Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:17])=[CH:7][N:6]=1)[CH2:10]2
Reactant: Brc1cnc(O[C@H]2CN3CCC2CC3)nc1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1ccccc1-c1cnc(O[C@H]2CN3CCC2CC3)nc1

Procedure:
The product of Example 19A (280 mg, 1.0 mmol) was coupled with 3-aminophenylboronic acid (Lancaster, 276 mg, 2.0 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.1) as a solid (230 mg, yield, 77%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.62 (m, 1H), 1.65-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.21-2.29 (m, 1H), 2.74-3.04 (m, 5H), 3.36-3.47 (m, 1H), 5.12-5.20 (m, 1H), 6.75 (ddd, J=8.2, 2.1, 1.0 Hz, 1H), 6.89 (ddd, J=7.4, 1.7, 1.0 Hz, 1H), 6.93 (t, J=1.8 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 8.74 (s, 2H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19](/[CH:22]=[C:23](/[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])\[C:24]#[N:25])[S:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:22]([C:19]2[S:20][CH:21]=[C:17]([Br:16])[CH:18]=2)[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cc(Br)cs1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Br)cs2)C1(C#N)c1ccc(Cl)cc1F
Yield: 20.2 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(4-bromo-thiophen-2-yl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.7 g, 8 mmol) prepared in Example 70a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.9 g, 20%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.CS(C)=O.[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20]>O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:26][CH2:27][N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: CC(C)N1CCNCC1
Reactant: Clc1ccc(-c2ccc(Cl)nc2)cc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1
Temperature: 100 °C
Yield: 85.2 %

Procedure:
A mixture of 2-chloro-5-(4-chlorophenyl)pyridine (500 mg, 2.23 mmol), DMSO (2.0 mL) and 1-isopropylpiperazine (3 mL, 23.4 mmol) was stirred and heated on a 100° C. oil-bath overnight. The reaction mixture was poured into water (75 mL), and the solid was isolated by filtration, washed with water and dried. The crude product was purified by column chromatography on silica gel (Kiselgel 60, mesh 0.040-0.63) eluting with a mixture of ethyl acetate and methanol (4:1). Collecting the proper fractions afforded 600 mg (85%) of 1-[5-(4-chlorophenyl)pyridin-2-yl]-4-isopropylpiperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[C:4]([Cl:13])[C:3]=1[OH:14].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[CH:22]=1>>[Cl:13][C:4]1[CH:5]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[CH:22]=1
Reactant: Cc1cc(CCCCCBr)on1
Reactant: Oc1c(Cl)cc(-c2ccco2)cc1Cl
Product: Cc1cc(CCCCCOc2c(Cl)cc(-c3ccco3)cc2Cl)on1
Yield: 40 %

Procedure:
5-{5-[2,6-Dichloro-4-(2-furanyl)phenoxy]pentyl}-3-methylisoxazole [II; R1 and R2 =Cl, Het=2-furanyl] was prepared from 2,6-dichloro-4-(2-furanyl)phenol and 5-(5-bromopentyl)-3-methylisoxazole according to the procedure of Example 1(c), and was obtained in about 40% yield as a pale-yellow oil which could be caused to crystallize from isopropyl acetate-hexane as a pale-yellow solid, m.p. 29-30° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[CH:7]=[C:6]2[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.[Br:26]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:26][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]=1[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2c(Br)c(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
To 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (200 mg, 0.6 mmol) in DMF (2.5 mL) was added a solution of N-bromosuccinimide (107 mg, 0.6 mmol) in DMF (1.5 mL) dropwise. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted in H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (1:1 CH2Cl2/hexane) to provide 3-bromo-1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (219 mg, 88%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[S:18]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc2cc(N(Cc3ccccc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from example 1, step d.) (1.13 g, 2.53 mmol) was dissolved in dimethylformamide (DMF) (30 mL), treated with K2CO3 (524 mg, 3.79 mmol), benzyl bromide (340 uL, 2.78 mmol), and stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed several times with water and concentrated under reduced pressure. This compound was purified by chromatography (EtOAc/Hex) prior to use in subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[CH:15][C:6]1=2.[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:37][CH2:36][CH2:35][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:22])=[CH:18][CH:17]=3)=[CH:15][C:6]1=2
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)C(=O)CN3)cc1
Product: O=C(NCCN1CCCC1)c1ccc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)C(=O)CN3)cc1
Yield: 26 %

Procedure:
4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (40 mg) was coupled to 2-pyrrolidin-1-yl-ethylamine as in General Procedure 8 to give the title compound as an off-white solid (26% yield). M.p.>200° C., LCMS: m/z=524.11 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.82 (4H, m), 2.60 (4H, m), 2.74 (2H, m), 3.59 (2H, m), 4.26 (2H, s), 4.85 (1H, bs), 5.56 (2H, s), 7.16 (1H, m), 7.32 (2H, d, J=8.1 Hz), 7.39 (2H, d, J=8.3 Hz), 7.82 (2H, d, J=8.3 Hz), 7.96 (1H, d, J=1.8 Hz).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].[F:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[C:23]([C:24]([OH:26])=O)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:13])=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:28]=[CH:27][C:11]2[C:12](=[O:13])[C:14]3[C:23](=[CH:22][C:21]4[C:16]([CH:15]=3)=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:24](=[O:26])[C:10]=2[CH:9]=1
Reactant: O=C(O)c1cc2ccccc2cc1C(=O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 34.9 %

Procedure:
200 g (1.5 moles) of powdered aluminium chloride and 40 g (684 mmol) of sodium chloride are heated together at 140°-150° C. After about 1.5 hours, 40 g (136 mmol) of 2-(4-fluorobenzoyl)-naphthalene-3-carboxylic acid are added to the melt. The dark red mixture is stirred at 140°-150° C. for one hour. Hydrolysis is then carried out at about 100° C. by slowly adding ice-water. The precipitate is filtered off and stirred with 10% sodium carbonate solution. It is then washed neutral with water and dried. The resulting product is sublimed at 230° C. 13.1 g (70% of theory) of 2-fluoro-5,12-naphthacenequinone are obtained.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12](OC)=[O:13])[CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([CH2:12][OH:13])[CH:3]=1
Reactant: COC(=O)c1cc(O)n2nc(C)nc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2nc(CO)cc(O)n2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
In 4 liters of ethanol was suspended 45.4 g of 7-hydroxy-5-methoxycarbonyl-2-methyl-s-triazolo[1,5-a]pyrimidine and 37.83 g of sodium borohydride was added little by little thereto, and the mixture was then stirred at room temperature for 3 hours. A residue obtained by removing ethanol was dissolved in 2 liters of water, and 500 ml of Amberlite IRC-50 (H+) (trade name) was added thereto and stirred. Subsequently, the mixture was filtered and after removing water from the filtrate, 500 ml of methanol was added to the filtrate and the mixture was stirred. Then, methanol was removed from the mixture to obtain a residue. These procedures were repeated three times. Then, 500 ml of ethanol was added to the residue and the mixture was condensed. Precipitated crystals were collected by filtration, washed with ethanol and dried to obtain 39.35 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[C:17]([NH2:19])=[NH:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[OH:25]/[CH:26]=[C:27](/[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)\[C:28](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[C:17]3[NH:19][CH:28]=[C:27]([CH2:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=4)[C:26](=[O:25])[N:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CN(Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(N(C)Cc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 8.9 %

Procedure:
To the solution of N-[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]-N-methylguanidine (100 mg, 0.212 mmol) and methyl (2Z)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (57.2 mg, 0.255 mmol) in NMP (1 ml) was added K2CO3 (117 mg, 0.850 mmol). It was heated with a microwave reactor at 130° C. for 1.5 h. Purification via MDAP then afforded the title compound as a white solid (10 mg, 8.8% yield). LCMS: rt=3.14 min, [M+H+]=532
Reaction SMILES: [CH2:1]([N:3]([C:21]1[CH:26]=[C:25]([O:27]C)[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:39]C)[CH:35]=2)[CH2:30]1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)[CH3:2].B(Br)(Br)Br.CO.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:20])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:10]=1)[C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:38][CH2:37][C:36]2[CH:35]=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=2[CH2:30]1)[CH3:2]
Reactant: CCN(Cc1ccc(N(C)CCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN(Cc1ccc(N(C)CCN2CCCCC2)cc1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{4-[methyl(2-piperidin-1-ylethyl)amino]benzyl}amine (108 mg) in dichloromethane (5 ml) was added boron tribromide (1.0 M solution in dichloromethane) (1.0 ml) on an ice bath. The solution was stirred for 30 minutes while warming to room temperature, then methanol (2 ml) was added thereto on an ice bath. A saturated aqueous solution of sodium bicarbonate was added thereto, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The resulting residue was purified by NH silica gel column chromatography (chloroform-methanol system) to provide the title compound (58 mg).
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=CC(OC3C=C(C(F)(F)F)C=CN=3)=CC=2)O1.C(C(N[C:33]1[N:38]=[C:37](Cl)[N:36]=[C:35]([C:40]([NH2:42])=[O:41])[CH:34]=1)C)(=O)N.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>[Cl-].[Na+].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.C(O)C.O>[N:38]1[CH:33]=[CH:34][C:35]([C:40]([NH2:42])=[O:41])=[N:36][CH:37]=1
Reactant: CC(Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1(C)OB(c2ccc(Oc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: NC(=O)c1ccncn1
Temperature: 100 °C

Procedure:
A sealed glass vial containing a mixture of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-(trifluoromethyl)pyridine (182 mg, 0.5 mmol), 6-(1-carbamoyl-ethylamino)-2-chloro-pyrimidine-4-carboxylic acid amide (122 mg, 0.5 mmol), PdCl2(PPh3)2 (28 mg, 0.04 mmol, Aldrich), Cs2CO3 (325 mg, 1 mmol, Aldrich) in a mixed solvent of ethylene glycol dimethyl ether (1 mL), water (1 mL) and ethanol (0.5 mL) was heated at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with brine (2 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The residue was purified via silica chromatography (0-10% MeOH/CH2Cl2) to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-trifluoromethyl)pyridine-2-yl)oxy)phenyl)pyrimidine-4-carboxamide as white solid, which was further triturated with methanol and dried under vacuum (59 mg, 26%). 1H NMR (400 MHz, DMSO-d6): 8.60 (2H, d, J=8.8 Hz), 8.44 (1H, d, J=5.2 Hz), 8.32 (1H, br), 7.98 (1H, d, J=6.8 Hz), 7.74 (1H, bs), 7.57-7.52 (3H, m), 7.27 (2H, d, J=6.4 Hz), 7.13 (1H, s), 7.02 (1H, bs), 4.59 (1H, m), 1.38 (3H, d, J=7.2 Hz). LC/MS: m/z=447 [M+H]+.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([Cl:19])[C:16](Cl)=[C:15]([Cl:21])[CH:14]=1>O.CS(C)=O>[Cl:19][C:17]1[CH:18]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=[C:15]([Cl:21])[C:16]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Reaction time: 2 h

Procedure:
32.5 g of potassium hydroxide flakes in 30 ml of water were added to 54.5 g (0.5 mole) of 4-aminophenol dissolved in 350 ml of dimethylsulfoxide, and 150 ml of a water/dimethylsulfoxide mixture were distilled off in vacuo at 15-20 mm Hg. 125 g (0.5 mole) of 1-trifluoromethyl-3,4,5-trichlorobenzene [nD20 : 1.5008 67- 68% of theory, compare J. Am. Chem. Soc. 57, 2066-2068 (1935) and U.S. Pat. No. 2,654,789] were then added to the reaction mixture at about 70°-80° C and the mixture was stirred for a further 2 hours at 120°-130° C. The substance was precipitated with water, filtered off, washed with water and recrystallized moist from an ethanol/water mixture, thus giving 40-50% of theory of 4-(2,6-dichloro-4-trifluoromethylphenoxy)-aniline of melting point 128°-130° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH2:31]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1.CCCCCC>[CH2:31]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:42][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCc1ccc(C=O)cc1
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC=Cc1ccc(CCCCCCCCC)cc1
Reaction time: 0.5 h

Procedure:
A suspension of 13.9 g of pentyltriphenylphosphonium bromide in 150 ml of tetrahydrofuran is cooled to -20° under argon, 21.2 ml of 1.6M butyllithium solution in hexane are added within a period of 5 minutes and the whole is stirred for a further 30 minutes at 0°-10°. 6 g of 4-nonylbenzaldehyde in 40 ml of tetrahydrofuran are added dropwise over a period of 30 minutes to the mixture, which has been cooled to from -60° to -70°. The reaction mixture is allowed to warm spontaneously to 0°-10°, stirred at this temperature for a further 45 minutes and concentrated by evaporation. The residue is taken up in hexane/ethyl acetate (1:1) and filtered over silica gel. The filtrate is concentrated by evaporation and chromatographed on silica gel with hexane. The title compound (mixture of cis- and trans-isomers) is obtained in the form of a colourless oil, which is used directly in the next stage.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:2]1.[Na].Cl.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C.C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:14][C:13](=[O:15])[N:12]([CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]2=[O:16])=[CH:2]1
Reactant: ClCCCN1CCCCC1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)N1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1NC(c2c[nH]c3ccccc23)C(=O)N1CCCN1CCCCC1
Reaction time: 18 h

Procedure:
5-(Indol-3-yl)hydantoin (8.6 g, 0.04 mole) in 200 ml of DMF was added to a solution of sodium (1.84 g, 0.08 mole) in 150 ml of anhydrous C2H5OH. N-(3-Chloropropyl)piperidine hydrochloride (7.9 g, 0.04 mole) was added and the mixture was heated to reflux with stirring for 18 hours, filtered and concentrated in vacuo to dryness. The concentrate was crystallized from aqueous methanol and twice recrystallized from aqueous DMF, yield 1.7 g, mp 233°-4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[CH3:24][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:16]=2)[CH:12]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2n1C
Reaction time: 0.25 h

Procedure:
Into a solution of ethyl 6-(4-methylphenyl)-1H-indole-2-carboxylate (0.9 g) in DMF (10 ml) was added at 0° C. sodium hydride (60%, 0.14 g), and the resulting mixture was stirred for 15 minutes. Into the reaction mixture was added methyl iodide (0.22 ml), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration of the organic layer under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:4) and further to recrystallization (ethyl acetate/hexane) to obtain ethyl 1-methyl-6-(4-methylphenyl)-1H-indole-2-carboxylate (0.80 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[Mg].Cl[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCCCC1Cl
Agent: [Mg]
Solvent: CCOCC
Product: COc1cccc(C2CCCCC2=O)c1

Procedure:
A mixture of 261.8 g of 3-methoxybromobenzene in 500 ml of ether is added dropwise to a 34.0 g sample of magnesium in 600 ml of ether. To the reaction mixture is added a suitable catalyst and the mixture is heated vigorously to initiate the reaction. The prepared Grignard Reagent is cooled in an ice bath while 185.6 g of 2-chlorocyclohexanone in 500 ml of ether is introduced. The ether is removed and xylene added and the xylene solution is refluxed for 1 hour. The solution is poured over ice and dilute hydrochloric acid, the organic layer separated, the aqueous layer extracted with benzene, the organic layer and benzene extracts are combined and washed with dilute sodium hydroxide solution, dried, filtered, and the solvent removed leaving a red oil. The oil is vacuum distilled to give a clear pink liquid of 2-(3-methoxyphenyl)cyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.[C:32](=[O:40])([O:37][CH2:38][CH3:39])[O:33][CH:34](Cl)[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:34]([O:33][C:32]([O:37][CH:38]([O:28][C:27](=[O:29])[C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:31])[CH3:30])[CH3:39])=[O:40])[CH3:35]
Reactant: CCOC(=O)OC(C)Cl
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)C(C)(C)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 110 °C

Procedure:
To a solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [100 mg, 0.218 mmol, Example 49(b)] in dimethylformamide (2 mL) is added 1-chloroethyl ethyl carbonate (0.053 mL, 0.392 mmol) and Cs2CO3 (142 mg, 0.436 mmol). The mixture is heated under microwave at 110° C. for 10 minutes, quenched with water, and extracted with ethyl acetate. Combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography eluting with 0 to 40% EtOAc in heptane to obtain 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 1-ethoxycarbonyloxy-ethyl ester as an oil which is treated with 1M hydrogen chloride in ether affording 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 1-ethoxycarbonyloxy-ethyl ester hydrochloride [80 mg, 64%, Example 50] as a solid. LC/MS: RT=2.94 minutes, MS: 576 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □7.36-7.8 (7H, m), 6.64 (1H, q), 6.6 (1H, s), 4.05 (2H, q), 3.96 (3H, s), 3.68 (2H, m), 3 (2H, m), 1.57 (6H, s), 1.38 (3H, d), 1.15 (3H, t). IC50=4 nM