Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CC([C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=2[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[CH:12]=2)=[O:8])C1.C[CH:25](C)[CH2:26][CH2:27][NH2:28].[CH3:30][CH:31]([CH3:35])[C:32](O)=[O:33].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:19]1[CH:18]=[CH:17][N:14]2[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]3[CH:5]=[CH:23][C:22]([CH:26]4[CH2:27][N:28]([C:32](=[O:33])[CH:31]([CH3:35])[CH3:30])[CH2:25]4)=[CH:21][CH:20]=3)=[CH:12][C:13]=12
Reactant: CC(C)C(=O)O
Reactant: CC(C)CCN
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccccc1C1CNC1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)C(=O)N1CC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1A, substituting -(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide for 3-methylbutan-1-amine and 2-methylpropanoic acid for 4-nitrobenzoic acid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.10 (t, J=5.9 Hz, 1H), 8.48 (d, J=7.0 Hz, 1H), 7.91 (m, 3H), 7.52 (d, J=1.0 Hz, 1H), 7.48 (m, 2H), 7.38 (s, 1H), 6.85 (dd, J=7.0, 1.7 Hz, 1H), 4.58 (t, J=8.6 Hz, 1H), 4.51 (d, J=5.9 Hz, 2H), 4.26 (t, J=9.0 Hz, 1H), 4.18 (dd, J=8.4, 6.0 Hz, 1H), 3.92 (m, 1H), 3.84 (m, 1H), 3.17 (d, J=5.0 Hz, 1H), 1.00 (dd, J=6.8, 1.6 Hz, 6H); MS (ESI(+)) m/e 377 (M+H)+.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[Cl:15][C:4]1[C:5]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2cccnc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ncnc2cccnc12
Temperature: 25 °C

Procedure:
To a stirred solution pyrido[3,2-d]pyrimidin-4-ol (B-2) (16 g, 109 mmol, 1.0 eq) in DCM (200 mL) and DMF (0.4 mL) at RT, oxalyl chloride (23.2 mL, 272 mmol, 2.5 eq) is added dropwise (over 5 min) and the resulting mixture is stirred at reflux overnight. The mixture is allowed to cool to RT and concentrated in vacuo. The residue is diluted with water (200 mL), neutralized with saturated aqueous NaHCO3 solution below 10° C. to adjust the pH to 8-9 and then extracted with ethyl acetate (4×100 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (16-50% ethyl acetate-petroleum ether) to afford the product, 4-chloropyrido[3,2-d]pyrimidine (B-3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([Cl:32])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>N1C=CC=CC=1.ClCCl>[ClH:32].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:30]([CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:20]=[CH:19][N:18]=[CH:23][CH:22]=3)[CH2:29][CH2:28]2)=[O:31])=[N:6][CH:7]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: Cc1ccc(NC(=O)c2ccccc2N)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccccc2NC(=O)C2CCN(c3ccncc3)CC2)nc1
Product: Cl
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a stirring solution of N-(5-methylpyridin-2-yl)-2-aminobenzamide (0.28 g, 1.2 mmol) in pyridine (5 mL) and dichloromethane (40 mL) was added a solution of 1-(4-pyridinyl)piperidin-4-ylcarbonyl chloride (0.55 g, 2.5 mmol) in dichloromethane (40 mL). After stirring overnight, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (300 mL) and 1 N NaOH (150 mL). The organic phase was separated and washed again with 1 N NaOH, followed by water and brine, then dried with MgSO4, filtered and concentrated in vacuo. The residue was then purified by preparative RPHPLC (C18), eluting with a linear gradient of 90/10 to 50/50 (0.01% HCl/acetonitrile) over 180 min. The pure product containing fractions were combined and lypholized to give 222 mg (40%) of a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[F:36][C:37]([F:43])([F:42])[CH2:38][CH2:39][CH2:40]Br>CN(C=O)C.O.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:40][CH2:39][CH2:38][C:37]([F:43])([F:42])[F:36])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-(benzoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (3.7 g, 9.61 mmol) in 40 mL of anhydrous DMF at 0° C. was added potassium tert-butoxide (1.6 g, 14.4 mmol) in one portion. The reaction mixture was stirred 20 m. and 4,4,4-trifluoro-1-bromobutane (Lancaster; Windham, N.H.; 2.6 g, 13.4 mmol) was added. The reaction mixture was warmed to room temperature over 30 min. and the n diluted with 100 mL of water and 200 mL of methylene chloride. The layers were separated. The organic layer was extracted with water and dried over sodium sulfate. Purification of the crude product by silica gel column chromatography (0-3% ethyl acetate/methylene chloride) gave 1.52 g (32%) of an off white foam.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.OB(O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)CCc1oc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 87.8 %

Procedure:
A mixture of methyl 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (1.50 g), dihydroxyphenylborane (650 mg), sodium hydrogen carbonate (1.68 g), tetrakis(triphenylphosphine)palladium (250 mg), toluene (50 mL), ethanol (25 mL) and water (25 mL) was stirred under an argon atmosphere with heating under reflux for 12 hrs. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography. Methyl 3-[4-(4-chlorophenyl)-2-phenyl-5-oxazolyl]propionate (1.50 g, 88%) was obtained as a yellow oil from a fraction eluted with hexane-ethyl acetate (6:1, volume ratio).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Cc1ccccc1N
Product: Cc1ccccc1Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 23.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and o-toluidine (0.07 mL, 0.65 mmol) to provide 240 (31 mg, 21% yield) as a yellow/green powder. LC-MS (M+H (parent)=302, obsd.=302). 1H NMR (400 MHz, d6-DMSO): δ 11.63 (s, 1H), 8.44 (dd, 1H), 8.37 (s, 1H), 8.33 (dd, 1H), 8.10 (d, 1H), 7.55 (d, 1H), 7.33 (m, 2H), 7.25 (m, 2H), 7.11 (m, 1H), 7.07 (dd, 1H), 2.24 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[CH2:17]([C:12]1[C:11]([OH:14])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([F:3])[CH:13]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Oc1ccc(F)c2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1cc(F)c2cccnc2c1O
Temperature: 0 °C
Yield: 96.1 %

Procedure:
After a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel was replaced with Ar, 5 mL of DMF and NaH (0.88 g, 60 mass % article, 22.0 mmol) were placed therein and the temperature of the mixture was cooled to 0° C. or lower in an ice bath, followed by stirring of the mixture. 5-Fluoro-8-quinolinol (3.42 g, 21.0 mmol) dissolved in 30.0 mL of DMF was added dropwise to this over 1 hour. After the mixture was stirred at the same temperature for 30 minutes, allyl bromide (2.54 g, 21.0 mmol) was added dropwise thereto. Further, the mixture was stirred at the same temperature for 30 minutes, and then the internal temperature was slowly raised to 150° C. and the mixture was heated and stirred for 2 hours. This was cooled to room temperature, and then the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. Then, ethyl acetate was removed under reduced pressure and the resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 4.10 g of 7-allyl-5-fluoro-8-quinolinol as a white solid (yield: 96.0%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:19]([OH:21])=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)(=O)C>CCOCC>[CH3:24][O:20][C:19](=[O:21])[C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
(O-benzyl) Boc Serine 2.00 g (6.8 mmoles) was dissolved in 50 ml of ether. To this solution was added an ether solution containing freshly prepared diazomethane prepared from 5 g of Diazald using the procedure from Aldrich Technical Bulletin number AL-180. After stirring the solution for 30 minutes, glacial acetic acid was added dropwise until the solution became clear. The resulting solution was concentrated in vacuo to yield 2.00 g, 95% as a clear oil. 1H: (CDCl3); 7.3 (d, 5H), 5.5 (bs, 1H), 4.5 (s, 2H), 3.8 (m, 2H), 3.7 (s, 3H), 1.4 (s, 9H)
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=NC2C(=O)CCC[C:21]=2[CH:22]=1.[ClH:24].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>>[ClH:24].[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([C:27](=[O:28])[C:26]3[CH:25]=[CH:29][C:22]([CH3:21])=[C:13]([CH3:14])[CH:12]=3)[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1CCCC2
Reactant: Cc1cnc2c(c1)CCCC2=O
Reactant: C1CCOC1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCCc3c(C)ccnc32)cc1C
Reaction time: 0.5 h

Procedure:
After 0.5h, a 1.36M solution of butyl lithium (11.2ml, 0.017m) was added at 0.° C. and the mixture stirred at this temperature for a further 0.5h. A solution of 3,4-dimethylbenzonitrile (2.6g, 0.02m) in THF (20ml) was added rapidly and after 0.5h a solution of 2M hydrochloric acid (40ml) was added and the aqueous phase separated. This was basified with solid potassium carbonate and the mixture extracted with ether. The mixture was purified by chromatography on silica using ether as eluant. The isolated product was dissolved in ether and acidified with ethereal HCl to give 5,6,7,8-tetrahydro-4-methyl-8-(3,4-dimethylbenzoyl)quinoline hydrochloride (2.5g, 53%) m.p. 237°-9° C. (Found; C,72.25; H, 7.0;N, 4.4 C19H21NO.HCl requires C, 71.8; H, 7.1; N, 4.3%).
Reaction SMILES: [Na].[N+:2]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:4])=[O:3].[CH:11]1[CH:16]=[C:15]([CH:17]=[O:18])[C:14]([CH:19]=[O:20])=[CH:13][CH:12]=1.OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:18][CH:17]1[C:15]2[C:14](=[CH:13][CH:12]=[CH:11][CH:16]=2)[CH:19]([C:5]2([N+:2]([O-:4])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:20]1
Reactant: CO
Reactant: O=[N+]([O-])C1CCCCC1
Reactant: O=Cc1ccccc1C=O
Agent: O=S(=O)(O)O
Agent: [Na]
Product: COC1OC(C2([N+](=O)[O-])CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium metal (0.46 g, 0.02 g-atom) is added to MeOH (35 mL) portionwise at rt. When a homogeneous solution is obtained, nitrocyclohexane (12.92 g, 100 mmol) is added, followed by o-phthalaldehyde (8.38 g, 60.0 mmol). The resulting solution is stirred at rt overnight. The solution is brought to pH 2 by adding 1 N H2SO4 and stirred at rt for 60 min. White solids precipitate. The mixture is filtered, and the filtrate, from which an oil separates, is made basic by adding 10% NaOH solution. The solution is concentrated in vacuo to remove the MeOH, and the resulting aqueous solution is extracted twice with Et2O. The combined organic layers are washed once with brine, dried (MgSO4), filtered, and concentrated. After final drying on a vacuum pump, a yellow oil is obtained (17.29 g, 100%). The following data were obtained on a ca. 1:1 mixture of the cis and trans diastereoisomers. 1H NMR (CDCl3) 7.45-7.35 (m, 3), 7.20-7.10 (m, 1), 6.26 and 5.55 (isomer I, 2 d, 1 total, J=2.7, and 2.3 Hz, respectively), 5.98 and 5.38 (isomer II, 2 s, 1 total), 3.59 and 3.36 (isomers I and II, respectively, 2s, 3 total), 2.59 (m, 2), 2.22 (m, 2), 1.95-1.10 (m, 6).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2Cl)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc(C(=O)Nc2ccc(C(C)(C)C)cc2)c1Cl
Reactant: NCc1ccncc1
Product: Cn1ncc(C(=O)Nc2ccc(C(C)(C)C)cc2)c1NCc1ccncc1
Temperature: 160 °C

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide (530 mg, 1.80 mmol) and powered 40% KF/Alumina (1.04 g, effective 6.0 mmol of KF) were combined and treated with IpOH (6 mL). 4-(Aminomethyl)pyridine (3.9 g, 36 mmol) was added. The headspace of the reaction vessel was purged with argon and the reaction vessel was sealed. The reaction was then heated to 160° C. overnight with stirring. The reaction was cooled to RT and filtered under vacuum, washing the collected solid with fresh IpOH. The filtrate was concentrated under reduced pressure and the recovered material was eluted through a 17×2.5 cm column of silica gel with a 14:7:7:1 and 7:7:7:1 Hexane:MtBE:CH2Cl2:MeOH step gradient giving 1-methyl-5-[(pyridin-4-ylmethyl)-amino]-1H-pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide as a white foamy solid. MS: 364 (M+1). Calc'd. for C21H25N5O—363.46.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([O:14]C)=[O:13])=[CH:8][NH:9]2)=[CH:5][C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)=[C:18]([O:29][CH3:30])[CH:17]=1.O1CCCC1.[OH-].[Na+]>CO>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:5][C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)=[C:18]([O:29][CH3:30])[CH:17]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)c(OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1OC[C@@H]1CCCN1
Temperature: 65 °C
Reaction time: 41 h

Procedure:
To a solution of (S)-methyl 6-chloro-5-(3-methoxy-4-(pyrrolidin-2-ylmethoxy)phenyl)-1H-indole-3-carboxylate hydrochloride (22.6 mg, 0.050 mmol) in methanol (0.26 mL) was added tetrahydrofuran (0.26 mL) and sodium hydroxide (1 N in water, 0.26 mL, 0.26 mmol). The mixture was then sealed and heated to 65° C. After 41 h, the mixture was allowed to cool to 23° C., concentrated in vacuo, diluted with water (1 mL), then acidified to pH 7.5 with hydrochloric acid (1 N in water). The solid was filtered and purified by reverse phase HPLC to provide the title compound. MS (ES+) 401.2 (M+H)+. HPLC retention time: 1.44 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03% NH4OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:28].[OH:29]OS([O-])=O.[K+]>CO>[CH:1]1([CH2:7][C:8]2([C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH3:27])(=[O:29])=[O:28])=[CH:24][CH:25]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O
Reactant: CSc1ccc(C2(CC3CCCCC3)c3ccccc3-c3nccn32)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C2(CC3CCCCC3)c3ccccc3-c3nccn32)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 5-(cyclohexylmethyl)-5-[4-(methylthio)phenyl]-5H-imidazo[2,1-a]isoindole (38 mg) in MeOH (1 mL) was added water drop wise until the clear solution started to become turbid. Oxone (69 mg) was added at this time and stirred at room temperature 21 h. The reaction mixture was then diluted with MeOH, filtered and the filtrate was concentrated. Purification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 15-85% MeCN/water containing 0.05% NH4OH over 20 min at 20 mL/min) afforded title compound as a white solid. HRMS. Found, 407.1802; calcd for (M+H)+, 407.1788. 1H NMR (500 MHz, CDCl3): δ 7.89-7.85 (m, 3 H); 7.45-7.39 (m, 1 H); 7.37 (d, J=1.28 Hz, 1 H); 7.32-7.26 (m, 3 H); 7.24 (d, J=8.00 Hz, 1 H); 6.99 (d, J=1.29 Hz, 1 H); 3.01 (s, 3 H); 2.60 (dd, J=14.41, 4.34 Hz, 1 H); 2.41 (dd, J=14.40, 4.00 Hz, 1 H); 1.54-1.38 (m, 3 H); 1.33-1.19 (m, 2 H); 1.10-0.73 (m, 7 H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[N+:9]([C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([CH2:16][C:17](OCC)=[O:18])=O)([O-:11])=[O:10].Cl>CO>[N+:9]([C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:17](=[O:18])[CH:16]=1)([O-:11])=[O:10]
Reactant: CCOC(=O)CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: CO
Product: O=c1cc(-c2ccccc2[N+](=O)[O-])c2ccc(O)cc2o1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
0.1 mole resorcinol is reacted with 0.1 mole ethyl o-nitrobenzoylacetate in methanol at 0° C. while passing through for one hour gaseous hydrochloric acid, and then maintaining at ambient temperature for 24 hours. After recrystallisation from an acetone-water mixture, there are obtained 18 grams 4-o-nitrophenyl-7-hydroxy-coumarin. This compound melts at 230° C.
Reaction SMILES: [F:1][C:2]1([F:55])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([OH:42])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:43]([F:54])[C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)[CH2:4][CH2:3]1.C1(C)C(S(O[CH2:66][CH2:67][C:68]([OH:71])([CH3:70])[CH3:69])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[F:55][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([O:42][CH2:69][C:68]([CH3:70])([OH:71])[CH2:67][CH3:66])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[C@@H:43]([F:54])[C:44]2[CH:45]=[CH:46][C:47]([C:50]([F:52])([F:51])[F:53])=[CH:48][CH:49]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccccc1S(=O)(=O)OCCC(C)(C)O
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(O)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(O)COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1
Temperature: 80 °C
Reaction time: 2.8 h
Yield: 71.8 %

Procedure:
To 570 mg (0.741 mmol) of 2-[4-((5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)piperidin-1-yl]pyrimidin-5-ol, which was prepared by a method similar to that of Reference Example 14, 288 mg (1.11 mmol) of 3-hydroxy-3-methylbutyl toluenesulfonate and 198 mg (1.43 mmol) of potassium carbonate, 2 ml of N,N-dimethylformamide was added, and the reaction mixture was stirred at 80° C. for 2.8 hours. After completion of the reaction, toluene and water were added to the reaction solution to separate an organic phase. Further, the reaction mixture was extracted with toluene from the aqueous phase. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=78/22-50/50 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, then n-heptane was added thereto, and the precipitate was obtained by filtration to provide 455 mg of the title compound as a white solid (yield: 72%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15](O)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.P(Br)(Br)([Br:24])=O>CN(C=O)C.CCOC(C)=O.O>[Br:24][C:15]1[CH:16]=[CH:17][N:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:20]([CH3:21])=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:5]=3)[CH:8]=2)[C:13](=[O:19])[CH:14]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: O=P(Br)(Br)Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (3.0 g) in DMF (25 ml) was added phosphorus oxybromide (2.17 ml) at room temperature, and the mixture was stirred at 110° C. for 1 h. The mixture was diluted with EtOAc and water, quenched with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.70 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[NH:7][N:6]=1)=[O:4]>C(O)(=O)C.O1CCCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)[nH]n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
10.25 g (60 mmol) of 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 75 mL of acetic acid (AcOH) and 75 mL of tetrahydrofuran (THF). After a vacuum and argon cycle, 2.05 g (20% weight) of palladium on carbon (Pd/C 10 wt %) was added, the mixture was degassed again and filled with hydrogen from a balloon. The reaction mixture was stirred at rt under hydrogen atmosphere for 2 days. Analysis by thin layer chromatography (TLC) showed complete conversion of starting material to product. The mixture was then concentrated, the resulting purple colored oil was taken in 300 mL of ether, the finely dispersed purple impurity was filtered off, and the ether filtrate was evaporated to give 7.23 g (85% yield) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid as indicated by 1H NMR; whose structure was confirmed using 1H NMR