Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[CH2:41]([N:49]1[CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:41]([N:49]1[CH:53]=[C:52]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=4)[O:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:3]=2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 75.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)piperidine-1-carboxylate (intermediate 13) (150 mg, 0.222 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (100 mg, 0.334 mmol) using Pd(PPh3)2Cl2 (8 mg, 0.011 mmol) and sodium carbonate (59 mg, 0.557 mmol) in toluene/ethanol/water (4/1/1 ml) to afford 120 mg (75.0% yield) of the titled compound after column purification using 1% methanol in DCM as eluent. MS: m/z=718.4 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].CS([O:11][C@H:12]1[CH2:15][C@@H:14]([CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:18])[CH2:13]1)(=O)=O.CCO[C:29]([CH3:31])=O>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:18][N:17]([CH2:16][C@H:14]1[CH2:15][C@H:12]([O:11][C:12]2[CH:15]=[CH:3][C:2]([CH2:5][N:17]3[CH2:31][CH2:29][CH2:14][CH2:16]3)=[CH:1][CH:13]=2)[CH2:13]1)[C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[O-]
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1)C(=O)OC(C)(C)C

Procedure:
A solution on intermediate 1,4-(pyrrolidin-1-ylmethyl)phenol (5.5 g, 62 mmol) and potassium tert-butoxide (3.5 g, 31 mmol) in DMSO (100 mL) was heated to 100° C. under vigorous stirring in a flow of argon. The mixture was stirred at this temperature for 15 min. A solution of compound 8 (4.5 g, 15.5 mmol) in DMSO (100 mL) and tetrabutylammonium bromide (1.5 g, 9 mmol) were added. The mixture was stirred at 100° C. for 1 h and cooled. The residue was dissolved in EtOAc (200 mL). The solution was washed with water (300 mL), 1 N NaOH (2×100 mL), brine, dried with Na2SO4, and evaporated. The residue was purified by chromatography (silica gel, 63/100 μm, 60 g, CHCl3/hexane 20:80→100:0, CHCl3/MeOH 100:0→80:20 to furnish the title compound (5.56 g, 96%). 1H NMR-data (DMSO-d6): 7.17 (d, 2H, Ph, J=8.6); 6.73 (d, 2H, Ph, J=8.6); 4.68-4.85 (m, 1H); 3.47 (s, 2H, CH2); 3.33 (d, 2H, CH2, J=7.8); 2.78 (s, 3H, NCH3); 2.50-2.60 (m, 1H); 2.33-2.44 (m, 4H); 2.00-2.27 (m, 4H); 1.62-1.71 (m, 4H); 1.38 (s, 9H, Boc).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])([O-:18])=[O:17]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)ccc2ccccc12
Reaction time: 8 h

Procedure:
2-hydroxynaphthalene (1 g.) is dissolved in boiling acetic acid (30 ml.), and when the solution temperature reaches 45° C, a molecular equivalent amount of concentrated nitric acid is slowly added. After standing overnight at room temperature, the reaction mixture is mixed with water. The precipitated solids are filtered, washed with water, and purified by chromatography on alumina, to yield 1-nitro-2-hydroxynaphthalene.
Reaction SMILES: [CH2:1]1[O:39][C:38]2[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8](=[O:35])[C@H:9]([NH:20][S:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([CH3:33])[C:25]=3[CH3:34])(=[O:23])=[O:22])[C@@H:10]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:11])=[CH:4][C:3]=2[O:2]1.[CH2:40]1[O:48][C:47]2[CH:46]=[CH:45][C:44]([CH2:49]O)=[CH:43][C:42]=2[O:41]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:1]1[O:39][C:38]2[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8](=[O:35])[C@H:9]([N:20]([CH2:49][C:44]3[CH:45]=[CH:46][C:47]4[O:48][CH2:40][O:41][C:42]=4[CH:43]=3)[S:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([CH3:33])[C:25]=3[CH3:34])(=[O:23])=[O:22])[C@@H:10]([O:12][Si:13]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:14][CH3:15])[CH3:11])=[CH:4][C:3]=2[O:2]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CC[Si](CC)(CC)O[C@@H](C)[C@@H](NS(=O)(=O)c1c(C)cc(OC)c(C)c1C)C(=O)OCc1ccc2c(c1)OCO2
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CC[Si](CC)(CC)O[C@@H](C)[C@H](C(=O)OCc1ccc2c(c1)OCO2)N(Cc1ccc2c(c1)OCO2)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.1 %

Procedure:
To a solution of 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl-amino)-3(S)-(triethylsilyloxy)butyric acid 3,4-methylenedioxybenzyl ester (3.3 g, 5.7 mmol) in benzene (100 mL) at 0° C. was added 3,4-methylenedioxyphenyl methanol (1.3 g, 8.5 mmol), tri-n-butylphosphine (2.1 mL, 8.5 mmol), followed by 1,1′-[azodicarbonyl]dipiperidine (2.2 g, 8.5 mmol). The reaction mixture was allowed to warm to room temperature over 4 h. After 72 h, the reaction mixture was diluted with an equal volume of hexanes, cooled to 0° C. for 2 h and filtered. The residue was concentrated and chromatographed (300 g SiO2, 15% ethyl acetate-hexanes) to afford 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-(triethylsilyloxy)butyric acid 3,4-methylenedioxybenzyl ester (3.3 g) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:7][C:8]([C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH2:1]([NH:7][C:8]([C:10]1[N:11]=[N:12][C:13]([N:20]2[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]2)=[CH:14][CH:15]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CCCCCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid hexylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethyl-phenyl)methanone, the title compound was obtained as a white powder (35% yield). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.85, 7.72, 7.56, 7.34, 6.97, 4.00, 3.90-3.64, 3.48-3.28, 1.58, 1.29, 0.85. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.5, 134.3, 132.8, 129.5, 127.6, 127.2, 126.9, 125.4, 46.4, 44.6, 44.4, 41.3, 39.4, 31.5, 29.5, 26.6, 22.6, 14.0. MS (ES+) m/z (%) 464 (M+1).
Reaction SMILES: [Li]CCCC.C([Mg]Br)C.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[N:15]=[CH:14]2.CN([CH:24]=[O:25])C>C1(C)C=CC=CC=1.C1COCC1>[CH3:20][N:16]1[C:17]2[C:13](=[CH:12][C:11]([CH:24]=[O:25])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: CN(C)C=O
Reactant: Cn1ncc2cc(Br)ccc21
Agent: CC[Mg]Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1ncc2cc(C=O)ccc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A suspension of n-BuLi (7.33 mL, 11.73 mmol) and ethylmagnesium bromide (5.76 mL, 5.76 mmol) in toluene (30 mL) was stirred at −30° C. for 30 min, and then a solution of 5-bromo-1-methyl-1H-indazole (2.25 g, 10.66 mmol) in THF (5 mL) was added. After 1 h, anhydrous DMF (4.95 mL, 64.0 mmol) was added at −10° C. The reaction mixture was allowed to warm to rt and stirred for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution and concentrated in vacuo. The residue was diluted with water, extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (hexane:EtOAc=10:1) to give the title compound as a white solid (1.37 g, 76%). 1H-NMR (400 MHz, DMSO-d6) δppm 10.02 (s, 1H), 8.41 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H), 7.78 (d, 1H), 4.09 (s, 3H). LCMS (method A): [MH]+=161, tR=4.00 min.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=O)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])=[O:26])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NC(C)(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH (SEQ ID NO: 2) and 0.692 g (3.35 mmol) H-Pro-NHC(CH3)3 were dissolved in 34 ml of dry dichloromethane. After cooling to 0° C., 1.35 ml (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHCO3 solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution (1×). The organic phase was dried over sodium sulfate and evaporated to dryness to yield 1.8 g of the product which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].Cl>C1C=CC=CC=1>[CH2:15]([O:14][C:12]([C:8]1[C:9]([CH3:11])=[CH:10][C:2]([NH:1][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[C:3]([C:7]=1[CH3:17])[C:4]([OH:6])=[O:5])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)cc(NC(=O)C(C)C)c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To an ice-cooled mixture consisting of 500 mg of 2-amino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid, 15 ml of benzene, and 0.3 ml of pyridine was added dropwise with stirring a solution of 323 mg of isobutyryl chloride in 2 ml of benzene. After completion of the addition, the reaction mixture was further stirred for 5 hours at room temperature, and then heated to reflux for one hour. After cooling, the mixture was shaken with dilute hydrochloric acid and the layers were separated. The slightly acidic aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated. The resulting residue was recrystallized from ethyl ether/n-hexane to yield 523 mg of 5-ethoxycarbonyl-2-isobutyrylamino-4,6-dimethylbenzoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([O-:3])=[O:2]
Reactant: Clc1ncccn1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Oc2ncccn2)c1
Temperature: 150 °C
Yield: 76.2 %

Procedure:
A mixture of 3-nitrophenol (6.85 g), 2-chloropyrimidine (5.13 g) and potassium carbonate (6.81 g) in dimethylsulfoxide (50 ml) was heated at 150° C. for 30 minutes. The mixture was cooled and poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was collected and washed with isopropyl ether to give 2-(3-nitrophenoxy)pyrimidine (7.41 g).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([C:36]([OH:38])=O)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl.[CH3:40][O:41][C:42]1[CH:52]=[CH:51][C:45]([CH2:46][NH:47][CH:48]2[CH2:50][CH2:49]2)=[CH:44][C:43]=1[O:53][CH2:54][CH2:55][CH2:56][O:57][CH3:58]>CN(C)C=O.O.C(N(CC)CC)C>[CH:48]1([N:47]([CH2:46][C:45]2[CH:51]=[CH:52][C:42]([O:41][CH3:40])=[C:43]([O:53][CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:44]=2)[C:36]([C@@H:32]2[O:33][CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:29])[CH2:31]2)=[O:38])[CH2:49][CH2:50]1
Reactant: COCCCOc1cc(CNC2CC2)ccc1OC
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Hydroxybenzotriazole (175 mg), triethylamine (145 μl) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg) were added to a solution of (2R)-(tert-butoxycarbonyl)morpholin-2-carboxylic acid (200 mg) and N-[4-methoxy-3-(3-methoxypropoxy)benzyl]cyclopropanamine hydrochloride (a compound of Reference Example 1(2), 313 mg) in N,N-dimethylformamide (5 ml) successively and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture under ice-cooling and it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=1/1) to give tert-butyl(2R)-2-({cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}carbonyl)morpholin-4-carboxylate (368 mg) as a colorless oil.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]([C:13]2[CH:21]=[CH:20][C:19]3[C:15](=[C:16]([CH3:23])[N:17]([CH3:22])[N:18]=3)[CH:14]=2)[C:9](=[O:24])[CH:8]=1)(=O)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][N:10]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[C:16]([CH3:23])[N:17]([CH3:22])[N:18]=4)[CH:14]=3)[C:9](=[O:24])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: Cc1c2cc(-n3ccc(COS(C)(=O)=O)cc3=O)ccc2nn1C
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(COc4ccc(Cl)cc4)cc3=O)ccc2nn1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 13.1 %

Procedure:
To a solution of [1-(2,3-dimethyl-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-4-yl]methyl methanesulfonate (140 mg) and 4-chlorophenol (77 mg) in N,N-dimethylformamide (5 ml) was added potassium carbonate (120 mg) at room temperature, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol). The obtained residue was purified by HPLC to give the title compound (20 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:22])[C:3]=1[O:23][CH3:24].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](Cl)=[O:36].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([O:22][C:35]([C:26]2[CH:27]=[CH:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)=[O:36])[C:3]=1[O:23][CH3:24]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1OC(=O)c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
3-(4-chloro-6-fluoro-2-hydroxy-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.10 g, 0.27 mmol) was dissolved in dioxane (10 ml) and the solution added with 2-naphthoyl chloride (0.062 g, 0.33 mmol), triethylamine (0.033 g, 0.33 mmol). After stirred for 2 hr, solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ether=4/1). Yield: 0.12 g, 0.23 mmol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:20])[S:8]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[OH-].[Na+].CN(C)[CH:25]=[O:26]>O>[CH3:6][N:7]([CH3:20])[S:8]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:25]=[O:26])=[CH:16][NH:17]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc2c(C=O)c[nH]c2c1
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Phosphorus oxychloride (0.76 ml, 0.008 mol) was slowly added at 0° C. under nitrogen atmosphere to anhydrous N,N-dimethyl formamide (3.8 ml), 0.05 mol). The mixture was stirred for 15 minutes and a solution of 6-(N,N-dimethyl aminosulfonyl)indole (1.74 g, 0.0078 mol) in anhydrous N,N-dimethylformamide (4 ml) was added dropwise below 2° C. The reaction mixture was allowed to stand at room temperature for 20 h and diluted with water (10 ml). The solution was neutralized (pH 8) with 10% aqueous solution of sodium hydroxide. The mixture was cooled and the precipitated solid was collected by filtration and was recrystallized from ethanol to yield 1.05 g (54%) of the entitled product (mp 250–252° C.).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=1>>[F:13][C:12]([F:15])([F:14])[C:11]1[N:6]2[CH:5]=[N:4][C:3]([C:1]#[C:2][C:27]3[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.17) (178 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a red solid (159 mg, 62%). MS (ISN) 517.1 [(M+H)+]; mp 255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](O)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=[O:21])[N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: C1CCNCC1
Product: C[C@H]1C(=O)N(CCC(=O)N2CCCCC2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 73 %

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and piperidine gave the titled compound in 73% yield as white solid. MS: 441.1 (MH+, 2Cl).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:28]1[CH:29]=[CH:30][C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.NC1C=CC=CC=1>C(Cl)Cl.CCN(C(C)C)C(C)C>[C:32]1([NH:34][C:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:15])[CH:33]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 121 %

Procedure:
A mixture of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinecarboxylic acid (1.0 g, 4.7 mmol), CDI (1.3 g, 7.0 mmol) and HOBT (0.5 g) in CH2Cl2 (20 mL) and Hunig's base (2.0 mL) was cooled to 0° C. and stirred for 15 minutes. Then aniline (520 mg, 5.6 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. The mixture was concentrated and purified by SiO2 chromatography (eluent: 1:1 EtOAc:petroleum ether) to afford the title compound (1.3 g) as an oil. 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 9H), 2.10 (m, 2H), 3.0 (m, 1H), 3.7-4 (m, 4H), 4.2 (m, 1H), 7.21 (m, 1H), 7.40 (m, 2H), 7.51 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][Br:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1cc(CBr)ccc1Cl
Yield: 30.4 %

Procedure:
A mixture of 2-chloro-5-methylbenzonitrile (10.6 g, 69.9 mmol), N-bromosuccinimide (12.2 g, 68.5 mmol), and dibenzoyl peroxide (349 mg, 1.44 mmol) in benzene (350 ml) was refluxed 1.5 hours, cooled, and evaporated to dryness under vacuum. The residue was suspended in 7:3 (v/v) hexane-dichloromethane, filtered, and evaporated. The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane to provide 4.8 g (30%) 4-chloro-3-cyanobenzyl bromide, m.p. 55°-58° C.