Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH3:16][C:17]([S:20][S:21][CH2:22][C@H:23]([NH:27][C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C:24]([OH:26])=[O:25])([CH3:19])[CH3:18].[NH2:45][C@H:46]([C:54]([NH:56][C@H:57]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:55])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:53])[NH2:52].C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C)C=O>[NH:27]([C:28]([O:30][CH2:31][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:29])[C@H:23]([C:24]([NH:45][C@H:46]([C:54]([NH:56][C@H:57]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:55])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:52])[NH2:53])=[O:26])[CH2:22][S:21][S:20][C:17]([CH3:18])([CH3:16])[CH3:19].[CH3:23][C:24]([OH:26])=[O:25]
Reactant: CC(C)(C)SSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCCNC(=N)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
2.2 g of DCC are added, at 0° C., to a stirred solution of 4.31 g (10 mmol) of Fmoc-Cys(StBu)--OH, 7.74 g of H-Arg-Phe-OtBu.2 HClO4 (oily substance obtained above), 1.35 g of HOBt and 1.3 ml of N-ethylmorpholine in 40 ml of dimethylformamide. The mixture is worked up in analogy to Example 1a. The residue is triturated with diethyl ether and dried.
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH2:20])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8].[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[C:21]1[CH:22]=[N:23][N:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=1)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@H:11]([CH3:35])[N:10]2[C:7](=[O:9])[CH3:8])(=[O:38])[CH3:37]
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (5.09 μL, 0.063 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.010 g, 0.025 mmol) in dichloromethane (200 μL). Acetic anhydride (3.56 μL, 0.038 mmol) was added, and the reaction stirred at rt for 18 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with 1 N aqueous HCl, and the organic phase was separated and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 440 [M+H]+.
Reaction SMILES: [C:1](=[N:5][OH:6])([NH2:4])[CH2:2][CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[Cl-].[C:23]([C:26]1[CH2:31][CH2:30][NH+:29]([CH3:32])[CH2:28][CH:27]=1)([OH:25])=O.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>CN(C=O)C.C(O)C>[C:33]([O-:38])(=[O:37])[C:34]([O-:36])=[O:35].[CH3:32][NH+:29]1[CH2:30][CH2:31][C:26]([C:23]2[O:6][N:5]=[C:1]([CH2:2][CH3:3])[N:4]=2)=[CH:27][CH2:28]1.[CH3:32][NH+:29]1[CH2:30][CH2:31][C:26]([C:23]2[O:25][N:5]=[C:1]([CH2:2][CH3:3])[N:4]=2)=[CH:27][CH2:28]1
Reactant: CCC(N)=NO
Reactant: O=C(O)C(=O)O
Reactant: C[NH+]1CC=C(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCc1noc(C2=CC[NH+](C)CC2)n1
Product: O=C([O-])C(=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
Propionamide oxime (440 mg; 5,0 mmol), dicyclohexylcarbodiimide (1030 mg; 5.0 mmol) and 4-carboxy-1-methyl-1,2,5,6-tetrahydropyridinium chloride (886 mg; 5,0 mmol) were mixed in distilled DMF. The mixture was stirred at 60° C. for 1 1/2 hours and evaporated in vacuo. To the residue was added water (50 ml) and the mixture was extracted with toluene (3×75 ml). pH was adjusted to 10 by means of 4N NaOH and extracted with toluene (3×100 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo. Upon dissolving the residue in ethanol (99.9%) (5 ml) a solution of oxalic acid (360 mg; 4,0 mmol) in ethanol (99,9%) (5 ml) was added. Crystallization gave the title compound in 15% yield. M.P. 170°-171° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Brc1ccccc1Oc1ncccn1
Temperature: 120 °C

Procedure:
To a 48 mL pressure tube containing a stirbar were added 2-chloropyrimidine (1.69 g, 14.7 mmol), 2-bromophenol (1.63 mL, 14.0 mmol), Cs2CO3 (5.49 g, 16.8 mmol) and DMSO (30 mL). The vial was sealed and heated at 120° Celsius for 15 hours. The reaction was then diluted with 100 mL of ethyl acetate and extracted with brine (2×50 mL). The organic layer was isolated, dried and concentrated to dryness to provide the crude product which was subsequently purified FCC to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.56 (s, 1H), 7.72-7.60 (dd, J=8.0, 1.6, 1H), 7.45-7.34 (m, 1H), 7.32-7.23 (m, 1H), 7.23-7.11 (m, 1H), 7.10-7.01 (t, J=4.8, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([OH:19])=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:24][N:12]1[C:13]2[C:14]([C:20]([F:21])([F:23])[F:22])=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:17][C:18]=2[C@@H:10]2[CH2:9][NH:8][CH2:26][CH2:25][C@H:11]12
Reactant: CN1c2c(cc(O)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: BrCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1c2c(cc(OCc3ccccn3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method as a yellow solid (60 mg, 61%) from (4aS,9bR)-8-hydroxy-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 71, 100 mg, 0.27 mmol), 2-bromomethyl-pyridine (141 mg, 0.56 mmol) and K2CO3 (156 mg, 1.12 mmol). MS (ESI): 364 (base, M+H).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=2[CH:10]=1.[CH2:23]([N:25](CC)[CH2:26]C)C.CNC>O1CCCC1.CN(C)C=O>[CH3:23][N:25]([CH3:26])[CH2:7][CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=2[CH:10]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCO)=C2
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2c(c1)CCC(CCN(C)C)=C2
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
Methanesulfonyl chloride (0.0393 ml, 0.469 mmol) was added to a dimethylformamide solution (2 ml) of N-[6-(2-hydroxyethyl)-7,8-dihydro-2-naphthalenyl]acetamide (102 mg, 0.426 mmol) obtained in Reference Example 102 and triethylamine (0.0652 ml, 0.469 mmol) under ice-cooling, which was stirred for 30 minutes. A tetrahydrofuran solution (0.64 ml) of 2N dimethylamine was added to the reaction mixture, which was stirred at 60° C. for 5 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, and extraction was conducted using 1N hydrochloric acid. Potassium carbonate was added to the extract to make it alkaline, and extraction was conducted using ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resulting residue was purified by alumina column chromatography (development solvent; ethyl acetate), to give the titled compound (57.5 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=1)[CH3:2].O.[NH2:26][NH2:27]>Cl.CC(O)C>[CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:11][CH:12]=3)[C:7](=[N:26][NH2:27])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc2c(c1)C(=O)c1cc(N(CC)CC)ccc1-2
Reactant: NN
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCN(CC)c1ccc2c(c1)C(=NN)c1cc(N(CC)CC)ccc1-2
Temperature: 25 °C
Yield: 79.2 %

Procedure:
2,7-Bis(diethylamino)-9-fluorenone (11.5 g, 35.66 mmol), 50 ml of 2-propanol, 98% hydrazine monohydrate (5.2 ml, 0.11 mol, from Aldrich), and 8 drops of concentrated hydrochloric acid (obtained from Aldrich) were added to a 100 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The mixture was refluxed with an intensive stirring until 2,7-bis(diethylamino)-9-fluorenone disappeared (1.5 hours). The reaction mixture was cooled to room temperature to form crystals. The crystals were filtered off, washed first with water, and then with a mixture of 2-propanol and n-hexane to yield 9.5 g (79%) of the hydrazone. The melting point was found to be 150–151° C. (recrystallized from 2-propanol). The 1H NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 7.50–7.20 (m, 4H, Ar); 6.82–6.50 (m, 2H, Ar); 7.10 (s, br, 2H, NH2); 7.00 (q, 8H, N(CH2CH3)2); and 3.75 (t, J=7.1 Hz, 12H, N(CH2CH3)2). An elemental analysis yielded the following results in weight percent: C, 74.69; H, 8.28; N, 16.52, which compared with the following calculated values for C21H28N4 in weight percent: C, 74.96; H, 8.39; N, 16.65.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: OCc1ccncc1
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2ccncc2)n1

Procedure:
Prepared by the method of Example 20 using pyridine-4-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.009 g.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])[CH:19]=2)[NH:14][CH:13]=1)[CH3:10].[Cl:30]CCl>>[ClH:30].[CH3:8][N:9]([CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[CH:19]=2)[NH:14][CH:13]=1)[CH3:10]
Reactant: CN(C)Cc1c[nH]c2ncc(/C=C/C(=O)OC(C)(C)C)cc12
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1c[nH]c2ncc(/C=C/C(=O)O)cc12
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a suspension of (E)-tert-butyl 3-(3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylate (120 mg, 0.39 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 30 minutes and concentrated to dryness. The resulting residue was solubilized in a solution of hydrochloric acid in dioxane (4N, 2 mL). After 10 minutes stirring at room temperature, the precipitate was filtered and washed with diethyl ether to afford the title product as a pale yellow solid (112 mg, quantitative).
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:24].C(N(CC)C(C)C)(C)C.[Cl:34][C:35]([Cl:40])([Cl:39])[C:36](Cl)=[O:37].C(OCC)C>ClCCl>[Cl:34][C:35]([Cl:40])([Cl:39])[C:36]([C:19]1[N:11]2[C:10]([CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:22]=[CH:23][C:2]([I:1])=[C:3]([CH3:24])[CH:4]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12]2)=[CH:21][CH:20]=1)=[O:37]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1I
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1I
Temperature: 25 °C
Reaction time: 23 h
Yield: 77627.2 %

Procedure:
To a solution of 10-(4-iodo-3-methylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (5.0 g, 0.0117 mmol) and N,N-diisopropylethylamine (3.25 mL, 0.0187 mol) in dry dichloromethane (50 mL) at room temperature under nitrogen was added dropwise trichloroacetyl chloride (1.95 mL, 0.0175 mol) and the reaction mixture was stirred at room temperature for 23 hours. Additional N,N-diisopropylethylamine (1.02 mL, 0.00583 mol) and trichloroacetyl chloride (0.65 mL, 0.00583 mol) were added and stirring continued at room temperature for 4 hours. The reaction mixture was then partitioned between dichloromethane (200 mL) and 2 M hydrochloric acid (200 mL). The organic phase was separated, washed with 2 M hydrochloric acid (200 mL) and water (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a black syrup. Purification by flash chromatography using a solvent gradient of 10 to 15% ethyl acetate in hexane gave an orange foam. Diethyl ether (100 mL) was added and the resulting suspension stirred vigorously for 4 hours then filtered to afford the title compound (5.21 g, 78%) as an off-white solid, m.p. 163° C.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[N:29]([CH2:33][CH2:34]O)[CH:30]([CH3:32])[CH3:31])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:51]=[N+:52]=[N-:53])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[N:51]([CH2:34][CH2:33][N:29]([CH:30]([CH3:31])[CH3:32])[C:28]([C:26]1[N:27]=[C:23]([N:21]2[CH2:20][CH2:19][CH2:22]2)[S:24][CH:25]=1)=[O:36])=[N+:52]=[N-:53].[Si:1]([O:18][CH:19]1[CH2:20][NH:21][CH2:22]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)N(CCO)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Product: CC(C)N(CCN=[N+]=[N-])C(=O)c1csc(N2CCC2)n1
Yield: 163.3 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-(2-hydroxyethyl)-N-isopropyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.46 g, 2.79 mmol) (obtained as described in Reference Example 59(1)) in tetrahydrofuran (73 ml) were added diphenylphosphoryl azide (0.90 ml, 4.18 mmol), triphenylphosphine (1.10 g, 4.18 mmol), and a 40% solution of diethylazodicarboxylate in toluene (1.54 g, 4.18 mmol) in an ice bath under an atmosphere of nitrogen, and then the mixture was stirred for 3 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (2:1) as the eluant to afford 1-{4-[N-(2-azidoethyl)-N-isopropyl-carbamoyl]-1,3-thiazol-2-yl}azetidine-3-t-butyldiphenylsilyloxyazetidine (1.38 g, yield 87%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12](=[O:18])[NH:13]3)=[CH:4][CH:3]=1.[CH3:19][N:20](C)C=O>>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12](=[O:18])[NH:13]3)=[CH:4][CH:3]=1)#[N:20]
Reactant: CN(C)C=O
Reactant: O=c1ccc2c(-c3ccc(Br)cc3)nccc2[nH]1
Product: N#Cc1ccc(-c2nccc3[nH]c(=O)ccc23)cc1
Reaction time: 96 h

Procedure:
A mixture containing 15 g of 5-(4-bromophenyl)-1,6-naphthyridin-2(1H)-one, 300 ml of dimethylformamide and 8.6 g of cuprous cyanide was refluxed with stirring for 96 hours, cooled and stripped to dryness using a rotary evaporator. To the residue was added 300 ml of concentrated aqueous ammonium hydroxide solution and 20 ml of glacial acidic acid. The resulting mixture was chilled in ice, next treated with 71 ml of (5.25% aqueous sodium hypochlorite solution, then stirred in an ice bath for 3 hours and allowed to stand at room temperature for 4 hours. The brown solid was collected, washed with water, dried, dissolved in 300 ml of boiling dimethylformamide, the hot solution treated with decolorizing charcoal and filtered, and the filtrate concentrated to dryness. The residue was recrystallized from dimethylformamide to produce 8.6 g of 5-(4-cyanophenyl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)#[N:2].[Si:27]([O:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42]2[NH:46][CH:45]=[N:44][N:43]=2)[CH2:37][CH2:36]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[Si:27]([O:34][CH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[C:17](=[O:19])[C:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[N:14][CH:13]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:43]3[N:44]=[CH:45][N:46]=[C:42]23)[CH2:37][CH2:36]1)([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2nnc[nH]2)CC1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OCC
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A mixture of ethyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate (1.8 g), N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4H-1,2,4-triazol-3-amine (1.4 g) and N,N-diethylaniline (30 mL) was stirred at 180° C. for 8 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.42 g, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Br[CH2:32][CH2:33]Cl.[OH:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[OH:35][CH:36]1[CH2:41][CH2:40][N:39]([CH2:32][CH2:33][N:20]2[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]4)/[S:22][C:21]2=[O:23])[CH2:38][CH2:37]1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: OC1CCNCC1
Reactant: ClCCBr
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CCC(O)CC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-3-[2-(4-Hydroxypiperidin-1-yl)ethyl]-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8), 1-bromo-2-chloroethane and 4-hydroxypiperidine following General Procedure G.
Reaction SMILES: B.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[O:14][C:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[O:16])=[N:12][N:11]=1>C1COCC1>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[O:14][C:13]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:16])=[N:12][N:11]=1
Reactant: O=C(O)CC1CCC(c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Agent: B
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CCC(CCO)CC2)cc1)c1nnc(Nc2ccccc2F)o1
Reaction time: 16 h
Yield: 45.8 %

Procedure:
Borane (1 mL of a 1M solution in THF) was added to a stirred solution of (4-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetic acid (Intermediate 45, 79 mg) in THF (2 mL). The reaction mixture was stirred for 16 hours. The mixture was evaporated and the residue dissolved in DCM (10 mL) then washed with brine (10 mL), dried and concentrated in vacuo to give a solid. This solid was purified by HPLC eluting with a gradient of acetonitrile/water containing 0.2% TFA to give the title compound (35 mg) as a solid, a ca. 2:1 trans:cis isomeric mixture; 1H NMR δ 10.90 (1H, s), 10.72 (1H, s), 8.01 (1H, t), 7.65 (2H, m), 7.33-7.12 (5H, m), 4.28 (1H, m), 3.46 (2H, bs), 2.58-2.40 (1H+ DMSO, m), 1.80 (3H, bs), 1.68-1.50 (4H, m), 1.49-1.31 (3H, m), 1.05 (1H, m); MS m/e MH+ 425.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:31](Cl)(=[O:33])[CH3:32].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:31](=[O:33])[CH3:32])[CH:7]=1
Reactant: CNc1cc(OC)c(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1cc(OC)c(Oc2ccnc(NC(C)=O)c2)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)-pyridin-2-amine (1 eq) and diisopropylethylamine (4 eq) in methylene chloride was brought to 0° C. Acetyl chloride (1.1 eq) was added dropwise and mixture stirred for 5 minutes. Reaction brought to room temperature and water added. Organic layer washed with brine, dried over sodium sulfate and concentrated to yield N-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide. HPLC=3.21 min; MS: MH+=333.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1>O1CCCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:9]2[C:8](=[O:11])[CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:10]2)=[CH:23][CH:22]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)COC1=CC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)COC1=CC(=O)C(Cc2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
3-Isobutoxycyclopent-2-enone (3, 0.130 g, 0.84 mmol) in anhydrous tetrahydrofuran (2.0 mL) was cooled to −78° C. and a freshly prepared 1M solution of lithium diisopropylamide (1.0 mL, 1.0 mmol) was added dropwise. The mixture was stirred at −78° C. for 45 min and a solution of 1-bromo-4-(bromomethyl)benzene (0.210 g, 0.84 mmol) in anhydrous tetrahydrofuran (3.0 mL) was added dropwise. The resulting mixture was stirred for 1 h allowing the temperature to rise to rt. The reaction was quenched with a saturated aqueous solution of ammonium chloride (3.0 mL). The aqueous phase was extracted with ethyl acetate (2×10 mL) and combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography using a gradient of ethyl acetate in hexanes as eluant provided 5 as a white solid (40% yield).