Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.CC([O-])(C)C.[K+].[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:20][C:21]=1[NH:22][CH:23]1[CH2:30][CH2:29][C:26]2([O:28][CH2:27]2)[CH2:25][CH2:24]1)=[O:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C[Si](C=[N+]=[N-])(C)C>CN1C(=O)CCC1.ClCCl.CO>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:20][C:21]=1[NH:22][CH:23]1[CH2:30][CH2:29][C:26]([OH:28])([CH2:27][O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[CH2:25][CH2:24]1)=[O:16]
Reactant: O[C@H]1CCOC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC2(CC1)CO2
Agent: CC(C)(C)[O-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CO
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(O)(COC2CCOC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
A solution of (S)-(+)-3-hydroxytetrahydrofuran (259 mg, 2.94 mmol) in dry NMP (1 mL) was added to a solution of KOtBu (271 mg, 2.42 mmol) in dry NMP (1 mL). The reaction was stirred at room temperature for 15 min, then a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-(1-oxa-spiro[2.5]oct-6-ylamino]-thiophene-2-carboxylic acid methyl ester (200 mg, 0.576 mmol) in dry NMP (4.0 mL) was added and the reaction heated in a 40° C. oil bath for 24 h. The reaction was poured into ice water, cooled to 0° C., neutralized with 5% citric acid to pH=5-6 and extracted with ethyl acetate. The organic layer was washed with 5% LiCl, brine, dried and concentrated to give a brown oil which was taken up in dichloromethane/MeOH (5.0 mL/1.0 mL) and treated with the dropwise addition of TMSCH2N2 (0.35 mL, 0.692 mmol, 2M in hexane). After 20 min, volatiles were removed under vacuum and the crude residue was purified by column chromatography on silica gel (Teledyne Isco Redisep Rf Gold™) eluting with 100% dichloromethane to 20% ethyl acetate/dichloromethane to give 5-(3,3-dimethyl-but-1-ynyl)-3-[4-hydroxy-4-(tetrahydro-furan-3-yloxymethy)-cyclohexylamino]-thiophene-2-carboxylic acid methyl ester (120 mg, 48%) as a colorless solid.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:9]([CH2:10]Cl)=[CH:8][CH:7]=[C:6]([Cl:12])[N:5]=1>C(#N)C>[Cl:3][C:4]1[C:9]([CH2:10][NH:2][CH3:1])=[CH:8][CH:7]=[C:6]([Cl:12])[N:5]=1
Reactant: ClCc1ccc(Cl)nc1Cl
Reactant: CN
Solvent: CC#N
Product: CNCc1ccc(Cl)nc1Cl
Yield: 83.7 %

Procedure:
In 50 ml of acetonitrile was dissolved 7.8 g (0.1 mole) of 40% aqueous methylamine and with stirring and ice-cooling, a solution of 3.9 g (0.02 mole) of 2,6-dichloro-3-pyridylmethyl chloride in 10 ml of acetonitrile was added dropwise over 5 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours and, then, concentrated. The residue was extracted with ether (30 ml×3 ) and dried over MgSO4. Finally, the solvent was distilled off to give 3.2 g of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([OH:16])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)(Cl)=O.[CH3:26]N(C)P(N(C)C)(N(C)C)=O.C[Sn](C)(C)C>C1(C)C=CC=CC=1.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Pd+2].O>[C:1]12([C:11]3[CH:12]=[C:13]([C:14](=[O:16])[CH3:26])[CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Pd+2]
Agent: C[Sn](C)(C)C
Agent: [CH2-]c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1ccc(C(C)=O)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
15.75 g (0.055 mol) of 3-(1-adamantyl)-4-methoxybenzoic acid, dissolved in 150 ml of toluene, are treated with 7.3 ml of thionyl chloride and heated to 100° C., for 3 h 30 min. The reaction medium is evaporated to dryness and 30 ml of hexamethylphosphoramide, 8 ml (0.0575 mol) of tetramethyltin and 22 mg of benzylbis(triphenylphosphine)palladium(II) chloride are then added under nitrogen to this evaporation residue. The reaction medium is heated to 65° C., for 30 min and is then left stirring at room temperature overnight. The reaction medium is poured into water and the mixture is extracted with ether. After chromatography on silica, 10.47 g (71%) of the expected derivative, melting point 138°-140° C., are isolated in the dichloromethane/hexane (60:40) eluent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:23]=[CH:22][C:10]([CH2:11][NH:12][C:13]3[S:14][C:15]([C:18]([O:20]C)=[O:19])=[CH:16][N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.[H-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:12]([CH2:11][C:10]2[CH:22]=[CH:23][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=2)[C:13]2[S:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1cnc(NCc2ccc(-c3cccnc3)cc2)s1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc(N(Cc2ccc(F)cc2)Cc2ccc(-c3cccnc3)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 250 mL round-bottomed flask was added methyl 2-(4-(pyridin-3-yl)benzylamino)thiazole-5-carboxylate (3 g, 9.22 mmol) and 1-(bromomethyl)-4-fluorobenzene (1.264 ml, 10.14 mmol) in dimethylformamide (46.1 ml). The mixture was cooled to 0° C., sodium hydride (0.738 g, 18.44 mmol) was added carefully; and the mixture was warmed to room temperature. After the mixture was stirred for about 30 minutes, it was found to be predominantely carboxylic acid. 1 N NaOH was added to complete the conversion; and a water work up followed by chromatography provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 18.5 %

Procedure:
Beginning with 3.0 gm (28.0 mMol) 6-methyl-1H-indole and 7.04 gm (45.7 mMol) 4-piperidone hydrochloride monohydrate, 1.1 gm (22%) of the title compound were recovered as a tan powder.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:7][CH:8]=2)C=N1.N1C2C(=CC=CC=2)CC1=O.[NH:31]1[C:39]2C(=CC=C(C=O)C=2)C=[N:32]1>>[NH:32]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=2)[CH:39]=[N:31]1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]ncc2c1
Reactant: O=Cc1ccc2cn[nH]c2c1
Agent: O=C1Cc2ccccc2N1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1

Procedure:
The title compound was synthesized according to the method described for (E)-3-((1H-indazol-5-yl)methylene)indolin-2-one except reacting oxindole (67 mg, 0.216 mmol) with 1H-indazole-6-carbaldehyde (73 mg, 0.238 mmol) to obtain 32 mg, 51%. 1H NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.89 (s, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H); MS ESI 262.0 [M+H]+, calcd for [C16H11N3O+H]+ 262.10.
Reaction SMILES: [ClH:1].[N:2]1([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19]CC4C=CC=CC=4)=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:27])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>CO.[Pd]>[ClH:1].[N:2]1([C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:27])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc(N2CCCCCC2)c2ccc(OCc3ccccc3)cc2n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(N2CCCCCC2)c2ccc(O)cc2n1
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A solution of 1.45 g (3.78 mmol) of 4-azepan-1-yl-7-benzyloxy-2-methyl-quinoline hydrochloride, product of example 39, dissolved in 120 ml of MeOH was treated with 700 mg of palladium on charcoal (10%) and then hydrogenated at RT for 2 h until HPLC analysis indicated the completion of the reaction. The catalyst was filtered off, washed with water, and the solution was concentrated in vacuo. The residue was triturated with diethyl ether, the solid obtained was filtered off by suction and dried in a high vacuum to give 1 g (90.4%) 4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride as a light gray solid. ISP mass spectrum, m/e: 257.2 (M+1 calculated for C16H20N2O: 257).
Reaction SMILES: CO.[N+:3]([C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[NH:8][C:9]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[NH:8][C:9]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccccc1Nc1cc(CCc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a mixed solution of methanol 2.0 mL and ethyl acetate 1.0 mL of 2-(2-nitroanilino)-4-phenethylbenzoic acid 20 mg was added 5% palladium-carbon 8 mg, and it was stirred under hydrogen atmosphere at room temperature for 3 hours. Insoluble matter was filtrated, and the solvent was removed under reduced pressure. Methanol was added to the obtained residue, and solid matter was filtrated to give 2-((2-aminophenyl)amino)-4-phenethylbenzoic acid 13 mg of white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([NH:19][CH2:20][C:21](O)=[O:22])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:22])[CH2:20][NH:19][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
Methyl 4-amino-benzoate (3.58 g, 23.70 mmol) and N-Boc glycine (4.15 g, 23.70 mmol) were stirred in DMF (50 mL) at room temperature. BOP (11.52 g, 26.07 mmol) was added followed by the addition of DIEA (6.18 mL, 35.55 mmol). The resulting mixture was stirred at rt for 1.5 h. It was quenched with sat'd NaHCO3 and EtOAc. The organic layer was washed with H2O, brine (3×), dried (MgSO4), and concentrated to dryness to give 4-(2-tert-butoxycarbonylamino-acetylamino)-benzoic acid methyl ester (7.18 g, yield: 98%). 1H NMR (CDCl3) δ 9.16 (s, br, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 3.98 (s, 2H), 3.89 (s, 3H), 1.45 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.BrC[CH:24]1[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH:24]2[CH2:26][CH2:25]2)[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Product: NC(=O)c1ccc(OCC2CC2)c(C(=O)Nc2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and (bromomethyl)cyclopropane by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:14]1[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]1=[O:21])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: O=C1Cc2ccccc2N1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=C1CCc2cc(Br)ccc21
Temperature: 110 °C
Yield: 11.2 %

Procedure:
A reaction mixture of 0.422 g 5-bromoindanone, 1.3 g oxindole and 0.9 ml piperidine in 3 ml of dimethylforamide was heated in a sealed tube at 110° C. overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The black residue was chromatographed on a silica gel column, eluting with ethyl acetate and hexane to give 73.0 mg of 3-(5-bromoindan-1-ylidene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[C:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:12]=2[C:27]#[N:28])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].Cl.C[N:31](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>ClCCl>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([NH2:31])=[O:18])=[C:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:12]=2[C:27]#[N:28])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)Nc1cc(-c2sc(C(=O)O)c(Cc3ccc(Cl)cc3)c2C#N)ccn1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2sc(C(N)=O)c(Cc3ccc(Cl)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a solution of 5-[2-(acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxylic acid (0.0710 g, 0.172 mmol) in dichloromethane (5.0 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0991 g, 0.517 mmol) and 1-hydroxybenzotriazole hydrate (0.0528 g, 0.345 mmol). The solution was stirred at room temperature for 30 minutes, then added 33% ammonium hydroxide (33:67 ammonia:water, 0.298 mL, 3.45 mmol) was added. The solution was then stirred at room temperature for 16 hours, then the mixture was concentrated and column chromatography was performed to yield the title compound (0.031 g, 42%). LCMS: (FA) ES+, 411. 1H NMR (400 MHz, d6-DMSO) δ: 10.79 (s, 1H), 8.50-8.46 (m, 2H), 8.14 (br s, 1H), 7.85 (br s, 1H), 7.47-7.43 (m, 1H), 7.39-7.34 (m, 2H), 7.29-7.24 (m, 2H), 4.41 (s, 2H), 2.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[NH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16](Cl)[N:15]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[NH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([O:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[Cl:1])[N:15]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1nc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 76.5 %

Procedure:
12.5 g of 2-chloro-4-trifluoromethylphenol, 10.0 g of 2-amino-3-nitro-6-chloropyridine, 10.5 g of potassium carbonate, and 200 ml of dimethyl sulfoxide were charged in a flask, and the mixture was allowed to react at 30° C. for twenty-four hours while stirring. After completion of the reaction, the reaction product was poured into water, followed by extracting with methylene chloride. The extracted phase was washed with water and dried, and the methylene chloride was distilled off under reduced pressure to obtain 14.7 g of a titled compound having a melting point of 80° to 84° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.Cl.Cl.[CH3:16][O:17][C:18]1[C:19]([N:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:16][O:17][C:18]1[C:19]([N:24]2[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][C:3]3[N:4]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:6][CH:7]=3)[CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccnc1N1CCCNCC1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccnc1N1CCCN(Cc2csc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Chloromethyl)-2-phenyl-1,3-thiazole (52 mg, 0.25 mmol), 1-(3-methoxy-pyridin-2-yl)-[1,4]diazepane dihydrochloride (70 mg, 0.25 mmol), and Cesium carbonate (325 mg, 1.0 mmol) were suspended in anhydrous DMF (1.25 mL). The mixture was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc and washed with H2O (3×25 mL), then brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified on silica (CH2Cl2:MeOH+1% NH4OH) to afford the product. 1H NMR (400 MHz, CDCl3) δ 7.94 (m, 2H), 7.79 (dd, 1H, J=1.6, 4.8 Hz), 7.40 (m, 3H), 7.15 (s, 1H), 6.96 (dd, 1H, J=1.4, 8.2 Hz), 6.66 (dd, 1H, J=4.8, 7.6 Hz), 3.93 (s, 2H), 3.80 (s, 3H), 3.71 (m, 4H), 2.98 (t, 2H, J=5.0 Hz), 2.85 (t, 2H, J=5.6 Hz), 2.04 (quin., 2H, J=5.9 Hz). MS (ES) m/z 381.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.S(=O)(=O)(O)O>CCOC(C)=O.CO>[Br:1][C:2]1[C:3]2[O:12][C:13]3[C:18](=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=3[CH3:20])[C:5](=[O:7])[C:4]=2[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(Br)c(Oc2cccc(C)c2C)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(Br)c2oc3c(C)c(C)ccc3c(=O)c2c1
Yield: 91 %

Procedure:
Following the method in Example 1, the crude 3-bromo-2-(2,3-dimethylphenoxy)-5-methyl-benzoic acid (16) was treated with sulfuric acid and recrystallized from EtOAc/MeOH to yield a light yellow solid, and the yield was 91%: Mp (EtOAc/MeOH) 236-238° C.; 1H-NMR [(CD3)2SO] δ 8.12 (s, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.42 (s, 1H), 2.55 (s, 3H), 2.46 (s, 3H); 13C-NMR δ 171.6, 153.6, 152.1, 143.3, 136.9, 128.0, 125.6, 125.3, 124.5, 123.9, 120.2, 120.0, 119.7, 21.8, 20.3, 12.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1/[CH:12]=[CH:13]/[C:14]([O:16]CC)=O>Cl.O1CCOCC1>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH:12]=[CH:13][C:14](=[O:16])[NH:1]2
Reactant: CCOC(=O)/C=C/c1c(N)cccc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2c(C(F)(F)F)cccc2[nH]1
Temperature: 100 °C

Procedure:
To a stirring mixture of (E)-ethyl 3-(2-amino-6-(trifluoromethyl)phenyl)acrylate in 4N HCl in dioxane (25 mL) was added concentrated HCl (2 mL). The resulting mixture was warmed to 100° C. overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCO3 solution until pH>7. A normal aqueous extraction with EtOAc was followed. The crude mixture was taken directly to the next reaction without further purification. Retention time (min)=1.892, method [1], MS (ESI) 214.0 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[I-].[Na+].[C:8]([O:16][CH2:17][C@@H:18]1[O:23][C@@H:22]([O:24][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH2:26]Br)[CH2:21][CH2:20][CH2:19]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[C:8]([O:16][CH2:17][C@@H:18]1[O:23][C@@H:22]([O:24][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH2:26][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:21][CH2:20][CH2:19]1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OC[C@H]1CCC[C@H](OC(CBr)c2ccc(Cl)cc2Cl)O1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1)c1ccccc1
Temperature: 130 °C
Reaction time: 6.5 h
Yield: 48.2 %

Procedure:
8.24 g of imidazole and 12.0 g of sodium iodide were added to a solution of 19.70 g of trans-6-benzoyloxymethyl-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran in 150 ml of dimethylformamide, and the resulting mixture was stirred on an oil bath at 130° C. for 6.5 hours. The reaction mixture was then cooled, poured into water and extracted with diethyl ether. The ethereal extract was washed with aqueous sodium chloride and dried over anhydrous sodium sulphate, after which the solvent was evaporated off. The residue was purified by column chromatography through silica gel eluted with a B 100:25:1 by volume mixture of ethyl acetate, benzene and triethylamine, to give 9.25 g of the title compound as a liquid.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:12]([NH2:13])[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[CH:20][C:17]=1[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:43]>ClCCl.C(O)(=O)C.C(O)C.CCOCC>[ClH:43].[ClH:43].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[CH:20][C:17]=1[CH2:18][NH:13][C@H:12]1[CH2:11][CH2:10][CH2:9][NH:8][C@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(-n2cnnn2)cc1C=O
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(-n2cnnn2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of cis-2-phenyl-piperidin-3-yl-amine (1.22 mmol) and 2-methoxy-5-tetrazol-1-yl-benzaldehyde (1.22 mmol) in dichloromethane (25 ml) was added sodium triacetoxy borohydride (1.70 mmol) and 2 drops of glacial acetic acid. The mixture was stirred at room temperature under nitrogen atmosphere for 18 h. The solvent was evaporated in vacuo and the residue quenched with 2N solution of sodium carbonate (20 ml ) and extracted with ethyl acetate (3×50 ml). The organic layer was treated with 2N hydrochloric acid solution (20 ml) and the acidic portion basified with 2N sodium carbonate solution and extracted with dichloromethane (3×100 ml). The organic extracts were dried (MgSO4), filtered and concentrated to give a residue which was purified by FCC (dichloromethane/ethanol/ammonia-200:8:1) to give a white foam which was dissolved in ethanol (15 ml) and treated with 1M hydrochloric acid solution in ether (2.5 ml). The solvent was evaporated in vacuo and the resulting white solid triturated with isopropanol and filtered to afford the title compound. (49%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH2:11]([N:13]1[C:17]2=[N:18][C:19]3[C:24]([C:25]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:16]2[CH:15]=[N:14]1)=[CH:23][C:22]([OH:34])=[CH:21][CH:20]=3)[CH3:12].[OH-].[K+]>CS(C)=O>[CH2:11]([N:13]1[C:17]2=[N:18][C:19]3[C:24]([C:25]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:16]2[CH:15]=[N:14]1)=[CH:23][C:22]([O:34][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[CH:21][CH:20]=3)[CH3:12]
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(O)ccc3nc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OCCN4CCOCC4)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
A mixture of DMSO (6 ml), chloroethylmorpholine hydrochloride (1.23 g, 6.6 mmol), 1-ethyl-6-hydroxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (2 g, 6.6 mmol) and KOH (1 g) is stirred at room temperature overnight. The reaction mixture is partitioned between CH2Cl2 and water and the CH2Cl2 layer is separated and evaporated. The residue is purified by column chromatography on silica gel eluting with 10% ethanol/ethyl acetate to afford the product as the free base. The free base is recrystallized from hot ethyl acetate/hexane to afford 0.425 g of 1-ethyl-6-[2-(4-morpholinyl)ethoxy]-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow powder, m.p. 176°-178° C.