Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[N:27]=[N:28][N:29]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH:30]=4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[N:27]=[N:28][N:29]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH:30]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-c3cn(C4CCCC4)nn3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1CCN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cn(C5CCCC5)nn4)nc23)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a solution of 2-(1-cyclopentyl-1H-[1,2,3]triazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (85 mg, 0.14 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL). The reaction mixture was stirred at room temp for 3 h then concentrated. The residue was redissolved in CH2Cl2 (4 mL) and ethylenediamine (0.5 mL) was added. The reaction mixture was stirred at room temp for 0.5 h then concentrated. The residue was purified twice by silica gel chromatography (50% to 100% EtOAc/hexanes to 5% MeOH/EtOAc then 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH)) then triturated with Et2O to isolate 35 mg (52%) of 2-(1-cyclopentyl-1H-[1,2,3]triazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a white powder. MS: (M+H)+=488.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:13]([C:15]2[C:21]3[CH:22]=[C:23]([O:30][CH3:31])[C:24]([O:28][CH3:29])=[C:25]([O:26][CH3:27])[C:20]=3[CH2:19][CH2:18][CH2:17][CH:16]=2)=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(C)C.[Al+3].[Cl-].[Cl-].[Cl-].[NH4+].[Cl-]>C(Cl)Cl>[OH:4][C:5]1[CH:6]=[C:7]([C:13]([C:15]2[C:21]3[CH:22]=[C:23]([O:30][CH3:31])[C:24]([O:28][CH3:29])=[C:25]([O:26][CH3:27])[C:20]=3[CH2:19][CH2:18][CH2:17][CH:16]=2)=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)C2=CCCCc3c2cc(OC)c(OC)c3OC)cc1OC(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C(=O)C2=CCCCc3c2cc(OC)c(OC)c3OC)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
97 (0.07 g, 0.16 mmol) was dissolved in 10 mL of anhydrous CH2Cl2 under nitrogen at 0° C. Anhydrous AlCl3 (44 mg, 0.33 mmol) was added and the reaction mixture was stirred for 2 h at 0° C. Saturated NH4Cl (5 mL) was added and the organic phase was separated. The aqueous layer was extracted with CH2Cl2 (10 mL) and the combined organic phases were dried over Na2SO4, filtered, solvents evaporated under reduced pressure. The crude product was purified by column chromatography (30:70 EtOAc:Hexanes) to yield tan colored oil as product 24 (35 mg, 56% yield). Rf: 0.23 (60:40 Hex:EA).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.I[C:20]1[CH:21]=[N:22][N:23]([CH3:32])[C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.[Cl-].[Li+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][N:23]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[C:20]([C:6](=[O:8])[CH3:7])[CH:21]=[N:22]1
Reactant: Cc1ccc(-c2c(I)cnn2C)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnn(C)c1-c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Tributyl(1-ethoxyvinyl)stannane (95%, 1.39 mL, 3.88 mmol) was added to a mixture of 4-iodo-1-methyl-5-(4-methylphenyl)-1H-pyrazole (768 mg, 2.58 mmol), tetrakis(triphenylphosphine)palladium(0) (298 mg, 0.258 mmol) and lithium chloride (98%, 279 mg, 6.45 mmol) in N,N-dimethylformamide (20 mL), and the reaction was stirred at 90° C. for 18 hours. After cooling, the mixture was filtered through Celite, and concentrated in vacuo; silica gel chromatography (Gradient: 10% to 50% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 460 mg, 2.15 mmol, 83%. LCMS m/z 215.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H), 2.45 (br s, 3H), 3.69 (s, 3H), 7.28 (br AB quartet, JAB=8 Hz, ΔvAB=28 Hz, 4H), 7.99 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([CH2:19]C(OC(C)(C)C)=O)#[N:18]>C1COCC1>[N+:8]([C:7]1[C:2]([CH2:19][C:17]#[N:18])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCc1ncccc1[N+](=O)[O-]
Yield: 66 %

Procedure:
Using the procedure of R. B. Katz, M. Voyle, Synthesis, 314-316 (1989), a mixture of 2-chloro-3-nitro-pyridine (9.51 g, 60 mmol), K2CO3 (20.7 g, 150 mmol) and t-butyl cyanoacetate (13.0 mL, 90 mmol) in THF is heated at reflux temperature for 24 h, cooled and concentrated in vacuo. The residue is suspended in 1:1 water/CH2Cl2 and carefully acidified to pH 1 with concentrated hydrochloric acid. The layers are separated and the organic layer is dried over MgSO4 and concentrated in vacuo to a dark oil. This oil is treated with p-toluene-sulfonic acid monohydrate (1.0 g) and toluene, heated at reflux temperature for 2 h, cooled and decanted. The dark residue is washed with CH2Cl2. The combined CH2Cl2 washes and toluene superinnate are washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo to an oily solid. Trituration with 20:80 ethyl acetate:hexanes gives the title compound as an orange-brown solid, 6.50 g, (66% yield), mp 106-108° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH:34]1[CH2:38][CH2:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][CH:40]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:47][CH2:46][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([C:35]4[NH:36][CH2:37][CH2:38][N:34]=4)=[CH:40][CH:41]=3)=[O:29])[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)O
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: Cl
Product: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)NCCc1ccc(C2=NCCN2)cc1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-10-methoxy-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCCC1>[N:9]1([C:2]2[CH:7]=[C:6]([N:9]3[CH:13]=[CH:12][N:11]=[CH:10]3)[N:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: c1cn(-c2cc(-n3ccnc3)ncn2)cn1
Yield: 69.3 %

Procedure:
In anhydrous tetrahydrofuran, 298 mg of 4,6-dichloropyrimidine was substituted with 272 mg of imidazole. The reaction mixture was treated according to the procedure of Example 1 to yield 294 mg of 4,6-bis(1-imidazoly)pyrimidine, recrystallized from a mixture of isopropyl-alcohol and methanol, and having a melting point of 243°-244° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C@@:22]([OH:49])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[C@H:23]([S:25][C@@H:26]1[CH2:31][O:30][C@@H:29]([C:32]2[CH:41]=[CH:40][C:35]([C:36](OC)=[O:37])=[CH:34][C:33]=2[F:42])[O:28][CH2:27]1)[CH3:24]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:40]=[CH:41][C:32]([C@H:29]3[O:30][CH2:31][C@H:26]([S:25][C@H:23]([CH3:24])[C@:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[F:14])([OH:49])[CH2:43][N:44]4[CH:48]=[N:47][CH:46]=[N:45]4)[CH2:27][O:28]3)=[C:33]([F:42])[CH:34]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)c(F)c1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)cc3)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4) a reaction was carried out using commercially available 4-aminobenzonitrile (98 mg, 0.83,mmol), trimethylaluminium (0.78 ml, 1.07M n-hexane solution, 0.83 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-3-fluorobenzoate (109 mg, 0.21 mmol) obtained in Example 5(2) and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to give the title compound (95 mg, yield 75%) as a colorless oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=3)=[O:18])[CH:6]=1)=[O:4].Cl>C1COCC1.O.[OH-].[K+]>[Cl:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:17]([NH:16][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:15]3[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=3[CH:8]=1)=[O:18])=[CH:27]2
Reactant: COC(=O)c1cc(NC(=O)c2cc3cc(Cl)ccc3[nH]2)cc2c1OCCCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cc2c(c(C(=O)O)c1)OCCCO2)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-[(5-Chloro-1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (120 mg) was dissolved in a mixture of THF/water and 0.3 mL of 1N KOH. The reaction was stirred at room temperature overnight, made acidic with 1N HCl and then extracted with EtOAc. The organic extract was washed with water, brine and dried with MgSO4. This afforded 35 mg of product. MS POS: M+ 387/389.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+]=[N-]>C(O)C.[Pd]>[CH2:9]([O:8][C:6](=[O:7])[C@@H:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][NH2:1])[CH3:10]
Reactant: CCOC(=O)[C@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of ethyl 3-azido-2(S)-(tert-butoxycarbonyl)aminopropionate (0.5 g) and 10% Pd—C (0.1 g, 50% wet) in ethanol (5 ml) was hydrogenated at atmospheric pressure for 1 hour. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo to give 2(S)-(tert-butoxycarbonyl)amino-β-alanine ethyl ester (0.45 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].IC1C=C(C=CC=1C)C(O)=O.O=S(Cl)Cl.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][C:36]=2[C:42]([F:45])([F:44])[F:43])[CH2:30][CH2:29]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:39][C:38]1[CH:40]=[CH:41][C:35]([CH2:34][N:31]2[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]2)=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)=[O:6]
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(C(=O)O)cc1I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
3-Iodo-4-methylbenzoyl chloride (1.06 g, 3.8 mmol), prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCl2, was added to a solution of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (1.00 g, 3.6 mmol), Et3N (0.36 g 3.6 mmol), and a catalytic amount of DMAP in THF (20 mL). After stirring at rt for 2 hrs, the reaction was quenched with water. EtOAc was added and the layers separated. The combined organic layers were concentrated to dryness and purified by silica gel chromatography (eluent: 5% MeOH in CH2Cl2, MeOH was added 0.5% Et3N) to provide the desired product as an off-white solid (67.2%, 1.25 g). 1H NMR (300 MHz, CDCl3) δ: 8.29 (1H, s), 8.00 (1H, s), 7.85 ((1H, m), 7.73-7.76 ((2H, m), 7.31-7.34 ((1H, d, J=9.0 Hz), 3.64 (2H, s), 2.53 (8H, brs), 2.49 (3H, s), 2.33 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15](=[O:36])[CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[CH3:13][O:14][C:15](=[O:36])[CH:16]=[C:10]1[CH2:11][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:9]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC(c2cccc(Br)c2)C1
Solvent: ClCCl
Product: COC(=O)C=C1CC(c2cccc(Br)c2)C1
Yield: 99.6 %

Procedure:
3-(3-Bromo-phenyl)-cyclobutanone (2.00 g, 8.89 mmol) and Triphenyl-phosphoranylidene acetic acid methyl ester (8.33 g, 24.9 mmol) were dissolved in dichloromethane (30 mL) inside a CEM 80 ml microwave vessel. The solution was irradiated in a CEM Discover™ microwave instrument for 30 minutes at 120° C. Pressure reached a maximum of 180 PSI. Purification by column chromatography (isocratic elution; 10% diethyl ether in hexanes) afforded 2.49 gm of a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.90-3.00 (m, 1H) 3.02-3.14 (m, 1H) 3.17-3.28 (m, 1H) 3.46-3.58 (m, 1H) 3.62 (s, 3H) 3.63-3.71 (m, 1H) 5.74 (q, J=3.0 Hz, 1H) 7.27-7.35 (m, 2H) 7.39-7.43 (m, 1H) 7.50 (t, J=1.9 Hz, 1H); MS (EI) m/z 280 [M+.].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:16](=[O:17])[O:18][CH2:19][CH3:20])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
5-bromopyridin-3-amine (20 g, 116 mmol) was dissolved in DCM (500 mL) and pyridine (28.0 mL, 347 mmol) was added, followed by ethyl chloroformate (11.44 mL, 119 mmol) dropwise. The reaction mixture was stirred for 1.5 h at room temperature. The reaction mixture was diluted with DCM. The two phases were separated and the organic phase was washed with 10% CuSO4 solution (2×) sat. NaHCO3 solution (1×) Brine (1×) dried (Na2SO4) and evaporated. The residue was triturated with diethyl ether filtered and dried obtaining ethyl (5-bromopyridin-3-yl)carbamate (21.58 g, 76%) as a white solid. LCMS (m/z): 247.0 (MH+), 0.58 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.62-8.15 (m, 3H) 7.00 (br. s., 1H) 4.27 (q, J=7.0 Hz, 2H) 1.34 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCc3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A solution of 6-hydroxy-3,4-dihydro-1H-quinolin-2-one (2.93 g, 17.9 mmol) in DMF (20 mL) is treated with K2CO3 (4.97 g) and BnBr (4.61 g, 26.9 mmol). The suspension is stirred at room temperature for 4 hours and quenched with water (100 mL). The mixture is extracted with EtOAc (50 mL×2) and the combined organics are dried (Na2SO4), concentrated, and purified on silica gel chromatography column with 30-60% EtOAc/Hexanes to yield the title compound (4.40 g, 97%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>O1CCOCC1.C(N(CC)C(C)C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][O:23][C:16]([CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(O)c1conc1-c1ccc(I)cc1
Reactant: C=CCCCC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN(CC)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CCCC=Cc1ccc(-c2nocc2C(=O)O)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
3-(4-Iodophenyl)isoxazole-4-carboxylic acid (315 mg, 1.0 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 ml) and diethylisopropylamine (2.5 ml), methyl 5-hexenoate (179 mg, 1.4 mmol), tri-(o-tolyl)phosphine (122 mg, 0.4 mmol) and palladium acetate (22.4 mg, 0.1 mmol) were added, and the mixture was stirred overnight at 100° C. 1N Hydrochloric acid was added, and the mixture was extracted once with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=7:3-6:4) to give the title compound (250 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[OH:12][NH2:13].C([O-])([O-])=O.[K+].[K+]>CCO.CO>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:13][OH:12]
Reactant: O=Cc1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: ON=Cc1ccc(F)cc1F
Yield: 94.6 %

Procedure:
(Scheme 1, Compound C) To a mixture of 2,4-difluorobenzaldehyde (0.80 g, 5.6 mmol) and hydroxyamine HCl salt (0.43 g, 6.2 mmol) in EtOH (5 mL) was added K2CO3 (0.85 g, 6.2 mmol). The resultant mixture was stirred at rt for 24 hours. The mixture was diluted with MeOH (20 mL). The precipitates were filter off and washed with MeOH. The product from filtrate was purified by recrystalization (EtOAc/Hexanes). This compound was obtained as a white solid (0.84 g, 5.3 mmol, 94% yield). 1H NMR (DMSO-d6) δ 12.98 (br. s, 1H), 8.17 (s, 1H), 7.79 (m, 1H), 7.32 (m, 1H), 7.11 (m, 1H); Analytical HPLC 1.03 min. (95%); Mass Spec.: 158.06 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.[H-].[Na+].[CH3:24]I>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[O:14][CH3:24])[C:6]=2[N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)nc(Cl)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a solution of the compound from Example 12, Step B (188 mg, 0.6 mmol) in anhydrous DMF (6 mL) was added NaH (60% in mineral oil; 26 mg, 0.66 mmol). The mixture was stirred at room temperature for 0.5 h and then cooled. MeI (45 μL) was added at 0° C. and the reaction mixture allowed to warm to 15° C. in 5 h. Then the mixture was poured into ice-water (20 mL) and extracted with CH2Cl2 (100+50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried (Na2SO4). The evaporated residue was purified on a silica gel column with a solvent system of CH2Cl2/MeOH: 30/1. Appropriate fractions were pooled and evaporated to yield the title compound (50 mg) as a colorless glass.
Reaction SMILES: [C:1]1([NH:11][C:12]2[C:13]3[CH:20]=[C:19]([C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=4)[NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:27]([NH:31][C:32]([N:24]1[CH2:23][CH:22]=[C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[C:13]=3[CH:20]=2)[CH2:26][CH2:25]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N=C=O
Reactant: C1=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)N1CC=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension containing naphthalen-1-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine (120 mg, 0.35 mmol), tert-butyl isocyanate (35 mg, 0.35 mmol) and N,N-diisopropylethylamine (122 μL, 0.70 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred overnight at rt. The reaction mixture was poured into saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3×50 ml). The combined organics were washed with brine (3×50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (2 to 4% MeOH in DCM) gave the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.13 (1H, s), 8.08-8.02 (2H, m), 7.89 (1H, d, J=8.1 Hz), 7.74-7.71 (1H, m), 7.63-7.54 (3H, m), 6.55 (1H, d, J=8.3 Hz), 6.43 (1H, s), 5.83 (1H, s), 4.04 (2H, s), 3.55 (2H, t, J=5.6 Hz), 2.42 (2H, s), 1.34 (9H, s); MS (ES+): m/z 441.08 [MH+], HPLC: tR=2.59 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([S:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:22](=[O:23])[CH2:21][S:20][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:12]=1
Reactant: c1cc(CCNC2CCCCC2)ccn1
Reactant: CCCCSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSCC(=O)N(CCc1ccncc1)C1CCCCC1

Procedure:
N-[2-(4-pyridyl)ethyl]-N-cyclohexyl-α-(n-butylthio)acetamide was prepared by reacting 5.0 g. of N-cyclohexyl-[2-(4-pyridyl)ethyl]amine with 4.4 g. of α-(n-butylthio)acetic acid and 5.0 g. of N,N'-dicyclohexylcarbodiimide in 100 ml. of dichloromethane by the method of Example 2. Weight 2.57 g. Oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][CH2:9][CH:10]2[O:15][C:13](=[O:14])[C:12](=[CH2:16])[CH2:11]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].Cl>C1COCC1.C([Li])CCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][CH2:16][CH:12]2[CH2:11][CH:10]([CH2:9][S:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=3)[O:15][C:13]2=[O:14])=[CH:5][CH:4]=1
Reactant: C=C1CC(CSCc2ccc(OC)cc2)OC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CSCC2CC(CSCc3ccc(OC)cc3)C(=O)O2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-methoxybenzylmercaptane (0.47 ml) in THF (6 ml), n-butyllithium/n-hexane (1.6N, 0.18 ml) and 4-(4-methoxybenzylthiomethyl)-2-methylene-4-butanolide (compound No.1-2, 0.76 g) dissolved in THF (4 ml) was added dropwise at about -78° C. under nitrogen atmosphere. The mixture was stirred for an additional 15 minutes at -78° C. After restoring to room temperature, saturated aqueous ammonium chloride solution was added to the mixture. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give crude oil of the titled compound as a mixture of cis and trans forms. The ratio of cis and trans products is 2.2:1.0.