Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C@H:21]([OH:22])[C@H:20]([CH3:23])[CH:19]=[C:18]([CH3:24])[CH:17]=[C:16]([O:25][CH3:26])[C:14](=[O:15])[O:13][C@H:12]([C@H:27]([C@@H:29]([OH:57])[C@@H:30]([C@:32]2(OC)[O:37][C@H:36](/[CH:38]=[CH:39]/[CH3:40])[C@@H:35]([CH3:41])[C@H:34]([O:42][C@@H:43]3[O:48][C@H:47]([CH3:49])[C@@H:46]([O:50][C:51]([NH2:53])=[O:52])[C@H:45]([OH:54])[CH2:44]3)[CH2:33]2)[CH3:31])[CH3:28])[C@@H:11]([O:58][CH3:59])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:60])[CH2:6][C@@H:5]([CH3:61])[C@@H:4]1[OH:62].[BH3-]C#N.[Na+].CO.O.P([O-])([O-])([O-])=O>CCO>[CH3:1][CH2:2][C@@H:3]1[C@H:21]([OH:22])[C@H:20]([CH3:23])[CH:19]=[C:18]([CH3:24])[CH:17]=[C:16]([O:25][CH3:26])[C:14](=[O:15])[O:13][C@H:12]([C@H:27]([C@@H:29]([OH:57])[C@@H:30]([C@@H:32]2[O:37][C@H:36](/[CH:38]=[CH:39]/[CH3:40])[C@@H:35]([CH3:41])[C@H:34]([O:42][C@@H:43]3[O:48][C@H:47]([CH3:49])[C@@H:46]([O:50][C:51]([NH2:53])=[O:52])[C@H:45]([OH:54])[CH2:44]3)[CH2:33]2)[CH3:31])[CH3:28])[C@@H:11]([O:58][CH3:59])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:60])[CH2:6][C@@H:5]([CH3:61])[C@@H:4]1[OH:62]
Reactant: C/C=C/[C@H]1O[C@@](OC)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@](OC)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 ml of 0.5N HCI are added to a solution of 500 mg (0.57 mmol) of 21-O-methylconcanamycin A and 258 mg of NaBH3CN (4.11 mmol, 7 equiv.) in 65 ml of EtOH and the reaction mixture is then stirred at room temperature for 4 hours. The TLC monitoring is effected using RP 8-silica gel plates (Merck) (eluant: MeOH/H2O 9:2). For working-up, 60 ml of phosphate buffer (pH=7) are added, EtOH is removed in vacuo and the aqueous residue is extracted with CHCl3. Purification is carried out by MPLC chromatography on RP 18-silica gel (eluant: MeOH/H2O 8:2). The yield is 228 mg (47%), m.p.: 140° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C(#N)C>[CH3:2][N:3]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1)[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: CNC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CN(CCOc1ccc([N+](=O)[O-])cc1)C1Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
2-Methylamino-5-nitroindane hydrochloride (0.46 g), 2-bromoethoxy-4-nitrobenzene (0.49 g) [see C.A., (1960), 54, 11046a] and potassium carbonate (2 g) were heated under reflux in acetonitrile (50 ml)/ethanol (20 ml) for 20 hours. The solvent was then removed by evaporation in vacuo and the residue diluted with water and extracted with methylene chloride. The organic layer was dried (MgSO4) and evaporated to give an oil which was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated to give the title compound as an oil, yield 0.28 g.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15]O.[CH:18]1([N:21]2[C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[NH:23][C:22]2=[O:30])[CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[CH:18]1([N:21]2[C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N:23]([CH2:15][C:7]3[N:6]([CH2:5][CH2:4][CH2:3][CH:2]([F:17])[F:1])[C:14]4[C:9]([N:8]=3)=[N:10][CH:11]=[CH:12][CH:13]=4)[C:22]2=[O:30])[CH2:20][CH2:19]1
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Reactant: OCc1nc2ncccc2n1CCCC(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2nc3ncccc3n2CCCC(F)F)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a suspension of (1-(4,4-difluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 43-5 (470 mg, 1.9 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (431 mg, 2.3 mmol) and triphenylphosphine (613 mg, 2 3 mmol) in 14 ml dry THF was added (E)-diisopropyl diazene-1,2-dicarboxylate (0.6 ml, 2.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed with some diethyl ether to obtain the title product as a white powder (450 mg, 58%). m/z=399 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][C:11]([CH2:13][CH2:14][N:15]2[C@H:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:10][NH:9]1)C1C=CC=CC=1.CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[CH3:34][C:33]1[C:28]([C@H:16]2[CH2:17][CH2:18][CH2:19][C@@H:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:15]2[CH2:14][CH2:13][C:11]2[CH:12]=[N:8][NH:9][CH:10]=2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCC1=CNN(Cc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCc1cn[nH]c1
Temperature: 140 °C
Yield: 64.4 %

Procedure:
To a solution of (2′R,6′S)-1′-[2-(2-benzyl-1H-pyrazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.130 g, 0.288 mmol) in dry DMSO (0.70 mL) and THF (12 mL) was added 4 Å molecular sieve (˜1 g) pre-heated at 140° C., and KOtBu (0.600 g, 5.35 mmol). The solution was bubbled with air (pre-dried by passing through a NaOH column) at room temperature for 1 h. Saturated aqueous NH4Cl (20 mL) was then added. The mixture was filtered through a celite cake and the cake was washed with EtOAc throughout. The organic layer in the filtrate was collected, and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (200:10:1 CH2Cl2/CH3OH/NH4OH), affording a pale yellow solid (0.067 g, 64%) after precipitation from CH2Cl2/hexanes by evaporation under vacuum. 1H NMR (CDCl3) δ 1.60-1.85 (4H), 2.00-2.15 (m, 2H), 2.25-2.62 (m, 10H), 4.10-4.20 (m, 2H), 6.73 (s, 2H), 7.07-7.12 (m, 2H), 7.43 (d, 2H, J=7.2 Hz), 8.45 (s, br. 2H); 13C NMR (CD2Cl2) δ 19.02, 21.33, 25.61, 30.31, 50.86, 64.12, 118.85, 122.40, 132.22, 132.65, 138.78, 147.03, 160.46. ES-MS m/z 362 (M+H). Anal. Calcd. for C22H27N5.0.2H2O: C, 72.38; H, 7.56; N, 19.18. Found: C, 72.31; H, 7.70; N, 18.98.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[O:24]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25]1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:29][CH:26]2[CH2:27][CH2:28][O:24][CH2:25]2)[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: NC1CCOC1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCOC3)cc21
Temperature: 180 °C
Yield: 24.8 %

Procedure:
To a solution of Example A3 (2.0 g, 5.7 mmol) in NMP (10 mL) was added tetrahydro-furan-3-ylamine (1.5 g, 17.2 mmol) and DBU (1.7 g, 11.4 mmol). Nitrogen was bubbled through the mixture for 5 min and then it was heated in the microwave at 180° C. for 1 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(tetrahydrofuran-3-ylamino)-1,6-naphthyridin-2(1H)-one (0.57 g, 25% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.66 (s, 1H), 7.27 (d, J=6.4 Hz, 1H), 7.18 (d, J=11.2 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H), 6.33 (s, 1H), 5.31 (s, 2H), 4.46-4.42 (m, 1H), 4.08 (q, J=6.8 Hz, 2H), 3.89-3.81 (m, 2H), 3.75-3.69 (m, 1H), 3.55-3.52 (m, 1H), 2.22-2.17 (m, 1H), 1.83-1.79 (m, 1H), 1.20 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH:5]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:4]1)[CH3:2]>[Pd].C(O)C>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH:5]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC(N2CCOCC2)COc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CCN1CC(N2CCOCC2)COc2ccc(N)cc21
Yield: 87.3 %

Procedure:
9-Ethyl-7-morpholin-4-yl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (59 mg, 0.19 mmol) and 10% Palladium on Carbon (50% Wet) (25 mg) in Ethanol (10 mL) was shaken under an atmosphere of Hydrogen (40 psi) for 6 h. 9-Ethyl-7-morpholin-4-yl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamine (46 mg, 86%) was isolated following filtration and concentration. 1H-NMR (CDCl3): 6.64 (d, 1H, J=8.4 Hz), 6.06 (s, 1H), 6.00 (d, 1H, J=8.4 Hz), 4.28 (m, 1H), 4.12 (m, 1H), 3.69 (m, 5H), 3.23 (m, 3H), 2.95 (m, 1H), 2.66 (m, 4H), 1.19 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:22][C:21]=2[O:39][CH3:40])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:22][C:21]=2[O:39][CH3:40])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1COc1nn(Cc2ccccc2)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 245 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (0.23 g) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.03 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (0.26 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give {1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxybenzyl)oxy]-1H-pyrazol-4-yl}methanol as a colorless oil (0.52 g, yield 81%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.F[C:13](F)(F)[S:14](O)(=[O:16])=[O:15].CS(OS(C)(=O)=O)(=O)=O>>[CH3:13][S:14]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][C:2]([CH3:11])([CH3:1])[C:6]=2[CH:7]=1)(=[O:16])=[O:15]
Reactant: CC1(C)COc2ccccc21
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CS(=O)(=O)OS(C)(=O)=O
Product: CC1(C)COc2ccc(S(C)(=O)=O)cc21
Temperature: 135 °C
Yield: 119.7 %

Procedure:
A mixture of 3,3-dimethyl-2,3-dihydro-benzofuran (example 14c) (870 mg, 5.87 mmol), trifluoromethanesulfonic acid (0.1 mL, 1.17 mmol) and methanesulfonic anhydride (2.04 g, 11.74 mmol) was heated to 135° C. After reaching this temperature, the heater was removed and the mixture was cooled down to room temperature. The mixture was poured into a solution of ice-water. The aqueous layer was extracted twice with ethyl acetate and the organic combined extract was washed with water, an aqueous solution of sodium bicarbonate, brine, dried (MgSO4), filtered, and evaporated. The residue was chromatographed on silica gel (30% to 50% ethyl acetate in hexane) to afford 317 mg of 5-Methanesulfonyl-3,3-dimethyl-2,3-dihydro-benzofuran. 24% yield. 1H-NMR (300 MHz, CDCl3): 1.39 (s, 6H), 3.04 (s, 3H), 4.36 (s, 2H), 6.90 (d, J=8.2 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.74 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H).
Reaction SMILES: CC#N.[F:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.[Br:19]N1C(=O)CCC1=O.CCOC(C)=O>[Al]>[Br:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=2)=[N:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccnc(-c2cccc(F)c2)c1
Agent: [Al]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cccc(F)c2)ncc1Br
Temperature: 55 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
A MeCN (22 mL) solution of 2-(3-fluorophenyl)-4-methoxypyridine (2.21 g, 10.88 mmol) and N-bromosuccinimide (2.129 g, 11.96 mmol) in a 40-mL vial was wrapped in aluminum foil and stirred at 55° C. overnight. 22 h later, the reaction was cooled to rt, quenched with 1:1 sat. aq. NaHCO3:sat. aq. Na2S2O3 and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a brown oil. Column chromatography (50 g Snap Ultra column, 15% to 100% EtOAc/hept) afforded 5-bromo-2-(3-fluorophenyl)-4-methoxypyridine (0.420 g, 1.489 mmol, 13.69% yield) as a white amorphous solid. m/z (ESI) 282.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1O.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:32]1[CH:33]=[C:34]([C:37]([F:39])([F:40])[F:38])[CH:35]=[CH:36][C:31]=1[Cl:30]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: Cc1cccc(CO)c1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(COc2cc(C(F)(F)F)ccc2Cl)c1Br
Temperature: 25 °C

Procedure:
To a solution of (2-bromo-3-methylphenyl)methanol (0.5 g, 2.49 mmol), triphenylphosphine (1.31 g, 4.97 mmol) and 2-chloro-5-(trifluoromethyl)phenol (0.37 mL, 2.74 mmol) in DCM (12.4 mL) at 0° C. was added diethyl azodicarboxylate (1.97 mL, 4.97 mmol) and the reaction warmed to RT for 30 min. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-50% Hexene/EtOAc) to afford 2-bromo-1-((2-chloro-5-(trifluoromethyl)phenoxy)methyl)-3-methylbenzene as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:25][C:18]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:24]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccccc1
Reactant: Nc1ccccc1N
Solvent: CCO
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
In a 200 mL recovery flask were placed 4.5 g (15 mmol) of 1-(4-bromophenyl)-2-phenylethanedione, 1.8 g (17 mmol) of ortho-phenylenediamine, and 50 mL of ethanol. This solution was refluxed under nitrogen stream for 2.5 hours. After a predetermined time, the solution was cooled to room temperature, and the precipitated solid was collected by suction filtration. The collected solid was washed with ethanol; thus, 5.2 g of target white powder was obtained with a yield of 92%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.C([O-])C.[Na+].[CH2:15]([O:17][C:18](=[O:33])[CH:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:33])[C:19]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][C:4]=1[F:10])([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]
Reactant: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: Fc1cc(Br)ccc1CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCC(Cc1ccc(Br)cc1F)(C(=O)OCC)C(=O)OCC

Procedure:
4-bromo-2-fluoro-benzylbromide [76283-09-5] is reacted in ethanol with stoichiometric compounds of natrium ethanolate and octylmalonic acid diethylester to form 2-(4-bromo-2-fluoro phenyl)methyl-2-octyl malonic acid diethylester. After usual post-treatment and distillation a 50% aqueous potassium hydroxide solution is added to the methanolic solution and heated until the saponification has ended. After cooling sulfuric acid is added to adjust the pH to a value of 1-2. The 4-fold volume of water is added followed by multiple extraction of methyl-tert.-butylether. The combined organic phases are dried and the solvent is removed under vacuum, finally at 60° C. in the heating bath. The 2-(4-bromo-2-fluoro phenyl)methyl-2-octyl-malonic acid thus obtained after heating for several hours at 150-170° C. is decarboxylated to obtain 3-(4-bromo-2-fluoro phenyl)-2-octyl-propionic acid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>>[C:16]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[CH:18][C:19]([C:22]([N:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:23])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CCNc1ccccc1-2
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2ccccc2-c2ccccc21

Procedure:
As described for Example 26, 6,7-dihydro-5H-dibenz[b,d]azepine is reacted with [1,1'-biphenyl]-4-carbonyl chloride to give the product as a solid.
Reaction SMILES: [N+](C1C=C(O)C=CC=1)([O-])=O.[N+:11]([C:14]1[CH:30]=[CH:29][C:17]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[O:23][CH:24]=2)=[CH:16][CH:15]=1)([O-])=O.ClCC1OC(C(OC)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[NH2:11][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[O:23][CH:24]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc(COc2ccc([N+](=O)[O-])cc2)co1
Agent: COC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cccc(O)c1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(COc2ccc(N)cc2)co1
Yield: 101.8 %

Procedure:
Preparation of 4-(4-nitrophenoxymethyl)-2-methoxycarbonyl-furan 3-Nitrophenol (1.0 g, 7.19 mmole), methyl 5-(chloromethyl)-2-furoate (1.38 g, 7.90 mmole) and anhydrous K2CO3 (1.19 g, 8.60 mmole) in acetone (30 mL) were refluxed for 8 h. The reaction mixture was cooled and diluted with water. The resultant white solid was filtered, washed with water and air dried overnight to give 1.81 g (90%) of the desired product. 1H NMR (CDCl3): δ 7.86 (dd, 1H, J=2.3 and 8.2 Hz), 7.80 (t, 1H, J=2.3 Hz), 7.45 (t, 1H, J=8.2 Hz), 7.27 (dd, 1H, J=2.3 and 8.2 Hz), 7.17 (d, 1H, J=3.5 Hz), 6.58 (d, 1H, J=3.5 Hz), 5.13 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[C:18]1([CH:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1ccc(C2CCCN2)cc1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CCCC3c3ccccc3)cnc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 2-phenylpyrrolidine (21 mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature and concentrated to dryness. LC/MS showed the presence of the target compound and no starting material after 24 h. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a pale yellow solid. This solid as triturated in acetone, filtered, washed with acetone and dried to give the title compound (7 mg, 17%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ncc(-c3cccnc3)cc12
Reaction time: 1 h

Procedure:
To (3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (P-1399, R═H, 500 mg, 1.44 mmol) in dimethylformamide (26 mL) was added Dess-Martin periodane (674 mg, 1.59 mmol). The reaction was stirred for one hour and the reaction was poured into water. All solids were filtered and purified by silica gel column chromatography eluting with 3% methanol in dichloromethane to give the compound (536, 295 mg, 59%). MS (ESI) [M+H+]+=345.2.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14]>CO>[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11]([S:5][CH2:2][CH:3]=[CH2:4])=[C:12]([CH3:15])[C:13]=1[CH3:14]
Reactant: C=CCS
Reactant: COc1nnc(Cl)c(C)c1C
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OC)c(C)c1C

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.73 g(0.01 mol) of 3-methoxy-4,5-dimethyl-6-chloropyridazine obtained from Preparation 5. The reaction solution was refluxed for one hour and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.