Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 119.8 %

Procedure:
To a solution of methyl 3-hydroxy-4-methoxybenzoate (4.87 g, 26.7 mmol) and 2-chloro-5-nitropyridine (4.24 g, 26.7 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (8.13 g, 58.8 mmol), and the mixture was stirred at 60° C. for 14 hr. The reaction solution was cooled to room temperature, diluted with water, and extracted with a mixed solvent (1:1, 100 mL) of ethyl acetate and hexane. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (9.73 g) as an orange syrup substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1)([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[S:11]1[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cnccc2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccccc1-c1nc2cnccc2s1
Yield: 72.7 %

Procedure:
A suspension of 2-(2-nitrophenyl)thiazolo[4,5-c]pyridine (1.170 g, 4.6 mmol), Fe powder (1.26 g, 22.8 mmol) and NH4Cl (1.97 g, 36.8 mmol) in CH3OH:H2O (4:1, 80 mL) was refluxed for 6 hrs. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was poured into water. The precipitate was collected by filtration, and washed with water (20 mL×3) to afford 2-thiazolo[4,5-c]pyridin-2-yl-phenylamine as a yellow solid (0.760 g, yield: 73%).
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:57]([O:59][CH2:60][CH3:61])=[CH2:58])CCC>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.O1CCOCC1>[CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)[C:9]=1[C:57]([O:59][CH2:60][CH3:61])=[CH2:58]
Reactant: CCOC(=O)C1CCC(Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)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
Solvent: C1COCCO1
Product: C=C(OCC)c1c(CC2CCC(C(=O)OCC)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a 2-5 mL microwave vessel was charged ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4m, 150 mg, 0.19 mmol), Pd(PPh3)4 (33 mg, 0.029 mmol), tributyl (1-ethoxyvinyl)tin (190 μL, 0.56 mmol), and 1,4-dioxane (2 mL). The vial was flushed with argon and sealed. The reaction was heated to 100° C. for 18 hours. After 18 hours, the solvent was removed in vacuo and the residue was purified via silica gel chromatography to yield the title compound. Yield=113 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[C:11]1([CH:17](P(=O)(OCC)OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O.CC(C)([O-])C.[K+]>O>[C:11]1([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:5][C:4]2[CH:3]=[C:2]([Br:1])[CH:9]=[C:8]([Br:10])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: CCOP(=O)(OCC)C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1cc(Br)cc(C=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 73.7 %

Procedure:
Under an atmosphere of argon, 3,5-dibromobenzaldehyde (12.1 g, 46 L mmole) and diethyl diphenylmethylphosphonate (15 g, 49 mmole, 1.1 eq) were dissolved into dimethyl sulfoxide (DMSO) (60 ml). To the resultant solution, potassium t-butoxide (6.2 g, 55 mmole, 1.2 eq) was added in small portions and the obtained solution was stirred at the room temperature for 9 hours and left standing for one night. After water (60 ml) was added, the reaction mixture was subjected to extraction with ethyl acetate (250 ml). The obtained organic layer was washed with water (100 ml) and a saturated aqueous solution of sodium chloride (50 ml) and dried with magnesium sulfate. Then, the solvent was removed by distillation and a deep brown oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane and hexane+3% dichloromethane, successively) and a white solid (14.0 g, 74%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[N:35](C)[N:34]=[N:33][N:32]=4)[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1.[C:37]([O-])(=O)/C=C/C([O-])=O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[N:32]=[N:33][N:34]([CH3:37])[N:35]=4)[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCc4nnnn4C)CC2)cn3-c2ccc(F)cc2)n1
Solvent: CCO
Product: Cn1nnc(CCN2CC=C(c3cn(-c4ccc(F)cc4)c4ccc(-c5nnn(C)n5)cc34)CC2)n1

Procedure:
Yield 0.9 g of 1-(4-fluorophenyl)-5-(2-methyltetrazol-5-yl)-3-[1-[2-(1-methyltetrazol-5-yl)-ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole, fumarate (17b). Mp 171-173° C. (ethanol). 1H NMR (DMSO-d6): δ 2.55-2.65 (m, 4H), 2.80 (t, 2H), 2.90 (t, 2H), 3.15 (t, 2H), 3.30 (broad s, 2H), 4.05 (s, 3H), 4.45 (s, 3H), 6.25 (broad s, 1H), 6.60 (s, 2H), 7.45 (t, 2H), 7.60-7.70 (m, 3H), 7.80 (s, 1H), 7.90 (d, 1H), 8.60 (s, 1H); MS m/z (%): 485 (MH+, 35), 346 (27), 140 (100).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH:4]([CH3:6])[CH3:5].CC(C)([O-])C.[K+].[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:45](=[O:46])[C:44]([CH2:47][CH2:48][CH:49]=O)=[C:43]([C:51]3[CH:56]=[CH:55][C:54]([S:57]([CH3:60])(=[O:59])=[O:58])=[CH:53][CH:52]=3)[CH:42]=[N:41]2)[CH:36]=[CH:37][C:38]=1[F:39]>C1(C)C=CC=CC=1>[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:45](=[O:46])[C:44]([CH2:47][CH2:48][CH:49]=[CH:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:43]([C:51]3[CH:56]=[CH:55][C:54]([S:57]([CH3:60])(=[O:58])=[O:59])=[CH:53][CH:52]=3)[CH:42]=[N:41]2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2CCC=O)cc1
Reactant: CC(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CC=CCCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of isoamyltriphenylphosphonium bromide (414 mg, 1 mmol) and potassium t-butoxide (112 mg, 1 mmol) in toluene (25 mL) was refluxed for 30 minutes and then cooled to room temperature. The crude aldehyde was added and the mixture was refluxed for 14 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and was washed with water, 10% citric acid, brine, dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica gel, 1:1 hexanes-ethyl acetate) provided the title compound as an oil (yield: 120 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 0.74 (d, J=7 Hz, 6H), 1.44 (m, 1H), 1.70 (t, J=7 Hz, 2H), 2.22 (m, 2H), 2.54 (m, 2H); 3.30 (s, 3H), 5.29 (m, 2H), 7.51 (m, 1H), 7.63 (m, 1H), 7.74 (d, J=9 Hz, 2H), 7.82 (m, 1H), 8.02 (s, 1H), 8.10 (d, J=9 Hz, 2H). MS (APCI+) m/z 473 (M+H)+ and (APCI−) m/z 471 (M−H)−, m/z 507 (M+Cl)−. Anal. calc. for C25H26F2N2O3S: C, 63.54; H, 5.54; N, 5.92. Found: C, 63.74; H, 5.67; N, 5.58.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]2[O:14][CH2:15][C@@:10]1([CH2:27][O:28]S(C)(=O)=O)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][C:19]([NH2:26])=[N:20][C:21]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](O[Na])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].CCOC(C)=O.C([O-])(O)=O.[Na+]>CS(C)=O.[Cl-].[Na+].O>[CH2:1]([O:8][C@@H:9]1[C@@H:13]2[O:14][CH2:15][C@@:10]1([CH2:27][O:28][C:33](=[O:34])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][C:19]([NH2:26])=[N:20][C:21]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC[C@]12CO[C@H]([C@H](n3cnc4c(Cl)nc(N)nc43)O1)[C@H]2OCc1ccccc1
Reactant: O=C(O[Na])c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)c2ncn([C@@H]3O[C@]4(COC(=O)c5ccccc5)CO[C@H]3[C@H]4OCc3ccccc3)c2n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
Compound 84 (4.49 g, 9.32 mmol) was dissolved in DMSO (200 mL) and BzONa (6.76g, 46.6 mmol) was added. The reaction was stirred at 100° C. for 16 h. The reaction allowed to cool to room temperature and EtOAc (200 mL) and brine:sat. aq NaHCO3 (1:1, 400 mL) was added. The mixture was transferred to a separatory funnel. The phases were separated and the aq-phase was extracted with EtOAc (3×200 mL). The combined organic phase was washed with brine (half-sat., 2×200 mL), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by DCVC (Ø=6 cm, 50-100% EtOAc in n-heptane v/v, 5% increments, 2×100 mL fractions, 0-10% MeOH in EtOAc v/v, 10% increments, 100 mL) yielding nucleoside 85 (3.30 g, 70%) as a white powder. Rf=0.40 (35% n-heptane in EtOAc (v/v)). ESI-MS m/z found 508.2.; 510.1 ([MH]+, calcd. 508.1). 1H NMR (DMSO-d6, 400 MHz): δ 8.05 (s, 1H, H8), 7.98 (d, 2H, J=7.3 Hz, Bz), 7.68 (t, 1H, J=7.3 Hz, Bz), 7.53 (t, 2H, J=7.7 Hz, Bz), 7.25-7.15 (m, 3H, Bn), 7.05-7.00 (m, 4H, Bn, NH2), 5.98 (s, 1H, H1′), 4.85 (s, 2H, H5″), 4.67 (d, 1H, J=1.8 Hz, H2′), 4.50 (d, 1H, J=12.1 Hz, CH2), 4.35 (d, 1H, J=2.0 Hz, H3′), 4.34 (d, 1H, J=11.7 Hz, CH2), 4.16 (d, 1H, J=8.4 Hz, CH2), 3.98 (d, 1H, J=8.1 Hz, CH2). 13C NMR (DMSO-d6, 100 MHz): δ 165.1 (PhCO), 159.6, 152.9, 149.0 (C2, C4, C6), 140.6 (C8), 136.7, 133.5, 129.2, 128.9, 128.7, 128.0, 127.9, 127.7,127.6 (Ph), 123.2 (C5), 86.7 (C4′), 85.9 (C1′), 79.9 (C3′), 75.8 (C2′), 72.5, 72.1 (5′, CH2Ph), 60.4 (C5″).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][CH2:9][C:10]([N:12]([C@H:14]([CH3:36])[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:13])=[O:11]>>[OH:8][CH2:9][C:10]([N:12]([CH3:13])[C@H:14]([CH3:36])[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)=[O:11]
Reactant: ClCc1cscn1
Reactant: Cc1cc(Nc2ncnc3cccc(OC[C@@H](C)N(C)C(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(OC[C@@H](C)N(C)C(=O)CO)c23)ccc1OCc1cscn1
Yield: 29 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[(1R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide (obtained as described in Example 96, preparation of starting materials) to give the title compound as a foam in 29% yield; NMR spectrum (DMSO-d6 373K) 1.26 (d, 3H), 2.24 (s, 3H), 2.83 (s, 3H), 3.97 (s, 2H), 4.35 (m, 1H), 4.46 (t, 1H), 4.95 (m, 1H), 5.24 (s, 2H), 7.08 (d, 1H), 7.18 (d, 2H), 7.35 (d, 1H), 7.42 (s, 1H), 7.46 (d, 1H), 7.70 (m, 1H), 8.41 (s, 1H), 9.07 (s, 1H), 9.50 (s, 1H); Mass spectrum MH+ 494.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][Mg]Br.C(OCC)C>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([CH:23]([OH:24])[CH3:25])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 50 mL round bottom flask, 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde (0.5 g, 0.001457 mol) and THF (25 mL) was added and cooled to 0° C. To the flask was slowly added 1.5 M methyl magnesium bromide in diethyl ether (0.145 mL, 0.002186 mol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to provide the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 40% ethyl acetate in hexane [0.3 g, 57%]. 1H NMR (300 MHz, CDCl3): δ 8.05 (d, J=1.2 Hz, 1H), 7.83 (d, J=6.3 Hz, 1H), 7.71 (dd, J′=6.6, J″=1.2 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.40 (d, J=2.7 Hz, 1H), 4.91 (q, J=4.8 Hz, 1H), 3.89 (s, 8H), 1.63 (d, J=4.8 Hz, 3H). LC-MS (ESI): Calculated mass: 359. 1; Observed mass: 360.1 (RT: 1.58 min).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[F:14][C:15]1[CH:16]=[C:17]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:18]=[CH:19][C:20]=1[NH:21]N.C(O)C.Cl>O>[F:14][C:15]1[CH:16]=[C:17]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:18]=[CH:19][C:20]=1[N:21]1[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1cccnc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NN)c(F)c2)C(=O)O1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3nccc3-c3cccnc3)c(F)c2)C(=O)O1
Yield: 42.5 %

Procedure:
(E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (58 mg, 0.327 mmol) and (S)—N-((3-(3-fluoro-4-hydrazinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (94 mg, 0.327 mmol) were combined with a solvent, ethanol (3 mL), and then the mixture was slowly heated to reflux, followed by addition of concentrated hydrochloric acid (40 μL). The reaction mixture was maintained under reflux until completion of the reaction as monitored by TLC. Then, the reaction mixture was poured into water and then was extracted with dichloromethane. The dichloromethane layer was rotary evaporated. The residue was purified with column chromatography to afford 55 mg light yellow solid, with a yield of 40.7%, melting point: 83.7-85.9° C., HPLC: 98.2%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([C:21]1[C:20]2[N:25]=[CH:26][N:27]([CH3:28])[C:19]=2[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:12]([C:29]([F:32])([F:30])[F:31])[CH:13]=2)[N:22]=1)#[N:24]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCCN)c(C(F)(F)F)c3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCCNS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (31 mg) was added to the solution of 6-[4-(3-Aminopropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg) in DCM (1 ml) containing DIPEA (44 uL). The mixture was stirred at rt for 1 hour, then solvent removed under vacuum and residue dissolved in NMP (1 ml) and purified by HPLC to give expected product, N-(3-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl)methanesulfonamide.
Reaction SMILES: FC(F)(F)C([O:5][C@@H:6]1[CH2:10][C:9](=[O:11])[O:8][C:7]1=[O:12])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=1.C(N/C(=N\C(C)C)/O[C:31]([CH3:34])([CH3:33])[CH3:32])(C)C>ClCCl>[OH:5][C@H:6]([CH2:10][C:9]([O:8][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:11])[C:7]([O:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:12]
Reactant: CC(C)/N=C(\NC(C)C)OC(C)(C)C
Reactant: O=C1C[C@@H](OC(=O)C(F)(F)F)C(=O)O1
Reactant: COc1ccc(CO)cc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](O)CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a solution of (R)-2,5-dioxotetrahydrofuran-3-yl 2,2,2-trifluoroacetate (85 g, 401 mmol) in Dichloromethane (DCM) (600 mL) was added (4-methoxyphenyl)methanol (150 mL, 1202 mmol). The mixture was stirred at rt for 3 h and then extracted three times with 10% aqueous solution of NaHCO3. The combined aqueous extracts were washed with DCM, acidified to pH 2 with 2 N HCl, and then extracted with DCM. The organic layer was dried over sodium sulfate and filtered. To the filtrate was added (E)-tert-butyl N,N′-diisopropylcarbamimidate (161 g, 802 mmol) dropwise over 1 h. The mixture was stirred at rt overnight. The precipitate was removed by filtration and the filtrate was purified by normal phase automatic silica column chromatography (Combiflash RF), eluting with EA/Hexane (10-80%) to afford (R)-4-tert-butyl 1-(4-methoxybenzyl) 2-hydroxysuccinate (62.5 g, 201 mmol, 50.2% yield) as a colorless oil. LCMS: (M+Na)+: 333.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:35]=[C:34]([O:33][CH3:32])[C:39]=1[O:40][CH3:41]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CC(=O)NCc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(CNC(C)=O)cc4)c3c2)cc(OC)c1OC
Yield: 53.1 %

Procedure:
N-{-4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzyl}-acetamide (Intermediate CC, 24 mg, 0.048 mmol), 3,4,5-trimethoxyphenyl boronic acid (13 mg, 0.058 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2 mg, 0.002 mmol) were combined in CH3CN (1 ml) and 1 M Na2CO3 (2 ml) and heated in a microwave reactor at 150° C. for 20 min. EtOAc was added, washed with water, dried and purified by silica gel chromatography eluting with 0-4% MeOH:DCM to give 11 mg (53%) of the title compound. MS ESI (m/z): 432.2 (M+1)+, calc. 431.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([OH:21])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24].[Al].C(Cl)Cl>CO>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([OH:21])[C:8]2=[S:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c(O)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Al]
Solvent: ClCCl
Solvent: CO
Product: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Temperature: 175 °C
Yield: 121.9 %

Procedure:
159b (0.062 g, 0.21 mmol) was ground together with P4S10 (0.047 g, 0.105 mmol) in mortar and pestle to form grey powder. The powder was stirred under argon in a flask fitted with condenser and heated to 175° C. for 2 h. The reaction flask was covered with aluminum foil during reaction. After 2 h of reaction, flask was cooled down to room temperature. 25 mL of CH2Cl2:MeOH (10%) mixtures was added and stirred for 15 min. This reaction mixture then washed with water (2×30 mL). Organic layer dried with Na2SO4 and evaporated to yield crude product which was purified by prep-TLC (Eluent —CH2Cl2:MeOH (8%) to give 162b (0.04 g, 60%) as olive green solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.82 (m, 3H), 7.50 (d, J=6.5 Hz, 1H), 7.43 (t, J=7.5 Hz, 2H), 7.34 (t, J=7.4 Hz, 1H), 6.97 (m, 1H), 6.66 (m, 1H), 4.62 (t, J=6.9 Hz, 2H), 4.48 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 168.59, 155.22, 148.03, 131.85, 130.17, 128.84, 128.29, 125.61, 119.84, 113.87, 112.28, 54.99, 46.95, 28.02. HRMS (EI) calcd for C16H16N4OS [M]+ 312.104. found 312.1060.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([CH3:31])[CH:25]=1>CN(C)C=O>[ClH:1].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH3:22])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[C:26]([CH3:31])[CH:25]=1
Reactant: CC1c2ccccc2CCN1c1nc(Cl)nc2ccccc12
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2C)c2ccccc2n1
Product: Cl
Yield: 78 %

Procedure:
In accordance with the same procedures as in Example 14, except that to a mixture of 1.61 g of the compound (5.20 mM) prepared in Example 2 and 15 ml of dimethyl-formamide, 0.89 ml of 4-fluoro-2-methylaniline(10.9 mM) was added, 1.76 g of the title compound was prepared.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:20])[CH2:17][NH:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:20])[CH2:17][N:18]([CH3:19])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitro-benzoyl chloride (1.396 g; 7.52 mmol), methylamino-acetic acid methyl ester hydrochloride (1.264 g; 9.06 mmol) and triethyl-amine (2.40 mL; 17.2 mmol) were reacted in DCM (35 mL). After 2 days the r×n was washed with water (1×10 mL), 1 M HCl (2×10 mL), water (1×10 mL) and satd NaHCO3 (2×10 mL). After drying over MgSO4, filtration through silica with a 10:1 DCM:i-PrOH wash and concd, the product was purified by MPLC (silica; 0-->10% i-PrOH in DCM gradient) yielding a pale yellow-orange solid (1.394 g; 73%) as a mix of rotamers. 1H NMR (CDCl3; major rotamer) δ 8.31 (m, 2H), 7.66 (m, 2H), 4.31 (s, 2H), 3.82 (s, 3H), 3.03 (s, 3H).