Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH2:25][CH:24]([CH2:26][N:27]([C:35]3[CH:39]=[CH:38][O:37][N:36]=3)C(OC(C)(C)C)=O)[O:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]=1.[ClH:40]>>[ClH:40].[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH2:25][CH:24]([CH2:26][NH:27][C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[O:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3=NOC(CN(C(=O)OC(C)(C)C)c4ccon4)C3)cc2F)CC1
Agent: Cl
Product: Fc1cc(C2=NOC(CNc3ccon3)C2)ccc1C1=CCNCC1

Procedure:
(5RS)-3-(3-Fluoro-4-(1-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-5-(N-(t-butoxycarbonyl)isoxazol-3-ylaminomethyl)-4,5-dihydroisoxazole (817 mg, 1.51 mM) was treated with ethanolic hydrogen chloride under essentially the conditions of the equivalent intermediate of Example 1, to give the desired product directly from the reaction mixture after washing with diethyl ether (310 mg). MS(ESP): 343 (MH+) for C18H19FN4O2 NMR (DMSO-d6) δ: 2.65 (br, 2H); 3.19 (dd partly overlapped, 1H); 3.23 (overlapping m, 4H); 3.47 (dd, 1H); 3.71 (br, 2H); 4.91 (m, 1H); 5.97 (d, 1H); 6.09 (br, 1H); 7.46 (overlapping m, 3H); 8.34 (d, 1H); 9.51 (br, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]([I:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](OC)=[O:14])=[CH:7]2.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11]([I:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][OH:14])=[CH:7]2
Reactant: COC(=O)c1ccc2c(Br)c(I)ccc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1ccc2c(Br)c(I)ccc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 5-bromo-6-iodo-2-naphthoate (0.37 g, 0.95 mmol) in toluene (10 mL) at −78° C. was added DIBAL (3 mL of a 1M solution in PhMe, 3 mmol) dropwise. The temperature was raised to 0° C. for 1 h. The reaction was quenched with 10 mL of 1M HCl, extracted with EtOAc and dried over Na2SO4. The organic extracts were evaporated to dryness to afford the titled compound.
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([C:19]3([CH3:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([C:19]4([CH3:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C1(C)CCCCC1)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2(C)CCCCC2)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.58 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]-1-methylcyclohexanecarboxamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:34]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:34][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=1)[C:14]([N:16]([CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])=[O:15]
Reactant: CCOC(CN(Cc1ccc(F)cc1F)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1ccc(F)cc1F)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Yield: 110.7 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (S)-(9H-fluoren-9-yl)methyl 3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(2,4-difluorobenzyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-17) (3.08 g, 4.4 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (2.33 g, 158%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:54])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][C@@H:28]1[C@@H:32]([CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH2:31][N:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=2[O:51][CH3:52])[C:29]1=[O:53]>C1COCC1>[CH3:19][O:20][C:21](=[O:54])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][C@@H:28]1[C@@H:32]([CH2:33][OH:34])[CH2:31][N:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=2[O:51][CH3:52])[C:29]1=[O:53]
Reactant: COC(=O)CCCC#CC[C@H]1C(=O)N(Cc2ccc(OC)cc2OC)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)CCCC#CC[C@H]1C(=O)N(Cc2ccc(OC)cc2OC)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 4.0 mL, 4.0 mmol) was added to a solution of 7-[(3R*,4R*)-4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-2-oxo-pyrrolidin-3-yl]-hept-5-ynoic acid methyl ester (680 mg, 1.31 mmol) in THF (13 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature. After 18 h at room temperature, THF was removed in vacuo and the residue was taken up in EtOAc (50 mL). The organic phase was washed with water (2×20 mL) and brine (20 mL) then dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (85% EtOAc/hexane→EtOAc, gradient) to afford 304 mg (57%) of 7-[(3R*,4R*)-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxo-pyrrolidin-3-yl]-hept-5-ynoic Acid Methyl Ester.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:7][N:6]([C:8]2([CH3:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].Cl>C1COCC1.O1CCOCC1>[CH3:21][C:8]1([N:6]2[CH2:7][C:4]([CH2:3][C:1]#[N:2])([N:22]3[CH:26]=[C:25]([C:27]4[C:28]5[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[C:29]=5[N:30]=[CH:31][N:32]=4)[CH:24]=[N:23]3)[CH2:5]2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC1(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.4 %

Procedure:
To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-4-methylpiperidine-1-carboxylate (30 mg, 0.05 mmol) in THF (2 mL) was added a 4 N solution of HCl in dioxane (2 mL). After being stirred at room temperature for 2 hours, the reaction mixture was evaporated under reduced pressure to give the title compound (31 mg, 99%), which was used for the next reaction. LC-MS found: 507.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.[Cu]I>[CH3:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(N2CCCC2)c2ccc(NS(C)(=O)=O)cc2n1
Temperature: 110 °C
Yield: 19 %

Procedure:
In a dried reaction flask flushed with argon a suspension of 169 mg (0.5 mmol) 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline and 57 mg (0.6 mmol) of methanesulfonamide, 325 mg (1 mmol) of cesium carbonate, 1.9 mg (0.01 mmol) copper (I) iodide in 1,4-dioxane was treated at RT with 5.7 mg (0.05 mmol) of trans-diaminocyclohexane and the mixture was heated at 110° C. (oil bath temperature) for 48 h under an argon atmosphere (for the gerneal method: Buchwald: J. Am. Chem. Soc., p7727, 2001). The reaction mixture was then cooled to RT, diluted with methylene chloride and filtered. The filtrate was concentrated in a vacuo, the residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (9:1:0.5) as eluent. Combination of the purified fractions and concentration in vacuo gave 29 mg (25.5%) of the desired N-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-methanesulfonamide which was re-crystallized from methylene chloride: light brown solid. ISP mass spectrum, m/e: 306.3 (M+1 calculated for C15H19IN3O2S: 306).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>CN(C=O)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([SH:1])=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(S)nc1
Reactant: Nc1ccc(F)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1ccc(S)nc1
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
To a solution of 6-mercaptonicotinic acid (0.85 g, 5.48 mmol) in 50 mL of DMF was added 4-fluoroaniline (1.0 mL, 11.0 mmol) and 2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 1.6 g, 6.6 mmol). The mixture was stirred for 30 minutes and the volatiles removed in vacuo. The resulting residue was diluted with ethyl acetate to yield a light tan solid that was isolated by vacuum filtration to give 0.63 g (47%) of the titled compound: 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.28 (m, 1H), 7.83 (m, 1H), 7.68 (m, 2H), 7.33 (m, 1H), 7.15 (m, 2H); MS (EI) m/z 247.05 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1>CO>[F:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]ccc2c1
Solvent: CO
Product: Fc1cnc2c(c1)CCN2
Yield: 48.7 %

Procedure:
500 mg of 5-fluoro-1H-pyrrolo[2,3-b]pyridine was added to 100 mL of methanol, followed by filtration. The filtrate was subjected to a reaction using a continuous hydrogenation reactor (H-Cube (registered trademark); manufactured by ThalesNano) under the condition of CatCart (registered trademark), Raney nickel (manufactured by ThalesNano), a flow rate of 0.5 ml/min, and a pressure of'50 bar (Full H2 mode), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 247 mg of 5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine as a white solid.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:58])=[C:11]([N:18]([CH2:27][C:28]2[N:29]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH:12]=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:16]([O:15][C:13]1[CH:14]=[C:9]([OH:8])[C:10]([F:58])=[C:11]([N:18]([CH2:27][C:28]2[N:29]([C:39]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)[C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH:12]=1)[CH3:17]
Reactant: CCOc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(O)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of Intermediate 113.2 (620 mg, 0.790 mmol) in 5 mL THF at rt, was added TBAF (1M, 0.79 mL, 0.790 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with sat. NH4Cl (2×), H2O (2×) and brine, dried (Na2SO) and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes, gradient) to afford 530 mg (100%) of Intermediate 113.3 as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[C:23](Br)[C:22]([OH:26])=[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][C:41](B(O)O)=[CH:42][CH:43]=2)[CH:38]=[CH:37]1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH3:35])[CH:37]=[CH:38]3)[C:22]([OH:26])=[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: O=C(OCc1ccccc1)c1c(OCc2ccccc2)nc(Br)c(O)c1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: Cn1ccc2cc(-c3nc(OCc4ccccc4)c(C(=O)OCc4ccccc4)c(OCc4ccccc4)c3O)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A mixture of benzyl 2,4-bis(benzyloxy)-6-bromo-5-hydroxynicotinate (0.23 g, 0.44 mol), 1-methyl-1H-indol-5-ylboronic acid (90 mg, 0.51 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), tri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.044 mmol) and KF (0.26 g, 4.4 mmol) in THF (2.0 mL) was stirred at 60° C. overnight under an Ar atmosphere. The mixture was filtered. The filtrate was evaporated and purified by silica chromatography (2-30% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-5-hydroxy-6-(1-methyl-1H-indol-5-yl)nicotinate (0.24 g, 96%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[N:26](C(OC(C)(C)C)=O)[CH:25]=2)O1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:26]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:32]2[C:24]([C:2]2[N:11]=[CH:10][C:9]3[NH:8][CH2:7][CH:6]4[CH2:12][O:13][CH2:14][CH2:15][N:5]4[C:4]=3[N:3]=2)=[CH:25]1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)c2cccnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: c1cnc2[nH]cc(-c3ncc4c(n3)N3CCOCC3CN4)c2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
A mixture of 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 50 mg, 0.221 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (114 mg, 0.331 mmol) and PdCl2(dppf) (8.07 mg, 0.011 mmol) were partially dissolved in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). The resulting brown suspension was stirred overnight at 100° C. By the following day, the coupling reaction was complete and the BOC group had also been removed. The reaction mixture was subsequently diluted with ethyl acetate and washed with brine (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was first purified by LC/MS using a gradient of 0-30% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The product and the starting material co-eluted, yielding no pure fractions. The fractions which contained product were concentrated and lyophilized to give a yellow solid, which was re-purified via LC/MS using a 15-40% gradient of CH3CN in H2O with 10 mmol NH4HCO3. The pure fractions were combined and lyophilized to give the title compound as a white solid (10 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 2.89-3.08 (m, 2 H), 3.12-3.26 (m, 1 H), 3.39-3.52 (m, 2 H), 3.52-3.67 (m, 1 H), 3.83-4.14 (m, 2 H), 4.45-4.63 (m, 1 H), 5.60-5.80 (m, 1 H), 7.04-7.23 (m, 1 H), 7.53-7.68 (m, 1 H), 7.91-8.03 (m, 1 H), 8.13-8.30 (m, 1 H), 8.59-8.78 (m, 1 H), 11.70-11.88 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C16H16N6O, 309.14; found 309.3.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:8])[CH2:6]Br.[F:9][C:10]([F:33])([F:32])[C:11]1[CH:12]=[C:13]([CH2:21][O:22][CH2:23][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>CN(C)C=O>[F:9][C:10]([F:32])([F:33])[C:11]1[CH:12]=[C:13]([CH2:21][O:22][CH2:23][CH:24]([O:25][CH2:6][C:5]([O:4][CH3:3])=[O:8])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=1
Reactant: COC(=O)CBr
Reactant: OC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Sodium hydride (25 mg, 60%) was added to a stirred solution of methylbromoacetate (84 mg) and the compound of Example 3 (200 mg) in dry dimethylformamide (0.5 ml). The mixture was stirred at 23° C. for 18 hrs, then partitioned between water and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 9:1 hexanes:ethyl acetate to give the title compound as a clear oil. 1H NMR (250MHz, CDCl3) δ3.60-3.68 (1H, m), 3.68 (3H, s), 3.80-3.94 (1H, m), 3.95-4.21 (2H, q), 4.64-4.80 (3H, m), 7.23-7.39 (5H, m), 7.80 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[S:13][C:6]=12.O=S(Cl)[Cl:31]>>[Cl:31][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=3[F:1])[CH:11]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CO)cc4)sc23)c(F)c1
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Yield: 100 %

Procedure:
The alcohol 51 (880 mg, 2.22 mmol) was suspended in SOCl2 (10 ml) and the reaction mixture was refluxed for 1 hour, cooled and carefully poured onto ice/water. A precipitate was formed which was collected by filtration, washed with additional cold water and dried under vacuum to afford the title compound 52 (919 mg, 100% yield), which was used without additional purification. MS (m/z): 415.1(100%) (M+H), 417.1 (36%) (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4cccc(C)c4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4cccc(C)c4)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(3-methylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 431 (M++1)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][S:21]([OH:24])(=[O:23])=[O:22])[C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][S:21]([OH:24])(=[O:23])=[O:22])[C:13]=3[N:14]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(OS(=O)(=O)O)c2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(OS(=O)(=O)O)c2nc(-c3ccc(N)cc3)sc2c1
Yield: 62.4 %

Procedure:
To a solution of 2-(4′-nitrophenyl)-6-methylsulfoxy benzothiazole (35 mg, 0.10 mmol) dissolved in ethanol (10 mL) was added SnCl2.2H2O (50 mg). The reaction mixture was heated to reflux for 1.5 hr. The solvent was then removed under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), washed with 1N NaOH, water, dried over MgSO4. Evaporation of the solvent afforded 2-(4′-aminophenyl)-6-methylsulfoxy benzothiazole (21 mg, 65%) as pale brown solid. 1HNMR (300 MHz, CDCl3) δ (ppm): 8.02 (d, J=6.2 Hz, 1H), 7.92 (d, J=8.7 Hz, 2H), 7.84 (d, J=2.4 Hz, 1H), 7.38 (dd, J1=2.4 Hz, J2=6.2 Hz, 1H), 6.78 (d, J=8.7 Hz, 2H), 2.21 (s, 3H, CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[C:12]=1[CH3:20].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[NH4+]>CN(C=O)C.C(O)C.[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:17][C:13]1[C:12]([CH3:20])=[C:11]([CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(N)cccc1CCC(=O)OC(C)(C)C
Temperature: 125 °C
Reaction time: 36 h

Procedure:
Under argon, 201 ml (1.39 mol) of tert-butyl-prop-2-enoate were added dropwise to a solution of 100 g (463 mmol) of 1-bromo-2-methyl-3-nitrobenzene, 322 ml (2.31 mol) of triethylamine, 28.18 g (92.58 mmol) of tri-2-tolylphosphine and 10.39 g (46.29 mmol) of palladium(II) acetate in 2 liters of DMF, and the mixture was then stirred at 125° C. for 36 h. After cooling to room temperature, the reaction mixture was stirred with saturated aqueous ammonium chloride solution and the organic phase was separated off. The aqueous phase was extracted three times with tert-butyl methyl ether, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. After filtration, the solvent was removed to dryness under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 9:1). This gave 89 g (338 mmol, 73% of theory) of the intermediate tert-butyl-(2E)-3-(2-methyl-3-nitrophenyl)prop-2-enoate as a colourless solid. 88 g (334 mmol) of this solid were dissolved in 2 liters of ethanol, 7 g of palladium on carbon (10%) were added at room temperature and the mixture was hydrogenated under atmospheric pressure for 18 h. After complete conversion, the reaction solution was filtered through kieselguhr and the filtrate obtained was concentrated under reduced pressure. This gave 61.3 g (260.5 mmol, 78% of theory) of the title compound as a colourless solid.