodoethane (0.16 mL, 2.02 mmol) was heated under microwave irradiation at 80° C. for 2×15 minutes. The resulting mixture was evaporated, morpholine (2 mL) was added and the mixture was heated under microwave irradiation at 130° C. for 30 minutes. Aqueous LiCl (5%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL, dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.131 g). [α]D=+27.2° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 71-74° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 13), 228, (10), 157 (12), 72 (26), 71 (bp).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Cl.[NH2:25][CH:26]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28]>>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH:26]([N:25]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])[C:27]([O:29][CH3:30])=[O:28])=[CH:36][CH:35]=1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: COC(=O)C(N)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (2.5 g, 0.013 mol), methanol (40 mL, 1 mol), triethylamine (4 mL, 0.03 mol) and methyl 2-amino-2-(4-chlorophenyl)acetate hydrochloride (4.0 g, 0.017 mol) and the reaction heated at 50° C. for 4 hours. The solvent was removed and the residue purified by flash chromatography (40 g silica gel, 0-10% MOH/DCM) to yield the product as a yellow solid. MS m/z=373.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19](F)=[CH:18][C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([N:37]4[CH2:36][CH2:35][NH:34][CH:33]([C:30]5[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[CH2:38]4)=[CH:18][C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: COc1ccc(C2CNCCN2)cc1
Product: CCOC(=O)c1cn(CC)c2nc3cc(N4CCNC(c5ccc(OC)cc5)C4)c(F)cc3cc2c1=O
Yield: 72.8 %

Procedure:
(RS)-3-Ethoxycarbonyl-1-ethyl-7-fluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 33, but starting with 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine (1.99 g) and (RS)-2-(4-methoxyphenyl)piperazine (2.3 g). (RS)-3-Ethoxycarbonyl-1-ethyl-7-fluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.2 g) is obtained in the form of a beige solid, m.p. 210°-212° c.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]=1[CH3:14])=O.[N+]([O-])(O)=O.[N:20]1([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:13][N:9]1[C:8]([CH3:14])=[C:7]([C:5]2[CH:4]=[CH:3][N:35]=[C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:31][CH:30]=3)[N:34]=2)[S:11][C:10]1=[O:12]
Reactant: Cc1c(C(=O)C=CN(C)C)sc(=O)n1C
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Solvent: O=[N+]([O-])O
Product: Cc1c(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)sc(=O)n1C

Procedure:
Condensation between 5-(3-dimethylamino-acryloyl)-3,4-dimethyl-3H-thiazol-2-one and N-(4-morpholin-4-yl-phenyl)-guanidine nitrate afforded the title compound. Anal. RP-HPLC: tR=17.5 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >95%). 1H-NMR (DMSO-d6) δ: 2.48 (3H, s, CH3), 3.03 (4H, m, 2×morph-NCH2), 3.08 (3H, s, CH3), 3.72 (4H, m, 2×morph-OCH2), 6.85 (1H, d, J=5.2, pyrim-H), 6.89 (2H, d, J=9.2, 2×ArH), 7.57 (2H, d, J=9.2, 2×ArH), 8.36 (1H, d, J=5.2, pyrim-H) and 9.35 (1H, s, NH). MS (ESI+) m/z 384[M+H]+ (C19H21N5O2S requires 383.5).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:62][N:63]([CH3:69])[CH:64]1[CH2:68][CH2:67][NH:66][CH2:65]1>CN(C=O)C.C(#N)C>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([N:66]1[CH2:67][CH2:68][CH:64]([N:63]([CH3:69])[CH3:62])[CH2:65]1)=[O:6]
Reactant: CN(C)C1CCNC1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(N)c(C(=O)N4CCC(N(C)C)C4)c3)cc12
Yield: 9.1 %

Procedure:
25 mg (66 μmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid and 72 mg (0.14 mmol) of (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate were dissolved in a mixture of 200 μL of DMF and 1 mL of acetonitrile. 100 μL (approx. 0.88 mmol, density unknown) of 3-(dimethylamino)pyrrolidine was added and the resulting mixture was irradiated in a Personal Chemistry® Optimizer to 100° C. for 30 min. The resulting mixtures was evaporated and the residue purified by flash chromatography on amine functionalized silica gel (Teledyne ISCO Inc.) using a gradient of ethyl acetate containing 15% of methanol in hexanes. The resulting material was then purified by mass-triggered reverse-phase HPLC to afford 2.9 mg (6 μmol, 10%) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(3-di-methylamino-pyrrolidin-1-yl)-methanone as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, 1H), 8.24 (s, br., 1H), 7.64 (dd, 1H), 7.55 (d(m), 1H), 7.46 (ddd, 1H), 7.38 (m, br., 1H), 7.21 (d, 1H), 7.09 (ddd, 1H), 5.45 (m, br., 2H), 3.83 (s, 3H), 3.75 (m, br. 1H), 3.64 (m, br. 1H), 3.47 (m, br. 1H), 3.24 (m, br. 1H), 2.18 (s, br. 3H), 2.09 (s, br. 3H), 2.01 (m, br. 1H), 1.80-1.65 (m, 2H), MS: m/z 475.2 (M+H+).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][OH:10])([CH3:3])[CH3:2].[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15](O)=[CH:14][C:13]=2[O:12]1.C1(N=C=NC2CCCCC2)CCCCC1>CCOCC>[CH:1]([O:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][O:10][C:16]1[CH:15]=[CH:14][C:13]2[O:12][CH2:11][O:19][C:18]=2[CH:17]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCC=CCO
Reactant: Oc1ccc2c(c1)OCO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: CC(C)OCCC=CCOc1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
A mixture of 7.2 g (0.05 mol) of 5-isopropoxy-2-penten-1-ol, 6.9 g (0.05 mol) of 3,4-methylendioxy-phenol, and 10.3 g (0.05 mol) of dicyclohexyl-carbodiimide is stirred at 105° for 16 hours. After cooling 50 cc of ether are added, the mixture is filtered and the filtrate is evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9 : 1 and 5-(5-isopropoxy-2-pentenyloxy)-1,3-benzodioxol is obtained as colourless oil which is identical with the product produced in accordance with Example 39.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([N:28]2[CH:36]3[CH:31]([CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:30][CH2:29]2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:28]1([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:36]2[CH:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29]1
Reactant: O=C(c1cc(Cl)ncn1)N1CCC2CCCCC21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCC2CCCCC21
Temperature: 25 °C

Procedure:
201 mg (0.69 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-on-dihydrochloride were added to 184 mg (0.69 mmol) (6-chloropyrimidin-4-yl)-(octahydroindol-1-yl)-methanone and 488 μL (2.8 mmol) DIPEA in 3 mL DMF. The reaction mixture was stirred at RT over the weekend and then purified by preparative HPLC-MS. The product fractions were combined and the organic solvent was removed using the rotary evaporator. The aqueous solution was neutralised with aqueous 1N NaOH solution and the precipitate obtained was suction filtered. The precipitate was washed with water and dried.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[CH2:44]([O:51][C:52]1[CH:61]=[CH:60][C:55]([C:56]([NH:58][NH2:59])=[O:57])=[CH:54][CH:53]=1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:59][NH:58][C:56](=[O:57])[C:55]3[CH:60]=[CH:61][C:52]([O:51][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:53][CH:54]=3)=[O:19])=[CH:21][CH:22]=2)[C:23]([O:25][CH3:26])=[O:24])=[O:10])=[CH:27][CH:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CCCCCCCOc1ccc(C(=O)NN)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a stirring solution of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid INT-1 (260 mg, 0.68 mmol) in THF (5 mL) were added 4-methylmorpholine (0.15 mL, 1.36 mmol) and isobutyl carbonochloridate (0.09 mL, 0.71 mmol). After stirring at room temperature for 2 h, 4-(heptyloxy)benzohydrazide (187 mg, 0.75 mmol) was added and stirring continued for another 2 h. The reaction mixture was poured onto NaHCO3 (50 mL) and extracted with DCM (3×20 mL). The combined organics were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (100% EA in iso-hexanes) to afford 297 mg (71%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoate INT-3 as an off-white foam. LCMS-ESI (m/z) calculated for C36H45N3O6: 615.8 found 616.0 [M+H]+, tR=2.89 min. (Method 4).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:10])([OH:9])[C:5]([F:8])([F:7])[F:6].[C:11](=O)([O:20]N1C(=O)CCC1=O)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.O>[F:6][C:5]([F:8])([F:7])[C:4]([OH:9])([CH3:10])[CH2:3][NH:2][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)(CN)C(F)(F)F
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(O)(CNC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirring suspension of amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate R) (1.5 g, 8.35 mmol) in DCM (50 ml) was added TEA 93.54 g, 35.0 mmol) followed by benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.983 g, 7.96 mmol). The mixture was stirred at RT for 6 hours and then diluted with water. The organic portion was separated using a phase separator and concentrated in vacuo. Purification by chromatography on silica eluting with 0-70% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.34 (6H, m), 5.98 (1H, s), 5.05 (2H, s), 3.31 (1H, m), 3.18 (1H, m), 1.21 (3H, s)LC-MS: Rt 1.05 min; MS m/z 278.1 [M+H]+; Method 2 min LC_v003.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[CH:16](=O)[CH2:17][CH2:18][CH3:19]>>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C1Nc2ccccc2C12CCCNC2
Reactant: CCCC=O
Product: CCCCN1CCCC2(C1)C(=O)Nc1ccccc12

Procedure:
The compound was prepared according to PROCEDURE 1, Method A by reaction with spiro[indoline-3,3′-piperidin]-2-one and butyraldehyde (10 equiv.). 13C NMR (CDCl3): δ 14.1, 20.6, 21.7, 29.1, 32.0, 49.0, 53.8, 58.5, 58.9, 109.9, 121.9, 126.4, 127.6, 134.9, 140.2, 182.4; MS (TSP): m/z (rel. int.) 260/259 (M+, 25/100).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)C.CO.[OH-].[Na+]>CCCCCC>[CH2:5]([OH:4])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC=CCCCCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: CCCCC=CCCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A portion of the acetate is removed and converted to the corresponding alcohol as follows. 15.0 g (67 mmol) of the 5-decenyl acetate, 35 mL of methanol and 34 mL of 2 M sodium hydroxide were added to a 250 mL round-bottomed flask. This mixture was stirred for 3 hours at room temperature. After 3 hours the hydrolysis was complete, 10 mL of hexane was added and the solution was washed with 10 mL of 1 M HCl, 10 mL of NaHCO3 -saturated water and 10 mL of brine. The organic phase was dried with sodium sulfate, filtered and the hexane removed under reduced pressure to yield 9.4 g of 5-decenol. GC analysis showed the isometric ratio to be 80:20 E:Z.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:26][C:27]1[CH:34]=[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[F:44])[C:32]([O:45][CH3:46])=[CH:31][C:28]=1[CH:29]=[O:30]>O1CCCC1>[Cl:26][C:27]1[CH:34]=[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[F:44])[C:32]([O:45][CH3:46])=[CH:31][C:28]=1[CH:29]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1)[OH:30]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: COc1cc(C=O)c(Cl)cc1OCc1ccc(Cl)cc1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(Cl)cc1OCc1ccc(Cl)cc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (68, 582.0 mg, 1.45 mmol, prepared as described in Example 22) was dissolved in tetrahydrofuran (10.0 mL) at −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 0.79 mL) was added to the reaction. The reaction was stirred for 1 hour, during which the temperature rose to 0° C. The reaction was cooled to −20° C. and 2-chloro-4-(4-chloro-2-fluoro-benzyloxy)-5-methoxy-benzaldehyde (140, 200 mg, 0.61 mmol) in tetrahydrofuran (7.0 mL) was added. The reaction was stirred for 1.5 hours during which time the temperature rose to 0° C. The reaction was quenched with methanol and adsorbed onto silica, then purified by silica gel chromatography, eluting with 0-20% ethyl acetate:hexanes, to provide the desired compound (141, 318 mg, 87%). MS (ESI): [M+H+]+=603.3, 605.3.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([NH:25][C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[CH3:33])=O)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:35]>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([Cl:35])=[N:25][C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[CH3:33])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(NC(=O)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C)c(N=C(Cl)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Temperature: 40 °C

Procedure:
To a mixture of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-N-(2,5-dimethylphenyl)-1-piperidinecarboxamide (i.e. the product of Step A) (0.406 g, 0.88 mmol) in dichloromethane (10 mL) was added phosphorus pentachloride (0.208 g, 1.0 mmol). The reaction mixture was heated at 40° C. for 16 h, and then concentrated under reduced pressure to provide the title compound as a foamy white solid (0.52 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([OH:29])=O)[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6][CH:7]=1.[CH3:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CO>[CH3:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([C:27]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([CH3:30])=[CH:32][CH:33]=3)=[O:29])[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6][CH:7]=1
Reactant: COc1cc(Nc2ncc(C)c(N3CCCC(C(=O)O)C3)n2)cc(OC)c1OC
Reactant: Cc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Nc2ncc(C)c(N3CCC[C@H](C(=O)NCc4ccc(C)cc4)C3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8.2 (380 mg, 0.866 mmol), TEA (0.362 mL, 2.60 mmol) and 4-methylbenzylamine (0.331 mL, 2.60 mmol) in DCM (21.7 mL) was added HATU (494 mg, 1.299 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was then concentrated and the residue was adsorbed onto a plug of silica gel and purified by chromatography through a 50 g silica gel column, eluting with 0.5 to 10% MeOH in DCM to give 8 as a stereomeric mixture. This mixture was brought up in a mixture of MeOH and DCM and purified by supercritical fluid chromatography using an ODH (21×250 mm, 5 um) column. The stereoisomer was then resolved with a mixture of 35% MeOH with 0.2% diethylamine going to 40% MeOH with 0.2% diethylamine at 4 minutes with a flow rate of 65 mL per minute to provide 8. 1H NMR (300 MHz, CDCl3) δ ppm 1.61 (br. s., 1H) 1.66-1.81 (m, 1H) 1.81-2.00 (m, 2H) 2.07 (s, 3H) 2.30 (s, 3H) 2.37-2.72 (m, 1H) 2.76-3.12 (m, 1H) 3.16-3.55 (m, 1H) 3.55-3.88 (m, 10H) 3.99 (d, J=11.98 Hz, 1H) 4.13-4.50 (m, 2H) 6.51 (br. s., 1H) 6.84 (s, 2H) 6.95-7.26 (m, 4H) 7.34 (br. s., 1H) 7.85 (s, 1H); M+H 506.27637.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29](=[O:32])[CH2:30][N:8]1[C:9](=[O:11])[CH:10]=[C:5]([NH:4][C:3]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:2]=2[F:1])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(=O)OC(C)(C)C)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and t-butylbromoacetate in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (1% MeOH/CH2Cl2 as eluant). Ethyl 1-(2-tert-butoxy-2-oxoethyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as a white solid (72%), m.p. (EtOAc/hexanes) 149-151° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.34 (s, 1H), 8.57 (s, 1H), 7.78 (dd, J=10.0, 1.9 Hz, 1H), 7.61 (dd, J=8.4, 1.0 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.43 (d, J=1.2 Hz, 1H), 4.62 (s, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.42 (s, 9H), 1.33 (t, J=7.1 Hz, 3H). Anal Calcd for C20H22FIN2O5: C, 46.5; H, 4.3; N, 5.4. Found: C, 46.7; H, 4.2; N, 5.5.