Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]=[C:11]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[C:10]([CH3:26])=[CH:9][C:8]=2[C:7]([CH3:28])([CH3:27])[CH2:6][CH:5]=1)([CH3:3])[CH3:2].[CH:29](=O)[CH3:30]>>[CH2:29]([N:14]([C:11]1[C:10]([CH3:26])=[CH:9][C:8]2[C:7]([CH3:28])([CH3:27])[CH2:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[CH:12]=1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1)[CH3:30]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3C(C)C)cc1
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)(C)CC=C3C(C)C)cc1
Yield: 50.1 %

Procedure:
Following General Procedure D, ethyl 4-[(8-isopropyl-3,5,5-trimethyl-5,6-dihydronaphthalen-2-yl)amino]benzoate (Compound 17, 0.48 g, 1.28 mmol) was reacted with acetaldehyde (0.9 mL, 12.8 mmol) to give 0.26 g (50%) of the title compound as a clear oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:7][CH:8]=1.[I-].[Li+].O.Cl>N1C(C)=CC(C)=CC=1C>[OH:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCC#Cc1cccc(OC)c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCCC#Cc1cccc(O)c1

Procedure:
1-(3-Methoxyphenyl)-oct-1-yne, (6.50 g, 0.03M), was dissolved in 2,4,6-collidine, (100 ml), and anhydrous lithium iodide (20.08 g, 0.15M), added. The reaction was stirred under nitrogen at reflux temperature for 48 h, then cooled and poured intro water, (500 ml), and acidified with dilute hydrochloric acid. The product was extracted into ethyl acetate, (twice), and the organic phases combined, washed with water (twice) and dried, (MgSO4). Evaporation of the solvent in vacuo yielded the crude product as a brown oil, which was purified by chromatography on silica gel, eluting with dichloromethane/n-hexane [1:1] to chloroform. 5.40 g (90%) of product was collected as a colourless oil. νmax (film) 1580, 1590, 1605, 2230 (weak) 3400 cm-1 ; δ(CDCl3) 0.85 (3H, distorted t, terminal CH3), 1.39 (8H, m, alkylene chain), 2.32 (2H, t, J 6 Hz, acetylenic CH2), 4.77 (1H, s, OH, exchanged with D2O), 6.78 (2H, m, aromatics), 7.02 (2H, m, aromatics).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:43])[CH2:14][N:15]1[CH2:34][C@@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)[C@:17]2([N:21]([CH3:22])[C:20](=[O:23])[N:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:18]2=[O:32])[CH2:16]1)(C)(C)C>C(Cl)Cl>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([C@H:33]2[C@:17]3([N:21]([CH3:22])[C:20](=[O:23])[N:19]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:18]3=[O:32])[CH2:16][N:15]([CH2:14][C:13]([OH:43])=[O:12])[CH2:34]2)=[CH:40][CH:39]=1)#[N:42]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(=O)OC(C)(C)C)C[C@H]2c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(=O)O)C[C@H]2c1ccc(C#N)cc1

Procedure:
Trifluoroacetic acid (4.8 ml, 59 mmol) was added to a solution of Example 63 (1.56 g, 2.95 mmol) in DCM (40 ml). The solution was refluxed for 3 h. It was then concentrated in vacuo and partitioned between EtOAc/aqueous NH4OH. The aqueous layer was acidified to pH=2 with SO2. The white precipitate was separated by filtration. The aqueous layer was extracted with DCM and concentrated to give white crystals which where combined with the precipitated solid to give, after drying, the above-titled compound (1.04 g), mp=220° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([I:11])[C:5]([CH3:12])=[CH:4][CH:3]=1.[F:13]C1C(C)=C(C=CC=1)N>>[F:13][C:4]1[CH:3]=[CH:2][C:7]([C:8]([OH:10])=[O:9])=[C:6]([I:11])[C:5]=1[CH3:12]
Reactant: Cc1c(N)cccc1F
Reactant: Cc1ccc(F)c(C(=O)O)c1I
Product: Cc1c(F)ccc(C(=O)O)c1I

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-2-iodo-3-methylbenzoic acid in Example A352 using 3-fluoro-2-methylaniline. MS (ESI) 281 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH2:14])=[C:12]([C:15]2[CH:16]=[N:17][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:19]=2[C:20]([F:23])([F:22])[F:21])[O:11][N:10]=1.O.[CH:32](O)=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH:14][CH:32]=[O:33])=[C:12]([C:15]2[CH:16]=[N:17][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:19]=2[C:20]([F:21])([F:23])[F:22])[O:11][N:10]=1
Reactant: O=CO
Reactant: Nc1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Solvent: O
Product: O=CNc1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4-amine (example B-36) (40 mg, 0.1 mmol) was dissolved in formic acid (3 mL). The mixture was stirred at room temperature overnight. To the reaction mixture was added water. The resulting precipitate was collected, washed with water and dried under vacuum. The product was purified by pTLC (EE/PE 2:1) to give 32 mg of the desired product (example B-48) (yield 75%). Result of LC/MS MH+: 484.82; NMR (CDCl3): 6.63 (t, 1H), 7.22 (m, 1H), 7.38-7.59 (m, 6H), 8.02 (s, 1H) 8.22 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[N:11]([C@H:22]([C:24]3[CH:41]=[CH:40][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:42][C:43]([F:59])([F:58])[O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[C:50](B(O)O)[CH:49]=[CH:48]2>C(COC)OC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:50]3[CH:49]=[CH:48][C:47]4[C:52](=[CH:53][CH:54]=[C:45]([O:44][C:43]([F:42])([F:59])[F:58])[CH:46]=4)[CH:51]=3)[N:11]([C@H:22]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:40][CH:41]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OB(O)c1ccc2cc(OC(F)(F)F)ccc2c1
Reactant: C[C@@H](c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1OS(=O)(=O)C(F)(F)F
Solvent: COCCOC
Product: C[C@@H](c1ccc(C(=O)NCCC(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2cc(OC(F)(F)F)ccc2c1
Temperature: 100 °C

Procedure:
tert-Butyl N-{4-[(1S)-1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate (10 mg, 0.016 mmol), 6-trifluoromethoxy-2-naphthylboronic acid (5.1 mg, 0.02 mmol), and TEA (14 ul, 0.1 mmol) were dissolved in dimethoxyethane (0.5 ml) and deoxygenated by vacuum-N2 fill cycles. The catalyst Pd(PPh3)4 (2 mg, 10% mol) was added and the mixture was deoxygenated again before heated in microwave reactor to 100° C. for 10 min. The mixture was quenched with 1.5 ml of CH3CN:H2O (3:1, with 5% TFA) and product separated through reverse phase preparative HPLC. The collected product was treated with 1 ml of TFA-DCM (1:2) for 30 min, and the residue lyophilized to give N-[4-((1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine as fine powder. NMR (500 MHz, DMSO-d6) δ: 1.91 (d, J=7.0 Hz, 3H); 2.46 (t, J=7.0 Hz, 2H); 3.41 (q, J=7.0 Hz, 2H); 5.78 (q, J=7.0 Hz, 1H); 7.21 (d, J=8.4 Hz, 2H); 7.22 (s, 1H); 7.57 (t, J=1.9 Hz, 1H); 7.58˜7.60 (m, 2H); 7.72 (d, J=8.4 Hz, 2 H); 7.94 (d, J=1.9 Hz, 2H); 8.04 (br s, 1H); 8.06 (br s, 1H); 8.09 (d, J=9.1 Hz, 1H); 8.13 (d, J=8.6 Hz, 1H); 8.44 (t, J=5.5 Hz, 1H). MS C32H24Cl2F3N3O4 Cald: 641.11; Obsd (M+1): 642.22.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([CH:20]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)[CH3:21])[CH:18]=O.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([CH:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[CH3:21])=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: CC(c1ccc2ncccc2c1)C(Cl)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(c1ccc2ncccc2c1)c1cnc2ncc(-c3ccc(Br)c(F)c3)nn12
Temperature: 110 °C
Yield: 60 %

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (100.0 mg, 0.3716 mmol, prepared as described for Example 7, Steps 1-5) and 2-chloro-3-quinolin-6-ylbutanal (0.10 g, 0.44 mmol, prepared as described for Example 122, Steps 1-4) in isopropyl alcohol (3 mL) was heated at 110° C. for 48 h. The mixture was adjusted to pH 9 by adding triethylamine. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel with MeOH in methylene chloride (0-8%) to afford the desired product (0.10 g, 60%). LCMS: (M+H)=448/450.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[N:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:9]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[N:10]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:9]=1
Reactant: COC(=O)c1ccc2c(-c3ccccc3Cl)nn(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-n2nc(-c3ccccc3Cl)c3ccc(C(=O)O)cc32)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a solution of methyl 3-(2-chlorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylate (0.25 g, 0.66 mmol) in methanol (1.5 mL) and tetrahydrofuran (2.9 mL) was added sodium hydroxide (1.0 M, 3.98 mL, 3.98 mmol). The mixture was heated to 50° C. and stirred for 1.5 h. The mixture was cooled to ambient temperature and 1.0 M hydrochloric acid (ca 4.0 mL) was added until pH<3. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1×7 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.24 g): LC-MS [M+1]=363.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH:19][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:15]
Reactant: CCN(CC)CCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (500 mg, 2.35 mmol), 2-diethylaminoethylamine (300 mg, 0.363 mL, 2.59 mmol) and triethylamine (262 mg, 0.359 mL, 2.59 mmol) in CH2Cl2 (7 mL) was stirred at room temperature for 18 hours. The mixture is then diluted with dichloromethane, and washed with brine. The organic layers is dried (MgSO4) and the solvent is removed under reduced pressure to yield the title compound, which is used as such for the next step.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:37][CH2:38][CH2:39][CH2:40][OH:41]>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCCCO
Product: Cc1cc(F)ccc1-c1cc(NCCCO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 87.5 %

Procedure:
A mixture of 2.0 g (3.8 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 5.6 g (75 mmol) 3-amino-1-propanol was heated at 180° C. under microwave irradiation for 40 min. Dilution with water was followed by extraction with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash chromatography gave 1.9 g (87%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:23]([Si:27]([CH3:47])([CH3:46])[O:28][CH2:29][CH:30]([C:37]([CH3:45])([CH3:44])[O:38][SiH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31]OS(C)(=O)=O)([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O.O>[C:23]([Si:27]([CH3:46])([CH3:47])[O:28][CH2:29][CH:30]([C:37]([CH3:45])([CH3:44])[O:38][SiH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)C(C)(C)O[SiH2]C(C)(C)C)c(C=O)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Ex-64A: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (10.0 g, 42.7 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (11.8 g, 85.4 mmol) and the resulting yellow slurry was heated to 80° C. Once at 80° C., methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propyl ester (Ex-50A, 19.5 g, 46.9 mmol) was added dropwise and the reaction was stirred for an additional 24 h at 80° C. and cooled to room temperature. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers was sequentially washed with a saturated sodium bicarbonate solution (1×150 mL), water (1×150 mL), and brine (1×150 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (100% ethyl acetate to 10% ethyl acetate/hexanes) gave 19.0 g (81%) of 2-[3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-4-methoxy-5-thiophen-2-yl-benzaldehyde as an off-white solid, mp 91–92° C. 1H-NMR (300 MHz, CDCl3) δ 10.37 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.6, 1.2 Hz), 7.29 (d, 1H, J=5.1 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.19 (d, 2H, J=6.0 Hz), 3.99 (s, 3H), 3.72–3.82 (m, 4H), 2.28 (pentet, 1H, J=6.0 Hz), 0.88 (s, 18H), 0.048 (s, 12H). MS (EI) m/z=550 ([M]+, 100%). Anal. Calcd. for C28H46O5SSi2: C, 61.05; H, 8.42; S, 5.82. Found: C, 61.20; H, 8.74; S, 5.69.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].CCN(CC)CC.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>CC(C)=O>[N+:27]([C:24]1[CH:23]=[C:22]([N+:30]([O-:32])=[O:31])[CH:21]=[CH:26][C:25]=1[O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(Br)c([N+](=O)[O-])c1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a suspension of 2-hydroxyisoindoline-1,3-dione (20.0 g, 0.12 mol) in acetone (400 mL) was added Et3N (14.9 g, 0.15 mol), the mixture was stirred at room temperature until it became a homogeneous solution, then 1-bromo-2,4-dinitrobenzene Y-1 (30.2 g, 0.12 mol) was added. The reaction was stirred at room temperature for 3 h, then poured into ice-water, the resulting precipitate was filtered and washed three times with cold MeOH, dried in vacuum to afford the title compound (38.1 g).
Reaction SMILES: [CH3:1][Mg]Cl.[F:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15](=[O:17])[CH3:16].[NH4+].[Cl-]>CCCCCCC.C1COCC1>[F:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]([OH:17])([CH3:1])[CH3:16]
Reactant: COc1ccc(C(C)=O)c(F)c1OC
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(F)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methylmagnesium chloride (3M in THF, 1.74 mL, 5.22 mmol) was added dropwise to a stirred solution of 1-(2-fluoro-3,4-dimethoxyphenyl)ethanone (J. Chem. Soc. Perkin Trans. 2 1994, 547-555) (646 mg, 3.26 mmol) in heptane (3.1 mL) and THF (1.4 mL) at −20° C. under N2. The reaction was allowed to warm to room temperature and was stirred for 4 h. 50% Saturated NH4Cl (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol as a colorless oil. LCMS calc.=197.1; found=197.1 (M−OH)+. 1H NMR (600 MHz, CDCl3) δ 7.14 (t, J=8.8 Hz, 1H), 6.61 (dd, J=8.8, 1.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.56-2.25 (br s, 1H), 1.58 (s, 6H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([O-:21])=O)[NH:16][C:13]3=[N:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C(N(CC)C(C)C)(C)C>>[N:45]1([C:19]([C:17]2[NH:16][C:13]3=[N:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=[C:12]3[CH:18]=2)=[O:21])[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: O=C([O-])c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(OCCCN3CCCC3)cnc2[nH]1)N1CCOCC1
Yield: 55 %

Procedure:
The title compound was synthesized in analogy to example 1 from lithium 5-(3-pyrrolidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, morpholine and N,N-diisopropylethylamine to give the desired product as a light yellow solid (55%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][C:16](B(O)O)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.C([O-])([O-])=O.[K+].[K+]>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>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([CH3:10])[N:12]=[CH:13]3)[N:7]=1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: COc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccnc(-c2ccc3c(cnn3C)c2)n1
Temperature: 185 °C

Procedure:
2-chloro-4-methoxypyrimidine (100.0 mg, 0.69 mmol), 1-methyl-1H-indazol-5-ylboronic acid (133.9 mg, 0.76 mmol), Pd(PPh3)4 (79.9 mg, 0.069 mmol), and K2CO3 (286.8 mg, 2.075 mmol) were taken in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed toluene (2.5 mL) and DMF (0.28 mL). The reaction mixture was heated in a microwave at 185° C. for 30 min, diluted with ethyl acetate, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.56 (dd, J=8.9, 1.3 Hz, 1H), 8.52 (d, J=5.8 Hz, 1H), 8.10 (s, 1H), 7.47 (d, J=8.9 Hz, 1H), 6.64 (d, J=5.8 Hz, 1H), 4.14 (s, 3H), 4.12 (s, 3H). LCMS-ESI+: calc'd for C13H13N4O: 241.1 (M+H+); Found: 241.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[H][H]>CCO.Cl.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: C=CCC(C(=O)O)c1ccc(C)c(-c2ccccn2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCC(C(=O)O)c1ccc(C)c(-c2ccccn2)c1
Yield: 59.6 %

Procedure:
4-Methyl-3-(2-pyridyl)phenyl-pent-4-enoic acid (0.5 g, 1.87 mmol) was dissolved in EtOH (15 ml) and 6N HCl (0.15 ml). 10% Palladium on carbon (0.08 g) was added and the reaction mixture was stirred under a balloon of hydrogen gas overnight. Then, additional 10% palladium on carbon (0.09 g) and 6N HCl (0.2 ml) were added and the reaction was stirred under a balloon of hydrogen gas for an additional 6 h. The reaction mixture was then filtered through a pad of Celite, azeotroped with toluene (40 ml) and was suspended in water (3 ml). Aqueous sodium hydroxide (1 M) was then added dropwise until the pH was adjusted to 7. The aqueous layer was then extracted with chloroform 2 times and the combined organics were dried with magnesium sulfate, concentrated in vacuo, and triturated with hexanes/Et2O to yield a white solid (0.3 g, 60%): MS ES(+) 270.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:32][C:33]1[S:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[C:36]([CH3:38])[N:37]=1>>[CH3:32][C:33]1[S:34][C:35]([S:39]([N:5]2[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]2)(=[O:41])=[O:40])=[C:36]([CH3:38])[N:37]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(C)c(S(=O)(=O)n2cc(C=O)c(C)c2-c2ccccc2)s1

Procedure:
By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and (2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl chloride (275 mg), the title compound was obtained as an oil (yield 27.8 mg, 8%).
Reaction SMILES: [I-].[CH2:2]([N+:4]1(C)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH3:3].[CH:12]1(N)CC1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH:2]1([N:4]2[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[CH2:3][CH2:12]1
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCN(C2CC2)CC1
Temperature: 78 °C
Yield: 53 %

Procedure:
1-Ethyl-1-methyl-4-oxopiperidinium iodide (Journal of the Chemical Society (1949), 708-15; 15 g, 55.74 mmol) was added to cyclopropylamine (Aldrich; 19.3 mL, 278.69 mmol) in toluene (150 mL). Sodium hydrogen carbonate (469 mg, 5.57 mmol) in water (21 mL) was added and the mixture heated at 78° C. over night. The mixture was cooled and the layers separated. The aqueous layer was extracted (×2) with ethyl acetate and the combined organics washed with brine, dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeOH/DCM) gave the title compound (4.1 g, 53%) as a pale brown liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(O)ccc2c2oc3ccccc3c12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(OCC3CO3)ccc2c2oc3ccccc3c12
Temperature: 55 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
In N,N-dimethylformamide was dissolved 10.0 g of 3-hydroxy-5H-benzofuro[3,2-c]quinolin-6-one, and to the solution were added 28.0 g of epibromohydrin and 5.5 g of potassium carbonate. The mixture was stirred at 55° C. for 3 hours. Into the reaction mixture was poured water, and precipitates were collected by filtration, washed with water, and dried to obtain 11.8 g of 3-(2,3-epoxypropoxy)-5H-benzofuro[3,2-c]quinolin-6-one.