Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C1COCC1.CN(C=O)C>[Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH:10]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(-c2c[nH]c3ccccc23)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Cl)ncc3Br)c3ccccc32)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
3-(5-Bromo-2-chloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 5, 1.23 g, 4 mmol) in THF (40.0 ml) and DMF (5 ml) was cooled to −10° C. Sodium hydride (0.19 g, 4.80 mmol) was added and the reaction was stirred at −10° C. for 30 min. 4-Methylbenzene-1-sulfonyl chloride (0.84 g, 4.40 mmol) was then added. The reaction mixture was allowed to warm to RT and stirred for 15 h. Water (10 mL) was added and the resultant solids were collected by vacuum filtration to give the title product (1.36 g, 73.5%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]=1[OH:22])([CH3:11])([CH3:10])[CH3:9].C=O.[CH2:25](NCCCC)CCC>C(O)C>[C:18]([C:14]1[CH:15]=[C:16]([CH:17]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:13]=1[OH:22])[CH2:25][C:4]1[CH:3]=[C:2]([SH:1])[CH:7]=[CH:6][N:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CCCCNCCCC
Reactant: Sc1ccncc1
Agent: C=O
Solvent: CCO
Product: CC(C)(C)c1cc(Cc2cc(S)ccn2)cc(C(C)(C)C)c1O
Temperature: 50 °C

Procedure:
4-Mercaptopyridine (11.1 g, 0.1 mol), 2,6-di-tertbutylphenol (20,6 g, 0.1 mol), paraformaldehyde (3.0 g, 0.1M) and di-n-butylamine (1 ml) are heated at 80° C. for two and half hours, after which time, thin layer chromatography (t.l.c.) showed the reaction to be complete. The reaction mixture is cooled to 50° C., ethanol (100 ml) is added and the product is crystallised as a pale yellow solid (24.7 g, 78.4% of theory) of m.p. 169°-171° C. (Found C=73.30; H=8.49; N=4.31; S=9.71 C20H27NOS requires C=72.95; H=8.21; N=4.26 and S=9.73%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C([Li])(C)(C)C.[Br-].[Mg+2].[Br-].Br[C:25]1[CH2:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2>CCOCC>[C:12]([C:4]1[CH:3]=[C:2]([C:25]2[CH2:33][C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: BrC1=Cc2ccccc2C1
Agent: [Br-]
Agent: [Li]C(C)(C)C
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)(C)c1cc(C2=Cc3ccccc3C2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
1-Bromo-3,5-di-t-butylbenzene (47.2 g, 0.175 mol) was dissolved in ether (500 mL) and cooled to -70° C. t-Butyllithium (200 mL of 1.7 M solution in pentane, 0.34 mol) was added at -70° C. over a two hour period. The solution was allowed to warm to room temperature slowly. Magnesium bromide etherate (46.5 g, 0.18 mol) was added and the slurry was stirred for one hour. The mixture was then cooled to 5° C. and 2-bromoindene (34.2 g, 0.18 mol) was added. The mixture was warmed to room temperature and then refluxed for three hours. The solution was cooled to room temperature and the reaction was quenched carefully with water. The layers were separated and the organics washed with salt brine and dried over magnesium sulfate. The solvents were evaporated and the product was distilled twice and recrystallized from hexane to give 37.1 g of product (70%).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Li]CCCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>C1COCC1>[CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:15])([CH3:17])[CH3:16])(=[O:12])=[O:11])=[C:7]([B:27]([OH:28])[OH:26])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
5-iso-Butyl-N-tert-butylthiophene-2-sulfonamide (10.6 g, 0.039 mol, see step (b) above) was dissolved in THF (165 mL) under N2 and then cooled to −78° C. n-BuLi (1.6 M, 60.19 mL, 0.096 mol) was added via a syringe. The reaction mixture was stirred at −20° C. for 4 h. The tri-iso-propylborate (13.3 mL, 0.058 mol) was then added via a syringe and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with 2 M HCl (20 mL). The organic phase was separated and the water phase was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine, dried and concentrated in vacuo. The product was used without further purification. MS (ESI+) m/z: 236.8
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:6]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[CH:7][C:8]([CH3:27])=[C:9]([CH:26]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:4].Cl.[F:33]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl>>[Br:1][CH2:2][C:3]([C:5]1[C:6]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[CH:7][C:8]([CH3:27])=[C:9]([CH:26]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)([F:33])[CH2:14][CH2:13]1)=[O:11])=[O:4]
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: Cc1cc(C2CCC2)c(C(=O)CBr)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Product: Cc1cc(C2CCC2)c(C(=O)CBr)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for preparation of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 235.2) but using compound 11.2 HCl salt instead of compound 1.5.
Reaction SMILES: Cl.C(O)C.[Br:5][C:6]1[C:7]([F:17])=[C:8]([CH3:16])[C:9]([F:15])=[C:10]([N+:12]([O-])=O)[CH:11]=1>O.[Fe]>[Br:5][C:6]1[C:7]([F:17])=[C:8]([CH3:16])[C:9]([F:15])=[C:10]([CH:11]=1)[NH2:12]
Reactant: Cc1c(F)c(Br)cc([N+](=O)[O-])c1F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c(F)c(N)cc(Br)c1F
Temperature: 50 °C
Yield: 52.9 %

Procedure:
To a suspension of iron powder (26.6 g, 100 mesh) in water (60 ml), with vigorous stirring at 50° C., was slowly added concentrated hydrochloric acid (4 ml). After hot ethanol (120 ml) was mixed, 3-bromo-2,6-difluoro-5-nitrotoluene (40 g) was added dropwise to the suspension at 75° to 78° C. during 30 minutes. The reacting mixture was refluxed for 1 hour, insoluble materials were filtered off through Celite pad, and then the materials were washed with hot ethanol. To the filtrate and washings were added ice water (400 ml) and the resulting precipitate was recrystallized from hexane to give the title compound (18.66 g) as pale brown needles, mp 68°-68.5° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:11](=[O:22])[N:12]([CH3:21])[C:13]3[C:18]([C:19]=2Cl)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.C[OH:25]>>[C:1]1([NH:7][C:8]([C:10]2[C:11](=[O:22])[N:12]([CH3:21])[C:13]3[C:18]([C:19]=2[OH:25])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:12]1[CH:13]=[CH:18][CH:19]=[CH:10][CH:11]=1
Reactant: Cn1c(=O)c(C(=O)Nc2ccccc2)c(Cl)c2ccccc21
Reactant: CO
Agent: N
Product: Cn1c(=O)c(C(=O)Nc2ccccc2)c(O)c2ccccc21
Product: c1ccncc1
Temperature: 100 °C

Procedure:
A reaction mixture consisting of N-phenyl-4-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (12 parts), concentrated aqueous ammonia (25 parts), and methanol (60 parts) is heated in an autoclave at 100° C. for 48 hours. After cooling to room temperature the precipitate formed is filtered off and recrystallized from pyridine and dried to give N-phenyl-4-amino-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (1). M. p. 248° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[N:4][C:5]([F:11])=[C:6]([Cl:10])[C:7]=1[CH2:8][OH:9].[Cl:13][C:14]([Cl:24])=[CH:15][C@@H:16]1[C@H:18]([C:19](Cl)=[O:20])[C:17]1([CH3:23])[CH3:22]>>[Cl:13][C:14]([Cl:24])=[CH:15][C@@H:16]1[C@H:18]([C:19]([O:9][CH2:8][C:7]2[C:2]([Cl:1])=[C:3]([F:12])[N:4]=[C:5]([F:11])[C:6]=2[Cl:10])=[O:20])[C:17]1([CH3:22])[CH3:23]
Reactant: OCc1c(Cl)c(F)nc(F)c1Cl
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1c(Cl)c(F)nc(F)c1Cl

Procedure:
By the method of Example 2, 0.5 g (0.002 mole) of 3,5-dichloro-2,6-difluoro-4-hydroxymethylpyridine (Example 15) was reacted with 0.5 g (0.002 mole) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride to produce, after purification using the Chromatotron, 0.3 g of (3,5-dichloro-2,6-difluoropyridin-4-yl)methyl cis-3-(2,2-di-chloroethenyl)-2,2-dimethylcyclopropanecarboxylate, compound 22 in the Tables below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:34])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>ClCCl.CO>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:34][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: COc1cc(N)ccc1OCCN1CCOCC1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCOCC1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 3-methoxy-4-(2-morpholin-4-ylethoxy)phenylamine. Yield: 20 mg (6.9% of theory); melting point: 209° C.-211° C.; C23H22ClF3N2O4 (M=482.89); calc.: molecular ion peak (M+H)+: 483/485; found: molecular ion peak (M+H)+: 483/485; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: N[C:2]1N(CC)[N:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=CC(S(C(F)(F)F)(=O)=O)=C[C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(O)(=O)C.O>[C:12]([OH:14])(=[O:13])[C:11]1[C:4](=[CH:3][CH:2]=[CH:18][CH:10]=1)[NH2:5]
Reactant: CCn1nccc1N
Reactant: O=C(O)c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-amino-1-ethylpyrazole (0.56 g, 5 mmol), 2-chloro-5-(trifluoromethylsulfonyl)benzoic acid (1.4 g, 4.9 mmol), K2CO3 (0.69 g, 5 mmol), Cu(OAc)<2>(0.1 g) and DMF (10 ml) is refluxed for 4 hours and then is cooled to room temperature and is allowed to stand for about 3 days. Water is added to the reaction mixture, and then the solution is acidified with acetic acid to a pH of about 5. The mixture is extracted with CH2Cl2 and then the CH2Cl2 layer is evaporated to afford N-(1-ethylpyrazol-5-yl)-5-trifluoromethylsulfonyl)anthranilic acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[C:25]([C@H:29]1[CH2:38][CH2:37][C@H:36]2[C@@:39]3([CH:59]=[CH2:60])[C@H:48]([C@@H:49]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]O)[CH2:50][C@:30]12[CH2:31][O:32][SiH:33]([CH3:35])[CH3:34])[C:47]1[CH:46]=[CH:45][C:44]([O:57][CH3:58])=[CH:43][C:42]=1[CH2:41][CH2:40]3)([CH3:28])([CH3:27])[CH3:26].[Br:61]C(Br)(Br)Br>ClCCl>[Br:61][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][C@H:49]1[CH2:50][C@@:30]2([CH2:31][O:32][SiH:33]([CH3:35])[CH3:34])[C@@H:36]([CH2:37][CH2:38][C@@H:29]2[C:25]([CH3:26])([CH3:28])[CH3:27])[C@@:39]2([CH:59]=[CH2:60])[C@H:48]1[C:47]1[CH:46]=[CH:45][C:44]([O:57][CH3:58])=[CH:43][C:42]=1[CH2:41][CH2:40]2
Reactant: BrC(Br)(Br)Br
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCO)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCBr)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Temperature: 0 °C
Yield: 97.1 %

Procedure:
1.62 g of triphenylphosphine and 420 mg of imidazole are added in succession to a solution of 2.11 g of alcohol 8 in 41 ml of dichloromethane. The solution is cooled to 0° C., and 2.05 g of tetrabromomethane is added. The reaction mixture is heated to room temperature and stirred until the reaction is completed. For working-up, it is diluted with dichloromethane, the organic phase is washed with water and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. Column-chromatographic purification (cyclohexane/ethyl acetate) yields 2.3 g of bromide 10 as a colorless, viscous mass (GC-MS: m/z theor.: 574, pract.: 574).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH:26]3[CH2:28][CH2:27]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C2CC2)c1OC
Temperature: 140 °C
Yield: 59.6 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.347 g), cyclopropyl boronic acid monohydrate (0.087 g), palladium chloride dppf adduct with DCM (0.07 g) and cesium carbonate (0.8 g) in THF (9 ml) and water (1 ml) was sealed in a microwave vial and degassed. The mixture was then heated in the microwave at 140° C. for 15 minutes. After cooling, the mixture was dried (MgSO4) and filtered through Celite. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of t-butyl methyl ether and cyclohexane with a gradient from 0-60% to give ethyl 6-(benzenesulphonylmethyl)-3-cyclopropyl-2-methoxybenzoate (0.187 g) as a gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][CH:33]1[CH2:35][CH2:34]1>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC2CC2)C1=O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a solution of 0.6 g (2.2 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 10 ml of tetrahydrofuran at −75° C. 2.2 ml (2.2 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 0.35 g (2.6 mmol) of bromomethyl-cyclopropane was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were re-extracted with water and dried (MgSO4) to yield 0.285 g (40%) of ((S)-1-cyclopropylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH2:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[C:33]([CH2:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3CC)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3CC)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M215) (255 mg, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (148 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[N:3]=1.CCN(CC)CC.[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:26]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:27])[CH:11]=[CH:10]2
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc2cc(Br)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(Br)ccc2n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-amino-6-bromoquinoline (250 mg, 1.121 mmol) in CH2Cl2 (7 mL) was added Et3N (0.94 mL, 6.726 mmol) and DMAP (137 mg, 1.121 mmol) followed by cyclohexanecarbonyl chloride (0.46 mL, 3.362 mmol). The reaction mixture was stirred at rt for 20 min and then diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 40% ethyl acetate/hexanes) to give the product. LCMS-ESI+: calc'd for C16H18BrN2O: 333.0 (M+H+); found: 333.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:12])=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[F:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:12])=[CH:4][N:3]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CCCNc1nc(Cl)ncc1I
Reactant: Nc1cccc(F)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1I
Temperature: 45 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 596 mg) and 3-fluoroaniline (1.11 g) in N-methylpyrrolidone (10 mL), (1S)-(+)-10-camphorsulfonic acid (2.32 g) was added at room temperature, and the mixture was stirred at 40 to 50° C. for 6 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate was added to the reaction mixture. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain N2-(3-fluorophenyl)-5-iodo-N4-propylpyrimidine-2,4-diamine (F2, 685 mg) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH2:16]([N:23]1[CH:27]=[C:26]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:25]=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:27]=[C:26]([CH2:28][N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])[CH:25]=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2cnn(Cc3ccccc3)c2)cc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1cnn(Cc3ccccc3)c1)c1ccc(C(C)C)cc1)CCC2
Yield: 45.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g) and [(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (2.22 g) as starting materials, N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.64 g) was obtained.
Reaction SMILES: C(Cl)CCl.[CH2:5]([CH2:9][C@H:10]([N:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[CH2:6][CH2:7][NH2:8]>CS(C)=O>[NH2:8][CH2:7][CH2:6][CH2:5][CH2:9][CH:10]([N:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12]
Reactant: NCCCC[C@@H](C(=O)O)N(CC(=O)O)CC(=O)O
Solvent: ClCCCl
Solvent: CS(C)=O
Product: NCCCCC(C(=O)O)N(CC(=O)O)CC(=O)O

Procedure:
A solution was prepared by the addition of 1 mmol of EDC and 0.2 mmol of NHS to 1 ml of DMSO, and 50 μl of the thus prepared solution was added onto the CMD film. The solution was then allowed to undergo the reaction at the room temperature for 30 minutes. After the solution was removed, washing with DMSO was performed one time. Also, a solution prepared by the addition of 0.1 mmol of AB-NTA (supplied by Dojin Kagaku K.K.) to 1 ml of DMSO was allowed to undergo the reaction for 12 hours. The solution was removed, and washing with ultra pure water was performed one time.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[CH:6][CH2:5]1>O.C1COCC1.CO>[O:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[CH:6][CH2:5]1
Reactant: COC(=O)c1ccc(C2=CCOc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C2=CCOc3ccccc32)cc1
Temperature: 50 °C
Yield: 89 %

Procedure:
Lithium hydroxide hydrate (0.80 g, 19.0 mmol) dissolved in water (20 mL) was added to a solution of methyl 4-(2H-chromen-4-yl)benzoate from reaction 34b (1.5 gm, 5.7 mmol) in THF (20 mL) and methanol (20 mL) under nitrogen atmosphere at room temperature. The reaction was heated to 50° C. for 2 h, allowed to cool, concentrated then partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give 4-(2H-chromen-4-yl)benzoic acid (1.29 g, 89%) as a tan solid. MS found: (M−H)+=251.
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH3:9][C:10]1[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])=[N:12][NH:13][CH:14]=1.[CH3:23]C1C(C2C=CC=CC=2)=NNC=1>>[CH2:8]([CH:2]([N:13]1[CH:14]=[C:10]([CH3:9])[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])=[N:12]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH3:23]
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: Cc1ccc(-c2n[nH]cc2C)c(C)c1
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2ccc(C)cc2C)n1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 4-methyl-3-(2,4-dimethylphenyl)pyrazole for 4-methyl-3-phenylpyrazole there is obtained α-ethyl-N,N,4-trimethyl-3-(2,4-dimethylphenyl)pyrazole-1-acetamide isolated as an oil.