Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])([O-])=O.[K+].[K+].CS(C)=O>C(OCC)C>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2F)CC1
Temperature: 120 °C
Yield: 25.5 %

Procedure:
To a sealed vessel were added 2-chloro-3-fluoro-5-bromopyridine (1) (10.50 g, 50 mmol), N-Boc-piperazine (9.30 g, 50 mmol), K2CO3 (8.28 g, 60 mmol), and DMSO (40 mL). The resulting mixture was heated at 120° C. for 12 hrs, then cooled down and diluted with ethyl ether (200 mL). The solution was washed with water (80 mL×2), brine (100 mL), dried, and concentrated. The residue was suspended in hexanes (150 mL) and the precipitation was formed. After removed the solid, the remaining solvents which contained the desired product were evaporated and subjected to chromatography column eluted with ethyl acetate/hexanes (0-10%) to afford 4.60 g (26%) of 11 as a colorless oil which was slowly solidified to be white solid. 1H NMR (CDCl3) δ 1.48 (9 H, s), 3.43 (4 H, m), 3.54 (4 H, m), 7.39 (4 H, dd, J=1.96, 12.04 Hz), 8.05 (1 H, m). LC/MS (M+1) 361.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:12][O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 30.5 %

Procedure:
A mixture of (4-nitro-phenyl)-methanol (3.0 g, 19.6 mmol), potassium carbonate (3.9 g, 28.1 mmol), acetonitrile (100 ml), and iodomethane (11 ml, 176 mmol) was heated at 50° C. for 48 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with hexane-dichloromethane (1:1 followed by 1:2) to yield 1-methoxymethyl-4-nitro-benzene (1.0 g, 31% yield).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12].[N:23]1([C:30]([CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([N:26]2[CH2:27][CH2:28][CH2:29][N:23]([C:30]([CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])[CH2:24][CH2:25]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(C1CCOCC1)N1CCCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1csc(N)n1
Solvent: ClCCl
Product: CC(C)(C)c1csc(NC(=O)N2CCCN(C(=O)C3CCOCC3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
To a solution of 62.8 mg (0.4 mmol) of 4-tert-butyl-thiazol-2-ylamine in DCM (2 mL) were added 98 mg (0.6 mmol) of 1,1′-carbonyldiimidazole and the reaction was stirred for 4 h at room temperature. A solution of 354 mg (0.8 mmol) of [1,4]diazepan-1-yl-(tetrahydro-pyran-4-yl)-methanone (triple trifluoroacetic acid salt, prepared according to Method L, above) in DCM (3 mL) was added and the reaction stirred for 18 h at room temperature. The reaction mixture was washed with 10% aqueous citric acid solution (5 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by mass-triggered preparative LCMS to afford 27.6 mg of 4-(tetrahydro-pyran-4-carbonyl)-[1,4]diazepane-1-carboxylic acid (4-tert-butyl-thiazol-2-yl)-amide.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([SH:23])[CH3:22].Cl>CN(C)C=O>[CH2:21]([S:23][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:22]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 9.25 mmol ethanethiol and the mixture was stirred at 90° C. for 30 min. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid which was used in the next step without further purification (yield 99%). MS (m/e): 259.0 ([M−H]−, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-])=O)[CH:22]=3)[C:17]2=[O:29])=[O:8])=[CH:5][CH:4]=1.C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH2:26])[CH:22]=3)[C:17]2=[O:29])=[O:8])=[CH:30][CH:31]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3ccc(N)cc3C2=O)cc1
Yield: 57.8 %

Procedure:
A solution of N-(4-methoxybenzoyl)-2-(5-nitro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)benzeneamine (1.11 g, 2.66 mmol) and 5% palladium-on-carbon (1.21 g) in 2:1 ethanol:ethyl acetate (200 mL) was placed under 1 atmosphere of hydrogen. After consumption of the starting material (about 2-3 h), the mixture was filtered through diatomaceous earth and the resulting filtrate concentrated in vacuo. Recrystallization from hexanes/ethyl acetate yielded 596 mg (58%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38]([CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:40])=[O:39]>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:45][CH2:46]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 735.4 [(M+H)+]
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[CH2:12](Cl)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[CH:13]=[CH2:12]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: C=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C(=O)c2ccccc21
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A 500 mL flask is charged with isatin (50 g, 339 mmol), allyl chloride (33.8 g, 441 mmol), potassium carbonate (93.9 g, 679 mmol), and DMF (100 mL). The mixture is stirred at 70° C. for 14 hours (complete conversion by TLC), and then diluted with DMF. After filtration over a pad of cellite and removal of the solvent, the product remained as red crystals (68 g) which are used directly in the next step. 1HNMR (CDCl3, 300 MHz) δ 4.34 (dtr, 1H, 3J=5.3 Hz, 4J=1.8 Hz, NCH2CHC═CH2); 5.27 (dm, 1H, 3J=10.3 Hz, NCH2CH═CHcls); 5.30 (d m, 1H, 3J=17.0 Hz, NCH2CHC═CHtrans); 5.82 (ddtr, NCH2CHC═CH2); 6.87 (d, 1H, 3J=7.9 Hz, H-7); 7.09 (br tr, 1H, 3J=7.3 Hz, H-5); 7.55 (dtr, 1H, 3J=8 Hz, H-6); 7.57 (dm, 1H, 3J=7.3 Hz, H-4). 13C-NMR (CDCl3, 75 MHz) δ 42.82 (NCH2); 111.11 (C-7); 117.77 (C-9); 118.80 (CH═CH2); 123.96 (C-5); 125.50 (C-4); 130.51 (CH═CH2); 138.48 (C-6); 150.96 (C-8); 158.02 (C-2); 183.29 (C-3).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.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>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A stirred solution at room temperature of methyl 4-bromobenzoate (8.84 g, 41.11 mmol), Pd(PPh3)2Cl2 (840 mg, 1.20 mmol) and Cul (455 mg, 2.39 mmol) in anhydrous THF (200 ml) was saturated with nitrogen for 15 min. Then, the solution under nitrogen was cooled down at 0° C., and trimethylsilylacetylene (7.2 ml, 50.91 mmol) and triethylamine (22 ml, 157.8 mmol) were added successively. The reaction mixture was allowed to warm up at room temperature. After 2 h, Pd(PPh3)2Cl2 (100 mg) and Cul (80 mg) and trimethylsilylacetylene (0.5 ml) were added again, and the reaction mixture was stirred overnight. Then, the reaction mixture was diluted with AcOEt and successively washed with a saturated aqueous solution of NH4Cl and brine, dried over MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane:5/95□10/90) to afford the title compound XXXI (9.05 g, 38.95 mmol, 94% yield) as a yellow sticky solid. 1H NMR: (400 MHz, CDCl3) δ (ppm): AB system (δA=7.67, δB=7.22, JAB=8.5 Hz, 4H), 3.63 (s, 3H), 0.00 (s, 9H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)N)=[CH:5][CH:4]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH2:11][CH2:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:31]3[CH2:32][CH2:33][N:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:36])([F:20])[F:35])[CH:23]=4)[CH2:29][C:30]=3[C:5]=2[CH:4]=1
Reactant: Cc1ccc(CCN(N)c2ccc(Cl)cc2)cn1
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(c2cccc(C(F)(F)F)c2)CC3)cn1
Yield: 8.5 %

Procedure:
To a stirred solution of N-(4-Chloro-phenyl)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-hydrazine hydrochloride (0.13 g, 0.5 mmol) in absolute ethanol (5 mL) was added 1-(3-Trifluoromethyl-phenyl)-piperidin-4-one (0.122 g, 0.5 mmol) at RT and then refluxed for 1 h. After completion (TLC), ethanol was evaporated. The crude was purified by preparative HPLC to provide desired compound as brown colored solid (0.02 g, 10% yield) 8-Chloro-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2-(3-trifluoromethyl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.020 g, 0.0425 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0053 g, 0.0425 mmol) in 1.5 mL THF was added and stirred for 30 min at RT. Precipitate was filtered and dried to give oxalate salt as brown solid (0.01 g, 43% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.C1COCC1.[NH2:15][C:16]1[C:17]([C:38](N(OC)C)=[O:39])=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH:23]=2)=[CH:20][N:21]=1>O>[NH2:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[C:28]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])=[N:18][C:17]=1[C:38]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:39]
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)c1nc(-c2cccc(C(=O)NCc3ccccc3)c2)cnc1N
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(-c2cccc(C(=O)NCc3ccccc3)c2)nc1C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
3-Fluorophenylmagnesium bromide (1.5 mL of a 0.5 M solution in TBF, 0.75 mmol) was added dropwise to a THF (10 mL) solution of 3-amino-6-{3-[(benzylamino)carbonyl]phenyl}-N-methoxy-N-methylpyrazine-2-carboxamide (0.10 g, 0.25 mmol) at 0° C. under N2. The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was diluted with water and extracted 3× with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was separated by preparative HPLC and lyophilized to give a yellow solid (4 mg, 4% yield). 1H NMR (400 MHz, d6-DMSO): δ 9.10 (t, 1H), 9.05 (s, 1H), 8.42 (bs, 1H), 8.01 (m, 2H), 7.86-7.80 (m, 2H), 7.74 (d, 1H), 7.57-7.51 (m, 2H), 7.47-7.43 (m, 2H), 7.38-7.32 (m, 2H), 7.28-7.24 (m, 2H), 6.47-6.59 (m, 1H), 4.50 (d, 2H). MS (EI) for C25H19FN4O2: 427 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[Cl:62])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[Cl:62])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2Cl)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 95 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(2-chloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow solid foam was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 127 mg (90%) of a white solid. MS (ISP) 445.4 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[O:15][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]=2[CH:8]=1)[CH3:5].[C:16]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:5][N:4]([CH2:6][C:7]1[O:15][C:10]2[CH2:11][N:12]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=1)[CH3:3]
Reactant: CN(C)Cc1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccccc1C(=O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.228 g (0.900 mmol) of the above N,N-dimethyl-(4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-ylmethyl)amine dihydrochloride, 0.24 g (1.1 mmol) of 2-benzoylbenzoic acid and 0.50 ml (3.6 mmol) of triethylamine in 30 ml of dichloromethane, 0.22 g (1.35 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (chloroform to chloroform/methanol=25/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25]OS(C)(=O)=O)=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][N:32]([CH2:33][CH2:34][OH:35])[CH3:31])=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: CS(=O)(=O)OCCCC#Cc1cc2c(cc1F)N(C(=O)Oc1ccc(Cl)cc1)CC2
Product: CN(CCO)CCCC#Cc1cc2c(cc1F)N(C(=O)Oc1ccc(Cl)cc1)CC2

Procedure:
In analogy to example 16.10, 6-Fluoro-5-(5-methanesulfonyloxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester and 2-(methylamino)ethanol were converted to yield 6-Fluoro-5-{5-[(2-hydroxy-ethyl)-methyl-amino]-pent-1-ynyl}-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as a colorless oil, MS: 430 (M, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-:21].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:21][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1O
Reactant: [OH-]
Reactant: CCCCCCCCBr
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCOc1ccc(C(=O)O)cc1Cl

Procedure:
In 40 ml of ethanol were dissolved 10 g of 3-chlorohydroxybenzoic acid and 8 g of octyl bromide, and 40 ml a 2N aqueous solution of potassium hydroxide was added to the solution and the mixture was refluxed for 6 hours. The solution was made acidic and the precipitated crystal was recovered and recrystallized from an ethanol/water mixed solvent to obtain 9.5 g of 3-chloro-4-octyloxybenzoic acid.
Reaction SMILES: [CH3:1]C(C)=O.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8][CH:7]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O>[CH3:1][O:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:20][CH3:17])=[CH:7][CH:8]=1
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(O)c2ccccc12
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(OC)c2ccccc12

Procedure:
To one liter of acetone were added 50.0 g (0.31 mol) of 1,4-dihydroxynaphthalene. To the resulting solution then were added 95.0 g (0.69 mol) of powdered potassium carbonate and 65 ml (0.69 mol) of dimethyl sulfate. The resulting mixture was stirred at reflux for 18 hours after which it was diluted with two liters of water and then extracted with methylene chloride. The organic extracts were combined,.dried over sodium sulfate, and evaporated in vacuo to give a black oil. The oil was distilled in vacuo to give 12.5 g of 1,4-dimethoxynaphthalene as an orange crystalline solid. b.p. 155° C. at 5 mm Hg.
Reaction SMILES: CS(O)(=O)=O.[N:6]1([C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[O:23]1[CH:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1.C[O-].[Na+]>CO>[OH:23][CH:25]([CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:24][N:9]1[CH2:10][CH2:11][N:6]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH2:7][CH2:8]1
Reactant: CS(=O)(=O)Nc1ccc(N2CCNCC2)cc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(N2CCN(CC(O)COc3ccccc3)CC2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Suspend a mixture of 20.0 g (56.9 mmol) of N-[4-(piperazin-1-yl)phenyl]methanesulfonamide methanesulfonate, 7.68 mL (56.9 mmol) of 1,2-epoxy-3-phenoxypropane and 3.07 g (56.9 mmol) of sodiummethoxide in 800 mL of 90% aqueous methanol and warm to 60° C. for 18 h. After 18 h, filter the precipitate and wash this precipitate with 100 mL of water and 100 mL of methanol. Suspend this solid precipitate in 500 mL of methanol and reflux for 1 h. After 1 h, cool the suspension to room temperature and filter to obtain the title compound.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])=O.[NH2:28][C:29]([NH2:31])=[O:30].Cl>CCO>[OH:27][C:21]1[CH:20]=[CH:19][C:18]([CH:16]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:31][C:29](=[O:30])[NH:28]2)=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2ccc(O)c(C(=O)O)c2)N1
Yield: 10.1 %

Procedure:
To a mixture of 1,2-diphenylethanone (200 mg, 1.03 mmol), 5-formyl-2-hydroxybenzoic acid (203 mg, 1.22 mmol), and urea (184 mg, 3.06 mmol) in anhydrous EtOH was added concentrated HCl solution (105 mg, 1.03 mmol). The reaction was refluxed for three days. The reaction mixture was concentrated, and purified by column chromatography and preparative HPLC to give Compound 86 as an off-white solid (40 mg, yield 10.2%). 1H NMR (DMSO-d6 400 MHz): δ 11.20 (s, 1H), 8.63 (s, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.42-7.50 (m, 2H), 7.13-7.28 (m, 5H), 6.90-7.00 (m, 4H), 6.75 (d, J=6.4 Hz, 2H), 5.10 (d, J=2.4 Hz, 1H); MS (ESI): m/z 387.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26].Cl>C(#N)C>[CH2:25]([N:15]1[CH2:16][CH2:17][CH:12]([C:4]2[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH3:26]
Reactant: CCI
Reactant: CS(=O)(=O)c1cc(F)cc(C2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cc(F)cc(S(C)(=O)=O)c2)CC1

Procedure:
Preparation according to Example 1: 4-[3-fluoro-5-(methylsulfonyl)phenyl]piperidine (0.4 g, 1.55 mmol), acetonitrile (5 ml), potassium carbonate (0.42 g, 3.0 mmol), 1-iodoethane (0.147 ml, 1.55 mmol). Yield: 0.28 g (63%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 176-178° C. MS m/z (relative intensity, 70 eV) 285 (M+, 15), 284 (16), 271 (16), 270 (bp), 84 (15).