Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](O)=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16].P(Cl)(Cl)(Cl)=O>>[Cl:16][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1

Procedure:
A mixture of EXAMPLE 410A (1.69 g), phosphorus pentachloride (2.03 g), and phosphoryl trichloride (0.97 mL) was heated at 90° C. for 3 hours. After cooling, the reaction mixture was poured into ice, and extracted with ethyl acetate three times. The extract was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 1:9 ethyl acetate\hexanes to give the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]([CH3:22])[CH3:21])[N:15]=1)[CH:8]=[C:7]2[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C.[Br:37][C:38]1[C:46]2[C:41](=[N:42][CH:43]=[N:44][C:45]=2Cl)[NH:40][N:39]=1.C(OCC)(=O)C>O1CCCC1>[Br:37][C:38]1[C:46]2[C:41](=[N:42][CH:43]=[N:44][C:45]=2[N:27]2[CH2:28][CH2:29][CH:24]([NH:23][C:7]3[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=4)[CH:10]=[C:9]([C:14]4[CH:19]=[CH:18][N:17]=[C:16]([N:20]([CH3:22])[CH3:21])[N:15]=4)[CH:8]=3)[CH2:25][CH2:26]2)[NH:40][N:39]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC3CCNCC3)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC3CCN(c4ncnc5[nH]nc(Br)c45)CC3)c2c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
To a solution of 4-(6-methoxy-4-(piperidin-4-ylamino)naphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (143) (196 mg, 0.43 mmol) and triethylamine (0.5 ml) in anhydrous tetrahydrofuran (8 ml) was added 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (122 mg, 0.52 mmol). The mixture was stirred at 50° C. for 24 hours before being poured into ethyl acetate (150 ml) washed with water (300 ml) and the organic layer dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow foam that was crystallized from dichloromethane and ethyl acetate to give 4-(4-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)amino)-6-methoxynaphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (144) as a yellow solid (145 mg) M.p.=167-172° C. 1H NMR (DMSO-d6) 400 MHz δ 8.4-8.33 (m, 2H), 7.9-7.8 (m, 2H), 7.52 (m, 2H), 7.24-7.2 (m, 1H), 7.15-7.12 (m, 1H), 5.9-5.74 (m, 1H), 4.56-4.53 (m, 2H), 3.95 (s, 1H), 3.9 (s, 3H), 3.41-3.26 (m, 2H), 3.22 (s, 6H), 2.28-2.25 (m, 2H), 1.97-1.75 (m, 2H), LCMS m/e 574 and 576 (M+) Calculated for C27H28BrN9O.CH2Cl2: C, 51.00; H, 4.59; N, 19.12; found C 51.00, H 4.39, N 18.85.
Reaction SMILES: [CH:1]1([N:6]2[C:15](OS(C(F)(F)F)(=O)=O)=[C:14]3[C:8]([CH2:9][C:10]([CH3:27])([CH3:26])[NH:11][C:12]([CH3:25])([CH3:24])[CH2:13]3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:1]1([N:6]2[C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:14]3[C:8]([CH2:9][C:10]([CH3:27])([CH3:26])[NH:11][C:12]([CH3:25])([CH3:24])[CH2:13]3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)Cc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC(C)(C)N1
Reactant: OB(O)c1ccccc1
Product: CC1(C)Cc2nn(C3CCCC3)c(-c3ccccc3)c2CC(C)(C)N1
Yield: 59.5 %

Procedure:
The title compound (129 mg) was prepared as in Example 294, using 263 mg of trifluoro-methanesulfonic acid 2-cyclopentyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl ester and 110 mg of phenylboronic acid. MS (ESI): exact mass calculated for C22H31N3, 337.25. found, m/z 338.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.56-7.49 (m, 3H), 7.32-7.30 (m, 2H), 4.51-4.44 (m, 1H), 3.12 (s, 2H), 2.72 (s, 2H), 2.03-1.88 (m, 6H), 1.61-1.57 (m, 2H), 1.45 (s, 6H), 1.35 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:16])[C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH:5]=[O:6].[BH4-].[Na+]>C1COCC1>[Br:16][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:12])[CH3:13])[CH2:5][OH:6]
Reactant: CN(C)S(=O)(=O)c1c(Br)cc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1c(Br)cc(CO)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
To a solution of OBS02013 (5.5 g, 14.21 mmol) in anhydrous THF (50 mL) was added sodium borohydride (0.59 g, 15.63 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (CARE!!) and filtered through a Celite pad. The filtrate was concentrated in vacuo and re-dissolved in DCM (200 mL). The organic layer was washed with brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the combined filtrates gave OBS02015 as a pale yellow oil (5.21 g, 94%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.55; 1H-NMR (270 MHz, CDCl3)=1.97 (1H, bs, OH), 3.11 (6H, s), 4.63 (2H, s), 7.55 (2H, t, J=1.5).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([S:17]([C:20]2[N:27]3[C:23]([S:24][CH:25]=[CH:26]3)=[N:22][C:21]=2[Cl:28])(=[O:19])=[O:18])[CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:28][C:21]1[N:22]=[C:23]2[N:27]([C:20]=1[S:17]([N:9]1[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7]([CH2:6][CH2:5][CH2:4][NH2:1])=[CH:8]1)(=[O:18])=[O:19])[CH:26]=[CH:25][S:24]2
Reactant: [N-]=[N+]=NCCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccc(F)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccc(F)cc12
Yield: 78 %

Procedure:
A mixture of 3-(3-azidopropyl)-1-[(6-chloroimidazo-[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-fluoro-1H-indole (180 mg, 0.41 mmol) and triphenylphosphine (161 mg, 0.62 mmol in THF and water is stirred under nitrogen for 24 h at room temperature and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/2M NH3 in MeOH: 98/2) to afford the title product as an off-white solid, 132 mg (78% yield), mp 139-141° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>C(O)C.O>[C:1]1([O:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(NCCOc2cccc3ccccc23)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCOc2cccc3ccccc23)cc1

Procedure:
A solution of 12 g of ethyl p-[2-(1-naphthyloxy)-ethylamino]benzoate and 15.8 g of potassium hydroxide in 100 ml of 95% ethanol is refluxed for 3 hours. The solution is diluted with 75 ml of water and acidified with concentrated hydrochloric acid. The solid is filtered, washed with 50% ethanol and with water. Recrystallization from ethanol gives the product as crystals, mp 193°-194° C.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[C:11]([O:24][CH3:25])[CH:10]=1)(C)C)(C)(C)C.Cl[C:27]1[N:28]=[N:29][C:30]([CH2:33][CH:34]2[CH2:39][C:38]([CH3:41])([CH3:40])[NH:37][C:36]([CH3:43])([CH3:42])[CH2:35]2)=[CH:31][CH:32]=1>>[CH3:25][O:24][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:27]1[N:28]=[N:29][C:30]([CH2:33][CH:34]2[CH2:35][C:36]([CH3:43])([CH3:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH2:39]2)=[CH:31][CH:32]=1
Reactant: CC1(C)CC(Cc2ccc(Cl)nn2)CC(C)(C)N1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Product: COc1cc(O)ccc1-c1ccc(CC2CC(C)(C)NC(C)(C)C2)nn1
Yield: 61.9 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using tert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (408 mg, 1.12 mmol) and 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine (200 mg, 0.75 mmol) affords 3-methoxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol (165 mg) MS [M+H+]=356.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([N:21]=[C:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17]1=[O:34])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)[C:17]1=[O:34])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1N=C1CCN(c2ccncc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
(3S)-3-(6-Chloronaphthalene-2-sulfonylamino)-1-[1-(4-pyridyl)-4-piperidinylideneamino}-2-pyrrolidone (600 mg) was dissolved in methanol (40 ml), combined with acetic acid (761 mg) while cooling on ice, followed by sodium cyanoborohydride (300 mg) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was combined with an aqueous solution of sodium carbonate, extracted with dichloromethane, dried, concentrated and purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from ethyl acetate to obtain the title compound (576 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:31](=[O:33])[NH2:32])[CH:5]=[CH:6][CH:7]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:31](=[O:33])[NH2:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(F)c1
Yield: 100 %

Procedure:
A solution of the {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester (40.0 mg, 0.089 mM) in 2 mL of trifluoroacetic acid was stirred at room temperature for 5 hours. The solvent was removed in vacuo. The residue was triturated with ethyl ether, then dried in vacuo to afford 35.0 mg (100%) of the {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ13.0 (br s, 1H), 7.75 (s, 1H), 7.6 (d, 1H, J=8 Hz), 7.5-7.25 (m, 5H), 7.2-6.8 (m, 4H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 3423, 3400, 1736, 1637, 1615, 1589, 1499, 1487, 1450, 1436, 1331, 1250, and 1156. MS (ES) m/e 391, 393.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].[Sn](Cl)(Cl)(Cl)Cl>ClC1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: COC(=O)c1ccc(OC)c(C(=O)c2ccccc2C)c1
Temperature: 140 °C
Yield: 2.3 %

Procedure:
4-Methoxybenzoic acid methyl ester (5.00 g, 30.1 mmol) and 2-methylbenzoyl chloride (4.88 g, 31.6 mmol) were dissolved in chlorobenzene (10 ml), tin(IV) chloride (9.41 g, 36.1 mmol) was added cautiously, and the mixture was heated to 140° C. for 3 h. The addition of the acid chloride and tin tetrachloride was repeated twice, and the mixture subsequently heated to 140° C. for 3 h each time. The mixture was poured onto 300 ml of ice/water and extracted with DCM. The combined extracts were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) and subsequently by RP HPLC (water/ACN gradient) to yield 200 mg of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:26]([CH2:25][C:23]([OH:24])=[O:22])[CH2:31][CH2:30][CH2:29][C:28]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([S:16][CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CSc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CSc1ccc2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methylthiophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:7])[CH:2]([CH3:4])[CH3:3]>[Pd].C(O)C>[CH2:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)NN=Cc1ccc2[nH]cc(CCN(C)C)c2c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)COC(=O)NNCc1ccc2[nH]cc(CCN(C)C)c2c1
Temperature: 65 °C
Reaction time: 21.5 h

Procedure:
A 50 ml pressure vessel is charged with N′-[3-(2-Dimethylamino-ethyl)-1H-indol-5-ylmethylene]-hydrazinecarboxylic acid isobutyl ester (Example 10; 1.76 g, 5.33 mmol), ethanol (25 ml), and the catalyst (5% Pd/C type E-4522, 325 mg). The vessel is sealed, purged with argon (three times and hydrogen (three times), heated in an oil bath to 65° C., and then pressurized with hydrogen (78.4 bar). The stirrer is started (900 rpm), and the hydrogenation allowed to proceed for 21.5 hours. After cooling to ambient temperature the pressure vessel is vented, and the reaction mixture filtered over a pad of Hyflo to remove the catalyst. Removal of the solvent gives the product as a pale yellow residue, which is pure by NMR. 1H-NMR (CD3OD, 300 MHz) δ 0.81 (d, 6H, J=6.8 Hz, CH(CH3)2); 1.78 (m, 1H, CH(CH3)2); 2.27 (s, 6H, N(CH3)2); 2.61, 2.83 (2 m, 2H each, CH2CH2NHMe2); 3.74 (d, 2H, J=6.6 Hz, OCH2); 3.90 (s, 2H, CH2N); 6.95 (s, 1H, H-2); 7.02 (dd, 1H, J=8.3 Hz, J=1.5 Hz, H-6); 7.19 (d, 1H, H-7); 7.43 (s, 1H, H-4). 13C-NMR (CD3OD, 75 MHz) δ 19.70 (CH3); 24.46 (CH2); 29.71 (CHMe2); 45.65 (N(CH3)2); 57.89 (CH2N); 61.64 (CH2NMe2); 72.57 (OCH2); 112.64 (CH); 113.85 (C); 120.42 (CH); 124.06 (CH); 124.33 (CH); 128.89 (C); 129.09 (C); 138.13 (C); 160.03 (C═O).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[NH2:10][C:11]1[C:12]([C:18](O)=[O:19])=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1>CN(C=O)C.O>[Br:17][C:15]1[CH:14]=[N:13][C:12]2[C:18](=[O:19])[N:9]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[N:10][C:11]=2[CH:16]=1
Reactant: COC1=NCCCCC1
Reactant: Nc1cc(Br)cnc1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ncc(Br)cc2nc2n1CCCCC2

Procedure:
A solution of 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (1.0 g, 8.8 mmol) and 3-amino-5-bromopicolinic acid (1.9 g, 8.8 mmol) in DMF (70 mL) was stirred at 130° C. for 48 h. The reaction mixture was diluted with H2O (300 mL) and extracted with DCM (3×300 mL). The combined organic layers were washed with saturated sodium carbonate and brine, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI):294, 296 (MH+).
Reaction SMILES: [CH:1]1([CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1.[C:19]([N:27]=C=O)(=[O:26])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:1]1([CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:19]([NH2:27])=[O:26])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Temperature: 50 °C
Yield: 9.7 %

Procedure:
The crude 4-(2-cyclopropyl-2-phenyl-ethyl)-pyridin-2-ylamine (70 mg) is dissolved in methylene chloride (2 mL). Then benzoyl isocynate (86 mg, 0.59 mmol) is added. The reaction mixture is sealed and heated at 50° C. for 16 hour. The solvent is then carefully removed and to the residue are added ethanol (2 mL) and potassium carbonate (61 mg, 0.44 mmol). The resulting mixture is heated at 85° C. for 45 min. Then solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×40 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by Gilson preparative HPLC affords 8 mg of the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:15])=[CH:6][CH:7]=1)=[O:20]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(CCCl)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 3.95 g of p-aminobenzophenone in 100 ml of chloroform was treated with 2.6 g of 3-chloropropionyl chloride and, after the addition of 26 ml of 1N sodium hydroxide solution, stirred at room temperature. The organic phase was separated, washed in sequence with water, 1N HCl and water, dried and evaporated. After recrystallization from methanol of the oil obtained there was obtained 4-(3-chloropropionamido)benzophenone, m.p. 135°-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2c1CC(=O)N2
Product: O=C(CCl)Nc1cccc2c1CC(=O)N2

Procedure:
The subtitle compound was prepared from 4-amino-oxindole (0.19 g) (J. Org. Chem., 1983, 48 (15), 2468-72) and chloroacetyl chloride (0.1 ml) by the method of Example 15 step (i). Yield: 0.25 g
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH2:4][C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[N:3]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4][C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: Cc1sc2c(c1C)CNC(Cl)=N2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CN1Cc2c(sc(C)c2C)N=C1Cl
Reaction time: 4 h

Procedure:
A mixture of 6.0 g of 2-chloro-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine, 5.52 g of ethyl bromoacetate and 12.5 g of powdered potassium carbonate in 300 ml of methyl ethyl ketone was heat-refluxed with stirring under a nitrogen atmosphere for 4 hours. After cooling, an insoluble inorganic salt was filtered off and the filtrate was concentrated in vacuo to give a crude oil of 2-chloro-3-ethoxycarbonylmethyl-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine. Because of the instability of the resulting compound, the crude oil was used in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: O=C(NCCc1cc(Cl)cc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1cc(Cl)cc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (60.0 mg, 0.115 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (230 μl, 0.115 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate (62.0 mg, 0.114 mmol, 99.1% yield) as a solid. MS (apci) m/z=521.9 (M+2H-Na)
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: C1CCNCC1
Reactant: BrCc1ccc(-c2nc3ccc(Br)cc3o2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2nc(-c3ccc(CN4CCCCC4)cc3)oc2c1

Procedure:
200 mg (545 μmol) 6-bromo-2-(4-bromomethyl-phenyl)-benzoxazole and 100 mg (1174 μmol) piperidine are stirred for 20 min in 4 ml THF at RT, the solv. is eliminated by rotary evaporation in vacuo. The residue is dissolved in ether and extracted with water, the org. phase is dried on magnesium sulphate and the solv. is eliminated completely in vacuo.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([NH2:22])[CH2:15]2.[OH-].[Na+]>S(Cl)(Cl)=O.C(Cl)Cl.C(OCC)(=O)C>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([NH:22][C:11]([C:10]1[CH:9]=[N:8][N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=13)=[O:13])[CH2:15]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: Cc1cccc2c(C(=O)O)cnn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc2c(C(=O)N[C@H]3CN4CCC3CC4)cnn12
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
A solution of 166 mg (0.945 mmol) of 7-methyl-3-pyrazolo[1,5-a]pyridinecarboxylic acid in 3 ml of thionyl chloride was heated under reflux for 30 minutes. Thionyl chloride was distilled off under reduced pressure and the residue was dissolved in 5 ml of methylene chloride. The resultant solution was added dropwise under ice cooling to a solution of 200 mg (1 mmol) of (R)-(+)-1-azabicyclo[2.2.2]octan-3-amine, which had been prepared in accordance with the procedure disclosed in Japanese Patent Application Laid-Open No. 196583/1988, in 5 ml of methylene chloride. The resultant mixture was stirred for 30 minutes under ice cooling and for additional 40 minutes at room temperature. 2N aq. NaOH solution was added to the reaction mixture and, after the mixture so obtained was stirred for 10 minutes, the organic layer was collected. Further, the water layer was extracted with methylene chloride and the extract was dried over anhydrous potassium carbonate. Methylene chloride was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column (chloroform:methanol=10:1, 5:1). An oily substance thus obtained was dissolved in ethyl acetate. The solvent was distilled off under reduced pressure, and crystals thus obtained were washed with ether, whereby 207 mg (0.73 mmol) of the title compound were obtained as white crystals (yield: 77.0%).