Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[CH2:23][C@@:13]3([C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:22])[CH2:12][C:9]2=[N:10][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I-:35].[K+].[OH-].[Na+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(#N)C>[I:35][C:6]1[CH:7]=[C:8]2[CH2:23][C@@:13]3([C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:22])[CH2:12][C:9]2=[N:10][CH:11]=1
Reactant: Nc1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Agent: O=N[O-]
Solvent: O
Solvent: CC#N
Product: O=C1Nc2ncccc2[C@@]12Cc1cc(I)cnc1C2
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (36.1 g, 523 mmol) in water (20 mL) was added dropwise over 5 min to a solution of (6S)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (prepared according to the procedures described in WO2008/020902, 66.0 g, 262 mmol) and p-toluenesulfonic acid (149 g, 785 mmol) in acetonitrile (650 mL) at 23° C. After stirring for 30 min, a solution of potassium iodide (109 g, 654 mmol) in water (20 mL) was added over 5 min. The resulting mixture was stirred at 23° C. for 40 min, then diluted with water (1 L) and basified by the addition of solid NaOH (33.0 g, 824 mmol) with stirring. Iodine by-product was reduced by the addition of 10% aqueous sodium thiosulfate solution and stirring for an additional 30 min. The solids were collected by filtration, washed with water, and dried under nitrogen atmosphere to give the title compound, which was used without further purification. MS: m/z=363.9 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[CH3:30]O>>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:4]=1[C:1]([O:3][CH3:30])=[O:2]
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Reactant: CO
Product: COC(=O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
Hydrogen chloride gas was bubbled through a stirred, boiling mixture of 30.0 g. (0.08 mole) of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole and 790 ml. of methanol for 1 hour. The mixture was stirred under reflux for 6 hours, cooled and filtered to provide 28.4 g. (91%) of solid. Recrystallization from acetonitrile gave colorless crystals, m.p. 164.5°-165.5°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)=[O:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O.C(Cl)Cl.O1CCOCC1.O>[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]4[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]([NH:19][C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=5)=[O:18])=[CH:13][CH:12]=4)=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2ccn3c(-c4ccc(CNC(=O)Nc5cccc(C(F)(F)F)c5)cc4)cnc3c2)cn1
Temperature: 40 °C
Yield: 56 %

Procedure:
Load a 5 mL septum capped vial with the following: small magnetic stir bar, 1-[4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-benzyl]-3-(3-trifluoromethyl-phenyl)-urea (208 mg, 0.46 mmol), 6-methoxy-pyridin-3-yl boronic acid (0.51 mmols, 1.1 Eq), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (23.6 mg), Pd(OAc)2 (5 mg), K3PO4 (218 mg, 1.03 mmol), dioxane:H2O 2:1 (3 mL). Deoxygenate the reaction with N2 and heat to 40° C. for 24 hours. Cool the mixture and pour into a separatory funnel containing CH2Cl2 (45 mL) and H2O (2 mL). Extract the CH2Cl2 and evaporate under reduced pressure. Mix the residue with CH2Cl2 and a small amount of acetone. Filter the resulting solid and rinse with a small amount of CH2Cl2 and air dry. Vacuum oven dry the solid at 40° C. to give the title compound in 56% yield: MS(ES), m/z 518 (M+1).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:13]([C:20]1[C:21]([CH3:37])=[N:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([C:31](N(OC)C)=[O:32])=[CH:25][CH:24]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1C=CN=C1>C1COCC1>[CH2:13]([C:20]1[C:21]([CH3:37])=[N:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([C:31]([C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1)=[O:32])=[CH:25][CH:24]=2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CON(C)C(=O)c1ccc2nc(C)c(Cc3ccccc3)c(C)c2c1
Reactant: Cn1cncc1I
Agent: CC(C)[Mg]Cl
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: Cc1nc2ccc(C(=O)c3cncn3C)cc2c(C)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A translucent solution of 5-iodo-1-methyl-1H-imidazole (197 mg, 0.946 mmol) in THF (1.5 mL) was stirred at 0° C. while iPrMgCl (2.01 M in THF, 0.43 mL, 0.864 mmol) was added dropwise under argon. The ice bath was immediately removed and the white mixture was stirred at room temperature for 15 minutes, and was then added rapidly dropwise to a solution of 3-benzyl-N-methoxy-N,2,4-trimethylquinoline-6-carboxamide (71.9 mg, 0.215 mmol, Intermediate 34: step c) in THF (0.5 mL) at room temperature. The resulting milky opaque mixture was stirred at room temperature for 1.5 hours, and was then quenched with 1 M aqueous NaHCO3 (6 mL) and extracted with EtOAc (2×6 mL). The combined organic layers were shown by LCMS to be a mixture of title compound and starting material, so the material was concentrated from THF (3×) and re-subjected to the above conditions but with reaction at 50° C. for 2 hours. The reaction was then worked up as described above, and the residue was flash chromatographed with a heptane to 100% EtOAc gradient to provide a 1:4 mol ratio of the title compound and N-methylimidazole.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[C:7]#[N:8].O.[CH:16]([NH2:18])=O>>[NH2:8][C:7]1[C:6]2[CH:5]=[C:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:3][C:2]=2[N:1]=[CH:16][N:18]=1
Reactant: NC=O
Reactant: N#Cc1cc(-c2ccccc2)oc1N
Solvent: O
Product: Nc1ncnc2oc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 2-amino-3-cyano-5-phenylfuran (9.18 g, 49.8 mmol) in formamide was heated to 180° C. After 3 hours, the solution was cooled to room temperature, poured into water (250 mL), and the resulting mixture filtered to afford 4-amino-6-phenylfuro-[2,3-d]pyrimidine (11.0 g, crude) as a brown solid. The solid was dissolved in acetic acid (150 mL) and bromine (6 mL, 18.7 g, 117 mmol) was added. The reaction mixture was then heated to 100° C. for 2 hours, cooled, and poured into sodium thiosulfate solution (250 mL, 0.5 N aq). 4-Amino-5-bromo-6-phenylfuro-[2,3-d]pyrimidine was then filtered off as a yellow solid (13.25 g, crude). A portion of this aminopyrimidine (4.48 g, crude, up to 15.4 mmol) was then dissolved in MeCN. Di-tert-butyl dicarbonate (7.00 g, 32.1 mmol) was added, followed by 4-(N,N)-dimethylaminopyridine (2.00 g, 16.4 mmol). The resulting solution was allowed to stir at room temperature for 3 days, and then concentrated in vacuo to a brown oil. Flash column chromatography (SiO2, EtOAc:hexane 1:6) afforded 4-di-tert-butyloxycarbonylamino-5-bromo-6-phenylfuro-[2,3-d]pyrimidine (2.39 g, 4.34 mmol) as an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([O:17]CC)(=O)[CH2:10][C:11]([O:13]CC)=O>>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][C:11](=[O:13])[CH2:10][C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=2)=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(NC(=O)CC(=O)Nc2cccc(C)c2)c1
Temperature: 170 °C
Reaction time: 8 h

Procedure:
100 mmol m-toluidine and 50 mmol diethyl malonate were put together and stirred overnight at 170° C. The formed ethanol was distilled off directly (100 mmol≡6.6 mL) on a stream of nitrogen. N1,N3-di(3-methylphenyl)malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 9.5 g N1,N3-di(3-methylphenyl)malonamide (yield 67.3%, purity 97.2%) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[N+]([C:15]1[CH:16]=C(S(O)(=O)=O)C=C[CH:20]=1)([O-])=O.B(O)(O)O.S(=O)(=O)(O)O.[OH-].[Na+]>OCC(CO)O>[CH2:1]([C:5]1[CH:11]=[C:10]2[C:8](=[CH:7][CH:6]=1)[N:9]=[CH:16][CH:15]=[CH:20]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Reactant: CCCCc1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Agent: [Na+]
Solvent: OCC(O)CO
Product: CCCCc1ccc2ncccc2c1
Temperature: 140 °C
Yield: 66.6 %

Procedure:
38.6 (259 mM) of 4-butylaniline, 80.5 g (875 mM) of glycerin, 25.0 g of m-nitrobenzenesulfonic acid, 7.6 g of ferric sulfate and 13.2 g of boric acid were placed in a 500 ml-three necked flask. To the mixture, 47.4 ml of conc. sulfuric acid was added dropwise over 20 minutes with stirring on an ice bath, whereby the temperature was increased from 8° C. to 50° C. The mixture was heat-refluxed at 135-145° C. for 2 hours under stirring. After the reaction, the reaction mixture was poured into ice water and alkalinized with 20% NaOH aqueous solution to pH=11, followed by extraction with toluene. The organic layer was washed with water and evaporated. The residue was purified by silica gel column chromatography (eluent: toluene/THF) to obtain 31.9 g of 6-butylquinoline (yield: 66.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:33]([O:35]CC5C=CC=CC=5)=[O:34])[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1.[OH-].[Na+]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:33]([OH:35])=[O:34])[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)OCc4ccccc4)ccc2O3)nc2c(OC)cccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)O)ccc2O3)nc2c(OC)cccc12

Procedure:
1′-[(4,8-Dimethoxyquinolin-2-yl)carbonyl]-6-(benzyloxycarbonyl)-spiro[chroman-2,4′-piperidin]-4-one (680 mg) was dissolved in 10 mL of THF and 10 mL of methanol, and vigorously stirred on 10% Pd/C under a hydrogen atmosphere for 21 hours. 1.2 mL of 1 N NaOH was added to it, and filtered through Celite, and the filtrate was concentrated. 20 mL of water was added to the residue, and extracted with ethyl acetate (3×20 mL). The aqueous layer was acidified with 1 N HCl, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated to obtain the intended compound. 1H-NMR (DMSO-d6) δ: 8.30 (1H, d, J=2.2 Hz), 8.11 (1H, dd, J=8.7, 2.2 Hz), 7.68 (1H, dd, J=8.3, 1.2 Hz), 7.52 (1H, dd, J=8.3, 7.7 Hz), 7.23 (1H, dd, J=1.2, 7.7 Hz), 7.21 (1H, d, J=8.7 Hz), 7.18 (1H, s), 4.35-4.28 (1H, m), 4.07 (3H, s), 3.94 (3H, s), 3.69-3.62 (1H, m), 3.50-3.22 (2H, m), 2.97 (2H, s), 2.12-2.04 (1H, m), 1.96-1.80 (3H, m). MS [M+H]+=477.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28](O)=[O:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(O)(C(F)(F)F)=O>CCOC(C)=O>[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:13]([C:14]#[N:15])[C:12]=2[Cl:20])[C:4]=1[F:21])=[O:29]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3Cl)c2F)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (60 mg, 0.174 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (27.9 mg, 0.174 mmol) and HOBT (26.6 mg, 0.174 mmol) was added EDC (33.3 mg, 0.174 mmol) and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(2,5-dichloro-3-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (28 mg, 0.046 mmol, 27% yield) as the TFA salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.66 (d, 1H), 7.29-7.49 (m, 2H), 6.97 (s, 1H), 4.64 (s, 2H), 2.34 (s, 3H). LC-MS (ES+) m/z 486.93, [M+H].
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]([OH:25])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:29]2N(O)N=[N:32][C:30]=2[CH:31]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:30]1([NH:32][C:23]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH2:31][CH2:29]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 174.5 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-phenyl-1H-1,2,3-triazole-4-carboxylic acid (203 mg, 0.604 mmol) obtained in Example 105a), HOBt (41.2 mg, 0.302 mmol, 0.5 eq.) and cyclopropylamine (0.056 ml, 0.785 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 3.0 ml), WSC (142 mg, 0.724 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 14 hr. Water (5 ml) was added to the reaction mixture and the mixture was stirred at 0° C. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (198 mg, 0.527 mmol, 87.3%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2)(=O)=O.C(O)(=O)C.[Sn].Cl>O>[SH:2][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCC2
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(S)cc2c1OCCC2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
238 g of 6-chlorosulphonylchroman-8- carboxylic acid and 645 ml of acetic acid were introduced into a 6-liter round-bottomed flask. The mixture was heated to 80° C. and 384 g of tin was added and the mixture was then cooled to 50° C. 1720 ml of hydrochloric acid (d=1.18) were then poured in dropwise, while maintaining the temperature between 55° and 60° C. first by cooling in an ice bath and then by heating in a water bath. Heating was then continued for 3 hours at 60° C. and the solution was poured into 6 liters of water. The precipitate formed was drained, washed with 1 liter of dilute hydrochloric acid followed by water and then air-dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=3)=[CH:11][N:10]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1.O>CN(C)C=O>[C:20]([NH:19][C:15]1[CH:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:40][CH:39]=4)=[O:43])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
40 mg (0,094 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butylpyridin-2-amine were dissolved in 2 ml of dry dimethylformamide and 12 μL (0.094 mmol) of p-trifluoromethylphenylisocyanate were added. The solution was stirred at room temperature for 3 hours. The reaction mixture was then poured into water and the product extracted several times with ethylacetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column eluted with dichloromethane-acetone 9/1, affording 40 mg (70% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].C(=O)([O-])[O-].[Ca+2].[C:15](Cl)(Cl)=[S:16].C(Cl)Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([N:7]=[C:15]=[S:16])[CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(F)cc1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1N=C=S
Temperature: 0 °C
Yield: 88.1 %

Procedure:
Under stirring at 0° C., a solution of 5-fluoro-2-methylaniline (1.23 g, 9.84 mmol) in methylene chloride (10 ml) was added dropwise to a mixture of calcium carbonate (2.46 g, 24.6 mmol) and thiophosgene (750 μl, 9.84 mmol) in a methylene chloride/water (1/1, 40 ml) mixture. After completion of the dropwise addition, the reaction mixture was stirred further at 0° C. for 35 minutes. The reaction mixture was poured in ice-1N HCR, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give 5-fluoro-2-methylphenyl isothiocyanate (1.45 g, 88%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH3:30][NH:31][CH2:32][CH3:33]>>[CH2:32]([N:31]([CH3:30])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:33]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C22H20ClN5O2, 421.9
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1.[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CS(C)=O>[O:31]1[CH2:30][CH:29]1[CH2:27][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[C:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1
Reactant: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(O)ccc12
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 54 %

Procedure:
To a solution of 50% aqueous DMSO (280 ml) containing sodium hydroxide (5.60 g, 140 mmol) was added 7-hydroxy-2,3-diphenylchromone (44.01 g, 140 mmol) and the resultant mixture was stirred until most of the solid went into the solution. Epichlorohydrin was then introduced into the suspension. The solution was stirred at room temperature (RT) for 2.5 days and solid formed during the reaction was collected from time to time (about twice a day). The white solid (total=47.58 g) was recrystallized from isopropyl alcohol several times to afford 28.15 g of relatively pure white prisms, m.p. 143°-145°; yield 54%. The mother liquor was concentrated to produce more crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1.[CH2:18]([C:20]1[CH:21]=[C:22]([CH3:32])[C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1)[CH3:19]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[C:22]([CH3:32])=[CH:21][C:20]([CH2:18][CH3:19])=[CH:25][N:24]=3)[CH2:27][CH2:28]2)=[O:8])=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cc1N1CCCS1(=O)=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 94.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoic acid (4.80 g) described in Preparation Example 178 and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (3.08 g) described in Preparation Example 53, the title compound (7.16 g) was obtained.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1.COS(OC)(=O)=O>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: Clc1cc(Cl)cc(I)c1
Agent: [Li+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: Cc1c(Cl)cc(I)cc1Cl
Yield: 93.2 %

Procedure:
To the mixture of LDA (5 mL, 8.6 mmol) in THF (20 mL) was added compound 1,3-dichloro-5-iodobenzene (2.35 g, 8.6 mmol) under −78° C. Then the mixture was added to the pre-cooled solution of (CH3)2SO4 (12 mL, 10.3 mmol) in THF (10 mL) under −78° C. The solution was concentrated under vacuum. The residue was diluted with EA, washed with 1N HCl, 1N NaOH, brine, dried over Na2SO4, concentrated under vacuum to give the desired product (2.3 g, 93% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:26][CH2:25][CH2:24][C:21]4[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc(CCNC2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 2-phenethylamine (61 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid. solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (30 mg) and a syn-form compound (24 mg).