Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:16][CH:17]1[N:20]([CH2:21][C:22](=[O:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19](=[O:32])[CH2:18]1)[CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.CCOCC>[CH2:12]([S:16]([CH:17]1[N:20]([CH2:21][C:22](=[O:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19](=[O:32])[CH2:18]1)=[O:9])[CH2:13][CH2:14][CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCSC1CC(=O)N1CC(=O)CCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCS(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (0.81 g, 0.0047 moles) in dichloromethane (50 ml) was added dropwise to a stirred solution of 4-butylthio-N-(4-phenyl-2-oxobutyl)azetidin-2-one (1.2 g, 0.0039 moles) in dichloromethane (50 ml) at -60° C. Stirring continued at -60° C. for 30 minutes then the mixture was poured into an aqueous solution of sodium hydrogen carbonate and sodium sulphite. The layers were separated and the aqueous was extracted with dichloromethane. The combined extracts were dried and evaporated to give a solid which was slurried in ether, filtered, washed with ether and petrol. The solid was recrystallised from ether to give the title compound as white crystals, 280 mg (22%), mp 145-6° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13](O)=[O:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1.Cl.C([N:26]([CH:29](C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.CN([CH:47]=[O:48])C>C(Cl)Cl>[CH3:47][O:48][N:26]([CH3:29])[C:13](=[O:14])[CH:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[S:5][CH2:4][CH2:3][C:2]2([CH3:21])[CH3:1])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CCS2
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C(=O)N(C)OC)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.44 g of (RS)-2-(4,4-dimethyl-thiochroman-6-yl)-heptanoic acid was dissolved in a mixture of 2.1 ml DMF/4.2 ml of methylene chloride, and 1.35 g of MeO(Me)NH.HCl was added followed by 2.47 ml of diisopropylethylamine and 0.53 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 4 hours, then the volatiles were removed in vacuo. The residue was taken up in 100 ml ethyl acetate and washed with one portion of 50 ml of water, one portion of 50 ml of 1N hydrochloric acid, one portion of 50 ml of saturated aqueous sodium bicarbonate solution and one portion of 50 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo, giving 0.49 g of a yellow oil. The crude product was used without purification. 1H NMR (CDCl3): 7.27 (d, J=1.8 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.95 (dd, J=8.1, 1.8 Hz, 1H), 3.48 (s, 3H), 3.35-3.20 (m, 1H), 3.15 (s, 3H), 3.05-2.95 (m, 2H), 2.00-1.90 (m, 2H), 1.75-1.55 (m, 2H), 1.32 (s, 3H), 1.26 (s, 3H), 1.35-1.20 (m, 6H), 0.85 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10]1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.[OH2:25]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[C:7]([CH:8]=1)[CH:10]=[O:25])#[N:2]
Reactant: O
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: N#Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(O)c(C=O)c1
Temperature: 100 °C
Reaction time: 9 h
Yield: 13 %

Procedure:
To a solution of 4-cyanophenol (25.0 g) in trifluoroacetic acid (150 ml) was added hexamethylenetetramine (50.0 g) and the mixture was stirred at 100° C. for 9 hours. After cooling to room temperature, sulfuric acid (50 ml) and water (300 ml) were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with dichloromethane. The extract was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/ethyl acetate=19/1 as an eluant to give the desired compound (4.3 g, yield 13%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl.ClCCl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:8]([C:7]1[C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1.[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:1])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ncc(-c3ccc(O)cc3)nc2Cc2ccccc2)cc1
Product: Cc1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-hydroxyphenyl)pyrazine (coelenteramine) (c-5) (prepared by the method described in Adamczyk M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (199 mg, 718 μmol) was dissolved in pyridine (1.5 mL) and to this was added 4-(dimethylamino)pyridine (9.0 mg, 74 μmol) and cooled to 0° C. To this was added p-toluenesulfonyl chloride (410 mg, 2.15 mmol) and stirred for 2 h after warming to room temperature. To this were added 2 M hydrochloric acid and dichloromethane to stop the reaction and, after separating the aqueous layer and organic layer, it was extracted 3 times with dichloromethane and was washed with saturated aqueous solution of sodium sulfate and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was dissolved in methanol (5 mL) and to this was added 10% (w/v) aqueous, solution of sodium hydroxide (1.2 mL) while stirring at room temperature and stirred at 65° C. for 30 min. After cooling to room temperature, to this was added 2 M hydrochloric acid to stop reaction and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by column chromatography (23 g, n-hexane/ethyl acetate=3/2) to give 3-benzyl-5-(4-hydroxyphenyl)-2-[(4-methylphenyl)sulfonylamino]pyrazine (coelentera-p-tosylamide) (c-35) as a yellow solid (155 mg, 37.1% (2 steps)). Rf=0.25 (n-hexane/ethyl acetate=3/2). Mp. 181-182.5° C. UV (MeOH) λmax (log ε) 336.5 (4.10), 291.5 (4.26), 277 (4.27). UV (pH 7.4 PB) λmax (log ε) 351 (4.14), 282.5 (4.37). 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3H), 4.27 (s, 2H), 6.81 (d, J=8.7 Hz, 2H), 7.17-7.24 (m, 1H), 7.25-7.32 (m, 4H), 7.36 (d, J=7.6 Hz, 2H), 7.79 (t, J=8.7 Hz, 4H), 8.53 (s, 1H), 9.77 (s, 1H), 10.74 (s, 1H). IR (KBr, cm−1) 474, 525, 546, 567, 610, 667, 698, 743, 816, 839, 876, 941, 1088, 1148, 1165, 1215, 1269, 1321, 1364, 1404, 1447, 1495, 1516, 1593, 1609, 3283. HRMS (FAB+) m/z 432.1382 (M+H, C24H22N3O3S requires 432.1382).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH2:21]([NH:24][CH:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][C:29]([O:37][CH3:38])=[C:30]([O:35][CH3:36])[CH:31]=2)[CH2:26]1)[CH:22]=[CH2:23]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:24]([CH2:21][CH:22]=[CH2:23])[CH:25]3[CH2:34][CH2:33][C:32]4[C:27](=[CH:28][C:29]([O:37][CH3:38])=[C:30]([O:35][CH3:36])[CH:31]=4)[CH2:26]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: C=CCNC1CCc2cc(OC)c(OC)cc2C1
Product: C=CCN(CCCN1CCc2cc(OC)c(OC)cc2CC1=O)C1CCc2cc(OC)c(OC)cc2C1

Procedure:
The title compound is prepared from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 2-allylamino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene analogously to Example 1. Mp: 226°-228° C.
Reaction SMILES: ClC[CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([O-:7])=[O:6].[C:10]([NH:13][C:14]1[C:15]([I:30])=[C:16]([N:25]([C:27](=[O:29])[CH3:28])[CH3:26])[C:17]([I:24])=[C:18]([C:21]([O-:23])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11].[K+].[I-].[Na+].[CH3:34]N(C)C=O>>[C:10]([NH:13][C:14]1[C:15]([I:30])=[C:16]([N:25]([C:27](=[O:29])[CH3:28])[CH3:26])[C:17]([I:24])=[C:18]([C:21]([O:23][CH2:34][O:7][C:5](=[O:6])[C:4]([CH3:9])([CH3:8])[CH3:3])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: CC(=O)Nc1c(I)c(C(=O)OCOC(=O)C(C)(C)C)c(I)c(N(C)C(C)=O)c1I
Reaction time: 4 h

Procedure:
Chloromethylpivalate (12.0 ml., 82.6 mmol) in dry DMF (130 ml) is added dropwise during 20 minutes at 50° C. to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (50.0 g, 75.0 mmol) and sodium iodide (600 mg, 4.0 mmol) in dry dimethylformamide (DMF) (750 ml). The precipitate is removed by filtration after stirring for 4 hours and the solvent removed at reduced pressure. The residue is dissolved in chloroform (400 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure and the residue recrystallized from acetone to give the title compound: 26.6 g (53%); m.p. 232°-234° C. 1H-N.M.R. (CDCl3): delta=1.26 (s, C(CH3)3); 1.82 (s, N(CH3)COCH3); 2.22 (s, NCOCH3); 3.08 (s, NCH3); 6.02 (s, CH2); 8.15 ppm (s, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Reactant: CC(C)(C)C(=O)Cl
Product: COc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(C)(C)C)cc1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(4-methoxyphenyl)propan-2-amine (90a, 20 mg, 0.05 mmol) and Pivaloyl chloride (19 μl, 0.15 mmol). Yield 13 mg (55%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C([Li:15])CCC>CCCCCC>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Li:15])[CH2:2][CH3:3]
Reactant: [Li]CCCC
Reactant: CCCc1ccc(I)cc1
Solvent: CCCCCC
Product: [Li]c1ccccc1CCC

Procedure:
Air in a dried four-necked flask was replaced with nitrogen, and 10 ml of n-hexane and 2.86 g (0.0116 mol) of p-n-propyliodobenzene were introduced. Then, 10 ml of a hexane solution of n-butyl lithium (0.0116 mol) was gradually added thereto under stirring to obtain a hexane solution of n-propylphenyl lithium.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[C:21](=O)[CH3:22]>C(O)C>[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][C:20]1[S:17][C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:18][C:21]=1[CH3:22]
Reactant: CC(=O)C(Cl)Cc1cccc(Cl)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C)c(Cc3cccc(Cl)c3)s2)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A suspension of 78.7 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea and of 71.6 mg (0.33 mmol) of 3-chloro-4-(3-chlorophenyl)-2-butanone in ethanol (3 ml) was heated over night to reflux to yield a yellow solution. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel with methylene chloride/methanol 19/1 yielding 55 mg (43%) [5-(3-chloro-benzyl)-4-methyl-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 425.1/427.2 (100/43) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.16 (s, 1H), 7.64 (s, 1H), 7.53 (s, 1H), 7.35-7.19 (m, 6H), 7.01 (s, 1H), 4.01 (s, 2H), 3.78 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[Se](=O)=[O:38]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:38])[C:5]2[C:9]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:10][N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:4]=2[CH:3]=1
Reactant: O=[Se]=O
Reactant: Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-(6-Chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine (Example 106, Step 1; 450.9 mg, 0.911 mmol) was dissolved in dioxane (10 mL) and selenium dioxide (303 mg, 2.73 mmol) was added. The reaction mixture was stirred at reflux over the weekend. The reaction was filtered over celite, rinsed with ethyl acetate, and concentrated in vacuo. The residue was diluted with DCM and filtered over celite. The filtrate was concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (5-40% EtOAc/Hexanes) gave 6-chloro-3-morpholino-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde. MS ESI calc'd. For C30H26ClN4O2 [M+H]+ 509. found 509.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][C:12]([NH2:14])=O)[C:4]=2[CH2:3][CH2:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.C(=O)([O-])O.[Na+]>[O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][C:12]#[N:14])[C:4]=2[CH2:3][CH2:2]1
Reactant: NC(=O)CCc1nccc2c1CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCCc1nccc2c1CCO2
Temperature: 25 °C
Reaction time: 0.22 h
Yield: 33.5 %

Procedure:
To a solution of 3-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)propanamide (435 mg, 2.26 mmol) in dichloromethane (10 mL) were added pyridine (384 μL, 4.75 mmol) and trifluoroacetic anhydride (384 μL, 2.72 mmol), and the mixture was stirred at room temperature for 13 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→70/30) to give the title compound (132 mg, yield 33%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[Cl:18].[C:19](=[O:21])=[O:20]>CCOCC>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a mixture of 65.2 ml of n-butyllithium (1.61M in hexane) and 100 ml of anhydrous ether was added dropwise 29.3 g of 4-bromo-3,5-dichlorobenzotrifluoride (3) in 30 ml of anhydrous ether at -78° C., followed by stirring for 20 minutes. Subsequently, 10 g of dry ice crashed into small pieces was added in small portions to the reaction mixture, followed by stirring at room temperature for 1.5 hours. Ice water was added to the reaction mixture, the mixture was thereafter extracted with ether, and the combined extract was subjected to reverse extraction with 10% aqueous sodium carbonate solution. The aqueous layer was acidified with 6N hydrochloric acid, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 20.4 g of the desired product in the form of white crystals (crude yield 79.1%). mp 117°~118° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].[Cl-].[Na+]>ClC1C=CC=CC=1>[Cl:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:18]2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: O=C(N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1)c1ccccc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 114.8 %

Procedure:
Benzoyl chloride (0.15 g) was added to the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-aminopiperidine obtained in Example 14 (amount: 3 g), and the pH of the mixture was kept from 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours, and chlorobenzene (3 ml) and sodium chloride (0.5 g) were added thereto. The mixture was stirred at 90° C. for 10 minutes. The water layer was removed, and the solvent was evaporated under reduced pressure to obtain the title compound as yellow crystal (0.42 g, yield: 100%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.[CH3:16]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:50][C@@H:51]([C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:64]=1[F:70])[C:52]1[CH:57]=[CH:56][C:55]([P:58]([CH3:62])(=[O:61])[O:59][CH3:60])=[CH:54][CH:53]=1>CN(C=O)C.O>[F:70][C:64]1[CH:65]=[C:66]([F:69])[CH:67]=[CH:68][C:63]=1[C@H:51]([NH:50][C:8]([C:7]1[C:2]([OH:1])=[N:3][C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:5][CH:6]=1)=[O:10])[C:52]1[CH:53]=[CH:54][C:55]([P:58]([CH3:62])(=[O:61])[O:59][CH2:60][CH3:16])=[CH:56][CH:57]=1
Reactant: COP(C)(=O)c1ccc([C@@H](N)c2ccc(F)cc2F)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (200 mg, 0.97 mmol) and DIEA (380 mg, 2.91 mmol) in DMF (3 ml) was added HATU (370 mg, 0.97 mmol). The mixture was stirred for 5 min at room temperature and then compound 20-e (351 mg, 0.97 mmol) was added. The resulting mixture was stirred at 60° C. for 3 hour. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (dichloromethane:methanol=20/1) to provide the product, 20-f, (400 mg, 80%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:9][C:10]1[C:11]([OH:20])=[C:12]([O:18][CH3:19])[CH:13]=[C:14]([CH:17]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C.CCCCCC>CN(C=O)C>[I:9][C:10]1[CH:17]=[C:14]([CH:13]=[C:12]([O:18][CH3:19])[C:11]=1[O:20][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:15]=[O:16]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(I)c1OCc1ccccc1

Procedure:
Benzyl chloride (30 g, 0.24 mol) was added to a solution of 5-iodovanillin (60g, 0.216 mol) in DMF (250 mL) containing potassium carbonate (50 g). The mixture was stirred at 80° C. for 1.5 h or until TLC (hexane ethyl acetate; 4:1, v/v; Rf 0.5) showed the reaction to be complete. The mixture was then cooled and the solvent was decanted into ice water (1 L). The product was extracted with ethyl ether and the ethereal layer was washed with water, dried, and evaporated in vacuo to an oil, which solidified upon standing: mp 53°-54° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](/[CH:10]=[C:11](\[C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)/[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)=[O:4].[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(/C=C(/C(=O)O)c2ccc(C(C)(C)C)cc2)s1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C(=O)O)c2ccc(C(C)(C)C)cc2)s1
Yield: 81.5 %

Procedure:
To 5-[(E)-2-(4-tert-Butyl-phenyl)-2-carboxy-vinyl]-thiophene-2-carboxylic acid methyl ester (600 mg, 1.7 mmol) in 50 ml THF and 10 ml 1NHCl was added 10% palladium on carbon (1.5 g). The resulting mixture was stirred under 50 psi hydrogen gas for 2 hours. The catalyst was filtered off and the solvent was evaporated. The residue was sonicated in hexane for 30 seconds. The solvent was filtered to afford 5-[2-(4-tert-Butyl-phenyl)-2-carboxy-ethyl]-thiophene-2-carboxylic acid methyl ester as a yellow solid (480 mg, 81%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C(N(CC)CC)C.[CH2:32]([C:34]1[C:42]2[C:41]([NH2:43])=[CH:40][CH:39]=[CH:38][C:37]=2[N:36]([CH2:44][C:45]2[CH:49]=[CH:48][N:47]([CH3:50])[N:46]=2)[N:35]=1)[CH3:33]>CN1C(=O)CCC1.[OH-].[Na+].CCOC(C)=O>[CH2:32]([C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[NH:43][C:10]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][CH:2]=2)=[O:12])[N:36]([CH2:44][C:45]2[CH:49]=[CH:48][N:47]([CH3:50])[N:46]=2)[N:35]=1)[CH3:33]
Reactant: CCc1nn(Cc2ccn(C)n2)c2cccc(N)c12
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2ccn(C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 87 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (47.6 mg, 0.294 mmol) in NMP (4 mL) was added 2,4,6-trichlorobenzoyl chloride (45.9 μL, 0.294 mmol) and triethylamine (40.9 μL, 0.294 mmol). The reaction mixture was stirred for 30 minutes. 3-Ethyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (50 mg, 0.196 mmol) was added and the mixture was heated at 87° C. for three hours. The mixture was cooled to ambient temperature and diluted with 10% NaOH aqueous solution (5 mL) and EtOAc (20 mL). The organic phase was washed with water and brine and concentrated under reduced pressure. The residue was triturated with Et2O to give the final product (52 mg). MS (ES+APCI) m/z=400 (M+H).