Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:6][CH2:5][CH:3]2[CH2:4][O:1][CH2:2]2)=[CH:12][CH:11]=1
Reactant: OCC1COC1
Reactant: Fc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2COC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.3 %

Procedure:
To a solution of oxetan-3-ylmethanol (1.00 g, 11.3 mmol) in DMF (10 mL) was added NaH (300 mg, 13.6 mmol) at 0° C. The mixture was then stirred at 0° C. for 10 min. 1-Bromo-4-fluorobenzene (2.30 g, 13.6 mmol) was added to the solution. The mixture was stirred at 90° C. for 2 h. The mixture was partitioned between water and EtOAc (30 mL×3). The combined organics was dried and concentrated to give the title compound (420 mg, 15% yield) as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.[OH-].[K+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([CH3:36])[C:28]=1[S:29]([CH2:32][N+:33]([O-:35])=[O:34])(=[O:31])=[O:30])[NH2:25].Cl>O1CCCC1.O>[CH3:36][C:27]1[CH:26]=[C:24]([NH:25][S:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:23]=[C:22]([CH3:21])[C:28]=1[S:29]([CH2:32][N+:33]([O-:35])=[O:34])(=[O:31])=[O:30]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
1.33 ml (16.4 mmol) of pyridine, dried over potassium hydroxide, and 2.54 g (12.3 mmol) of 4-methoxybenzenesulphonyl chloride are successively added to a solution, maintained under a nitrogen atmosphere, of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 40 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 24 h at room temperature and is then maintained at 40° C. for 1 h, after which it is poured into a mixture of water and ice. The aqueous solution obtained is brought to pH 1 by addition of 1N hydrochloric acid and is extracted with methylene chloride. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and recrystallization from a mixture of hexane and ethyl acetate, to give 1.1 g (33%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-4-methoxybenzenesulphonamide.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1Cl)=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:9])[CH3:6].O>CN(C)C=O>[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[N:1]=[N+:2]=[N-:3])=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:9])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1N=[N+]=[N-]
Reaction time: 18 h

Procedure:
Sodium azide (0.62 g; 0.009 M) was suspended in a solution of ethyl-4,7-dichloroquinoline-3-carboxylate E. F. Elslager, et al., J. Med. Pharm, Chem, 5, 550 (1962) (1.75 g; 0.006 M) in dry dimethyl formamide (20 ml) and this mixture stirred at ambient temperatures. After 18 hr. the mixture was poured into reapidly stirred water (200 ml), the resultant precipitate filtered off, dried at the pump and then recrystallised from ethanol (8 ml/g), 1.27 g (71%), m.p. 94.5° C., (Found: C, 51.7; H, 3.4; N, 20.2; Cl, 12.9% C12H9N4O2Cl requires C, 52.0; H, 3.3; N, 20.2; Cl, 12.8%); max (KBr) 2140, 1722, 1390, 1372, 1274, 1239, 1199 and 1058 cm-1, (CDCl3) 1.48 (t) and 4.55 (m) (CH3CH2), 7.59 (m), 8.11 (d), 8.32 (d) and 9.29 (s) (aromatic H's) m/e 276 (M+, 14%), 248 (9%), 218 (22%), 154 (29% 152 (100%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:21]2[CH:20]=[C:19]([CH3:22])[O:18][C:17]=2[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)=[O:12]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:9][O:10][C:11]([C:13]1[C:21]2[CH:20]=[C:19]([CH2:22][Br:1])[O:18][C:17]=2[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1ccc(OC)c2oc(C)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC)c2oc(CBr)cc12
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a well stirred refluxing solution of AIBN (40.0 mg, 1.0%) and N-bromo succinimide (3.4 g, 19.05 mmol) in carbon tetrachloride (60.0 mL) was added a Methyl-7-methoxy-2-methylbenzo[b]furan-4-carboxylate (from step 5) (4.0 g, 18.16 mmol) and refluxed for 2-3 hours. Reaction mixture was cooled to room temperature and filtered thorough Celite bed. The filtrate was concentrated under vacuo to give product (3.1 g) as brown oil. The product obtained was taken ahead for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([OH:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.[Cl-].[NH4+].C1C=CC2N(O)N=[N:32]C=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:32])=[O:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Yield: 90.5 %

Procedure:
A mixture of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxylic acid (1.70 g, 5.0 mmol) obtained in Example 35-B(viii), TEA (2.1 mL), ammonium chloride (803 mg, 15.0 mmol), HOBT (1.01 g, 7.5 mmol), EDCI (1.44 g, 7.5 mmol) and DMF (50 mL) was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure. To the residue was added saturated aqueous solution of sodium bicarbonate (30 mL). The resulting precipitate was collected by filtration and was washed with water and diethyl ether to give the title compound (1.54 g, 90%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:17][OH:18])[CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:15][O:18][CH2:17]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1
Agent: Cc1ccccc1S(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2COC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 4-(2-hydroxy-1-(hydroxymethyl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (7.62 g, 0.029 mol) in anhydrous THF (100 mL) at 0° C., a solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise. The resulting mixture was stirred at 0° C. for 30 min, then a solution of toluenesulfonyl chloride (5.26 g, 0.028 mol) in anhydrous THF (50 mL) was added by canula. The thick reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. A solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise and the reaction mixture heated at 60° C. for 2 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, pentane:EtOAc; gradient from 100:0 to 20:80) to afford 4-oxetan-3-ylpiperidine-1-carboxylic acid tert-butyl ester as a white solid (5.33 g, 75%). TFA (10 mL) was added to a solution of 4-oxetan-3-yl-piperidine-1-carboxylic acid tert-butyl ester (7.1 g, 0.029 mol) in DCM (100 mL) and the mixture stirred at ambient temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (50 g), the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10 to 85:15 to 80:20) to afford 4-Oxetan-3-ylpiperidine as a colourless oil which solidified on standing (2.05 g, 49%). 1H NMR (CDCl3, 300 MHz) δ 4.75 (dd, J=7.9, 6.0 Hz, 2 H); 4.52-4.42 (m, 2 H); 3.14-3.04 (m, 2 H); 2.81-2.67 (m, 1 H); 2.61 (td, J=12.2, 2.6 Hz, 2 H); 1.85-1.68 (m, 1 H); 1.60 (m, 2 H) and 1.02 (qd, J=12.2, 4.0 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(C(F)F)cc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, t-butyl bromoacetate (1.5 eq) and Cs2CO3 (1.5 eq) with MeCN as the solvent (in a sealed tube): MS (ES) m/z 341 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][CH2:39][O:40][CH:41]2[CH2:43][CH2:42]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][CH2:39][O:40][CH:41]2[CH2:43][CH2:42]2)=[CH:24][CH:25]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (30 mg, 0.08 mmol) in anhydrous DMF (1 mL) were added 2-cyclopropoxyethyl 4-methylbenzenesulfonate (intermediate BP) (20 mg, 0.08 mmol) and Cs2CO3 (52 mg, 0.16 mmol). The mixture was stirred at room temperature for 12 h. Then the reaction mixture was poured into water, extracted with EA, washed with brine, dried with anhydrous Na2SO4 and concentrated to an oil. The oil was purified by preparative HPLC to obtain compound BQ (11 mg) as a colorless oil. 1H NMR (CD3OD): δ 7.30 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.13 (m, 5H), 3.85 (m, 3H), 3.81 (m, 1H), 3.40 (m, 4H), 3.30 (m, 1H), 0.52 (m, 4H); MS ESI (m/z) 465 (M+H)+, calc. 464.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:33][CH:22]3[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([CH:15]3[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:33][CH:22]3[CH2:23][NH:24][CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([CH:15]3[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cn1nc(C2CC2)cc1Nc1ncc(Cl)c(NC2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1nc(C2CC2)cc1Nc1ncc(Cl)c(NC2CC3CNCC3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (751.2 mg, 1.58 mmol) in DCM (15 mL) was added a solution of HCl in EtOAc (15 mL, 60 mmol). The reaction mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (0.29 g, 95%).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2N)[CH2:3]1.S(=O)(=O)(O)O.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>O.[OH-].[Na+].[Cu].C(OCC)(=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:4]2[CH2:5][CH2:6][NH:7][CH:2]([CH3:1])[CH2:3]2)=[CH:32][CH:31]=1
Reactant: CC1CN(c2ccccc2N)CCN1
Reactant: Sc1ccc(Cl)cc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: O=N[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CN(c2ccccc2Sc2ccc(Cl)cc2)CCN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-Methylpiperazin-1-yl)phenylamine (0.96 g, 5 mmol) was dissolved in 30 mL water containing sulfuric acid (0.28 mL, 5.2 mmol) and the solution was cooled to 0° C. and sodium nitrite (0.36 g, 5.2 mmol) was added. The reaction was stirred for 30 minutes before the pH of the reaction was adjusted to pH 7 with sodium acetate. The diazonium salt solution was then added dropwise to a solution of 4-chlorothiophenol in a suspension of copper (0.3 g, 5 mmol) in 2 M NaOH (4 mL). After addition, the reaction mixture was heated to 60° C. for 30 minutes before being allowed to cool to room temperature and ethyl acetate (10 mL) was added. The reaction mixture was filtered and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic phases were dried (MgSO4) and volatile solvents evaporated in vacuo. The crude product was purified by flash chromatography using silica gel, eluting with ethyl acetate/methanol/ammonia 96:3:1. The pure product was isolated as a colourless oil. Yield (0.18 g, 11%) 1H NMR (CDCl3, 500 MHz) 1.12 (d, 3H); 2.6–2.72 (br m, 2H); 3.0–3.15 (m, 5H); 6.9 (m, 2H); 7.08 (d, 1H); 7.15 (m, 1H); 7.25–7.35 (m, 4H); MS (MH+) 319.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30]>C(#N)C>[Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:10][CH2:11][N:12]([CH2:30][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(Br)cccc1C=C1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CCN1CCC(=Cc2cccc(Br)c2CC)CC1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
To a solution of 4-[(3-bromo-2-ethylphenyl)methylidene]piperidine (D137) (1 g, 3.57 mmol) in Acetonitrile (10 mL) was added DBU (0.807 mL, 5.35 mmol) and ethyl 2-propenoate (0.429 g, 4.28 mmol). The reaction solution was heated to 60° C. for overnight. The solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with water, dried and concentrated to afford ethyl 3-{4-[(3-bromo-2-ethylphenyl)methylidene]-1-piperidinyl}propanoate (D138) (1.35 g), which was used directly without further purification. MS (ES): C19H26BrNO2 requires 379.1. found 380.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[C:16]3[O:25][CH2:26][O:27][C:15]=13)=[CH:10][C:9]([O:28][CH3:29])=[C:8]([O:30][CH3:31])[CH:7]=2)#[N:2].[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[O:23])=[C:16]3[O:25][CH2:26][O:27][C:15]=13)=[CH:10][C:9]([O:28][CH3:29])=[C:8]([O:30][CH3:31])[CH:7]=2)#[N:2]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(/C=C/C(=O)O)c4c3OCO4)c2cc1OC
Reactant: COCCN
Product: COCCNC(=O)/C=C/c1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2c1OCO2
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 16, (2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylic acid was reacted with 2-methoxyethylamine to give the title compound in 64% yield; NMR Spectrum: (DMSOd6) 3.22–3.43 (m, 7H), 3.95 (s, 3H), 3.96 (s, 3H), 6.1 (s, 2H), 6.74 (d, 1H), 6.87 (d, 1H), 7.07 (d, 1H), 7.32 (s, 2H), 7.73 (s, 1H), 8.22 (t, 1H), 8.48 (s, 1H), 9.62 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:10])[CH:3]=1
Reactant: COc1ccccc1
Reactant: O=C(O)c1cc(Br)sc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a solution of acid 1 (2.0 g, 8.28 mmol) in CH2Cl2 (50 mL) were added oxalyl chloride (0.87 mL, 9.94 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (30 mL) and cooled to 0° C. To the mixture was added anisole (0.9 mL, 8.28 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (1.2 g, 8.28 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min, warmed up to room temperature and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (50 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 2 (2.68 g, 98%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25]Br)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:28]([OH:31])([CH3:30])[CH3:29]>>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25][O:31][CH:28]([CH3:30])[CH3:29])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)O
Reactant: O=C(CBr)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: CC(C)OCC(=O)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 21 except starting with N-(1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-4-piperidyl)-2-bromoacetamide and isopropanol, the title compound was obtained as a white solid (39%), mp 134.5°-5.5° C.; MS(CI): 405 (M+H); NMR (300 MHz,DMSO-d6): 1.10(d, 6H, J=6.0 Hz), 1.52-1.61(br m, 4H), 2.28(br m, 2H), 2.46(s, 2H), 2.95(br m, 2H), 3.35(s, 2H), 3.58(septet, 1H, J=5.7 Hz), 3.65(br s, 1H), 3.78(s, 2H), 4.31(s, 1H), 6.92(br m, 4H), 7.19(d, 2H, J=7.0 Hz), 7.27(d, 2H, J=6.5 Hz), 7.34(d, 1H, J=8.0 Hz).
Reaction SMILES: [C:1]([C:6]1[N:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(OCC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[OH:2][CH2:1][C:6]1[N:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CCOC(=O)c1cc2ccccc2n1-c1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1cc2ccccc2n1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5.0 g of 2-carboethoxy-N-(3-pyridyl)indole in 75 ml of dry ether is cooled to 5° and 0.7 g of lithium aluminum hydride is added in portions. Cooling is suspended and the reaction mixture is stirred at room temperature under nitrogen for 18 hours and re-cooled to 5°. Sequential addition of 0.7 ml of water, 0.7 ml of 15% sodium hydroxide and 2.1 ml of water produces a fine precipitate which is removed by filtration through celite. The filtrate is dried over sodium sulfate and evaporated to yield crude 2-hydroxymethyl-N-(3-pyridyl)indole which is used without further purification; Rf (9:1 toluene:methanol, silica gel)=0.2.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.Cl.[NH2:14][C:15]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([O:24][CH3:25])[C:18]([O:26][CH3:27])=[CH:17][CH:16]=1>O>[CH3:25][O:24][C:19]1[C:20]2[C:21](=[O:23])[O:22][C:1](=[O:2])[NH:14][C:15]=2[CH:16]=[CH:17][C:18]=1[O:26][CH3:27]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N)c(C(=O)O)c1OC
Agent: Cl
Solvent: O
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1OC
Temperature: 25 °C
Yield: 125 %

Procedure:
Bis(trichloromethyl) carbonate (24.89 g, 84 mmol) was added into a solution of 6-amino-2,3-dimethoxybenzoic acid, Hydrochloride (28 g, 120 mmol) in Water (1.1 L). The mixture was stirred at r.t. over the weekend. The reaction mixture was filtered, the solid was collected and dried to afford 5,6-dimethoxy-1H-benzo[d][1,3]oxazine-2,4-dione (24 g, 105 mmol, 88% yield) as a light yellow solid. LCMS: (M+H)+: 223.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.O.[NH2:11][NH2:12]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH:11][NH2:12])=[N:6][CH:7]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncc(Br)cc1F
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of 5-bromo-2,3-difluoropyridine (15 g, 77 mmol)) in EtOH (250 ml) was added hydrazine hydrate (19.36 g, 387 mmol), the mixture was heated to reflux and stirred overnight (16 hr). The solvent of the reaction mixture was evaporated about half under reduced pressure, then cooling in an ice bath there precipitation was occurred, filtered and washed the product with a minimum of EtOH and water, dried in vacuum to obtain pure desired product as white powder (15 g, yield 94%). LCMS (method A): [M+H]+=206.0, 208.0, tR=1.01 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:3]1.[C:17]([CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(Cl)Cl.CCN(CC)CC>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:3]2)=[CH:15][CH:14]=1
Reactant: NC1CCCCN(Cc2ccc(Cl)cc2)C1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCC(=O)c1ccccc1)NC1CCCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-amino-1-(4-chlorobenzyl)homopiperidine (24 mg, 0.10 mmol) and 4-benzoylbutyric acid (1.2 equiv.) in CHCl3 (1 mL) was treated with EDCI (23 mg), HOBt (16.2 mg) and Et3N (15.2 μL), and stirred at 25° C. for 16 h. The reaction mixture was diluted with CH2Cl2 (0.5 mL), washed with 2 N aqueous NaOH solution (2×0.75 mL), dried by filtration through a PTFE membrane and concentrated to afford 1-(4-chlorobenzyl)-3-{(4-benzoylbutyryl)amino}homopiperidine (compound No. 994) (43 mg, 99%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 413 (M++H, C24H28ClN2O2).