Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=O)[CH2:15][CH3:16])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1.C1(C)C=CC=CC=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=[S:33])[CH2:15][CH3:16])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(=S)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 61.4 %

Procedure:
175 mg of 5-(4-fluorophenyl)-3-propionylamino-4-(4-pyridyl)pyrazole and 450 mg of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide were added to 30 ml of toluene, followed by heating under reflux for 2 hours. After the reaction mixture was cooled, 10% hydrochloric acid and ethyl acetate were added thereto. The aqueous layer was separated, neutralized with a saturation solution of sodium hydrogen carbonate, and extracted with chloroform-methanol (5:1). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (using chloroform-methanol (10:1) as the developing solvent). Thus, 113 mg (61% yield) of the title compound was obtained as pale-yellow crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].O[C:12]1C(C(OC2C=CC=CC=2)=O)=C[C:15]2[C:16]([CH:28]=1)=[C:17]1C(=CC=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18]1.[OH:38]C1C(C(OC2C=CC=CC=2)=O)=CC2C(C=1)=C1C(=CC=2)C2C(=CC=C(F)C=2)N1.OC1C(C(OC2C=CC=CC=2)=O)=CC2C(C=1)=C1C(=CC=2)C2C(=CC=C(Cl)C=2)N1>>[C:16]1([C:17]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:38])[C:15]2[NH:5][C:4]3[C:3](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[CH:2]=[CH:12][CH:28]=1
Reactant: O=C(Oc1ccccc1)c1cc2ccc3c4cc(F)ccc4[nH]c3c2cc1O
Reactant: O=C(Oc1ccccc1)c1cc2ccc3c4ccccc4[nH]c3c2cc1O
Reactant: CCc1cc(Cl)ccc1N
Agent: O=C(Oc1ccccc1)c1cc2ccc3c4cc(Cl)ccc4[nH]c3c2cc1O
Product: O=C(Nc1ccccc1)c1cccc2c1[nH]c1ccccc12

Procedure:
The reaction of an alkylamine, such as o-ethylaniline, with an acetic acid anhydride to form an acetanilide, such as 2'-ethylacetanilide. The resulting acetanilide can then be reacted with a hydrogen halide, such as hydrogen chloride, in the presence of hydrogen peroxide to form a halogenated product in the para position of the acetyl group, such as 2'-ethyl-4'-chloroacetanilide. The halogenated acetanilide can be hydrolyzed in an aqueous alcoholic solution of hydrochloric acid to form a halogenated o-ethylaniline, such as 2-ethyl-4-chloroaniline. This halogenated o-ethylaniline is then reaction with a phenyl 2-hydroxy-11H-benzo(a)carbazole-3-carboxylate derivatives, such as phenyl 2-hydroxy-8-fluoro-11H-benzo(a)carbazole-3-carboxylate, phenyl 2-hydroxy-8-chloro-11H-benzo(a)carbazole-3-carboxylate, or phenyl 2-hydroxy-11H-benzo(a)carbazole-3-carboxylate to form the corresponding carbazole anilide coupler such as 2-hydroxy-8-fluoro-11H-benzo(a)carbazole- 3-carbox-2'-ethyl-4'-chloroanilide, 2-hydroxy-8-chloro-11H-benzo(a)carbazole-3-carbox-2'-ethyl-4'-chloroanilide, 2-hydroxy-11H-benzo(a)carbazole-3-carbox-2'-ethyl-4'-chloroanilide, etc. These new carbazole anilide couplers can then be used to synthesize the trisazo pigments of the present invention.
Reaction SMILES: [S].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1C=CC=CC=1.C(C1C=C(O)C(=CC=1)[OH:24])(C)(C)C>N>[C:5]1([CH2:6][C:7]([NH2:2])=[O:24])[CH:10]=[CH:9][CH:8]=[CH:3][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Reactant: c1ccncc1
Agent: N
Agent: [S]
Product: NC(=O)Cc1ccccc1
Temperature: 170 °C

Procedure:
A mixture of sulfur (15 g, 58.4 mmol), pyridine (15 mL, 14.67 g, 185.5 mmol), aqueous ammonia (28%; 20 mL), styrene (8.66 g, 83.3 mmol) and 4-t-butylcatechol (0.23 g, 1.69 mmol) was heated to 170° C. for 10 minutes then rapidly cooled using the cold-finger. Phenylacetamide was obtained upon workup (5.7 g, 51%). No impurities were detected in the 1H n.m.r. or 13C n.m.r. spectra.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:20]=[C:21](CCN)[CH:22]=[CH:23][CH:24]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:22]=[CH:21][CH:20]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: NCCc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1cccc(Cl)c1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 14.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(3-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.24 g (14%) of the titled product as a white solid:
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([O:16][CH3:17])[CH:6]=2.CC[N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])C.Cl.CN1CCCC1>CS(C)=O>[CH3:17][O:16][C:7]1[CH:6]=[C:5]2[C:10]([N:11]=[C:2]([N:21]3[CH2:22][CH2:24][CH2:27][C@@H:25]3[CH3:26])[C:3](=[O:18])[NH:4]2)=[CH:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1cc2nc(Cl)c(=O)[nH]c2cc1OC
Agent: CN1CCCC1
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(=O)[nH]c2cc1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of methyl 3-chloro-7-methoxy-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.2 g, 4.47 mmol) in DMSO (20 ml) was added DIEA (1.16 g, 8.98 mmol) and methylpyrrolidine hydrochloride (650 mg, 5.35 mmol), and the reaction was stirred at 85° C. overnight. The reaction mixture was cooled to room temperature. The product was precipitated by the addition water, and the solids were collected by filtration to afford (S)-methyl 7-methoxy-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (1.0 g, 71%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](O)=[O:32].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20])=[O:32]
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: Cn1c(C(=O)O)cc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1c(C(=O)NC2N=C(c3ccccc3F)c3ccccc3NC2=O)cc2ccccc21
Reaction time: 4 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (50 mg, 0.186 mmol) was suspended in 1 ml of methylene chloride. 1-Methylindole-2-carboxylic acid (36.2 mg, 0.2 mmol) was added to the solution followed by the addition of 38.5 mg (0.2 mmol) of EDC. The pH of the solution was brought to 8 with 60 μl of triethylamine. After stirring for 4 hours the product was purified by preparative TLC on a 2000 μ silica gel plate with a 95:5:0.5 chloroform/methanol/water solvent system. The product band was collected and isolated by washing the silica with 90:10:1 CMW. yield 16.5 mg.
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:27]=[C:26]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH2:36][C:37]([O:39]C)=[O:38])[C:25]([C:41]([F:44])([F:43])[F:42])=[CH:24][N:23]=2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CO.O>[C:3]([O:7][C:8]([N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:27]=[C:26]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH2:36][C:37]([OH:39])=[O:38])[C:25]([C:41]([F:43])([F:44])[F:42])=[CH:24][N:23]=2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][OH:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN(CCO)C(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
LiOH (143 mg, 5.98 mmol) was added to a solution of methyl 2-(2-(2-(2-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A73) (0.440 g, 0.748 mmol) in THF (10 mL), MeOH (1 mL) and water (1 mL) and the resulting mixture stirred at room temperature for 20 hours. Additional LiOH (107 mg, 4.48 mmol) was added and the mixture heated to 40° C. for 24 hours. The volatiles were removed in vacuo. The residue was diluted with a 10% citric acid solution (20 mL) and 1 M HCl (0.5 mL) until pH 3 was obtained. The resulting precipitate was collected by filtration and dried to give the title compound A74 as a pale yellow solid (0.421 g, 98%); 1H NMR (300 MHz, d6-DMSO) δ 10.21 (s, 1H), 8.67 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.24-7.17 (m, 6H), 4.38 (brs, 2H), 3.64 (brs, 2H), 3.47-3.03 (m, 8H), 1.42 (s, 9H). LCMS-B: rt 7.786 min; m/z 575 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.Cl[CH2:17][C:18]([CH2:20]Cl)=O.O.O.O.C([O-])(=[O:27])C.[Na+].[OH-].[Na+]>O.C1(C)C=CC=CC=1.CS(C)=O>[OH:27][CH2:17][C:18]1[N:13]=[C:11](/[CH:10]=[CH:9]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:20]=1
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)CCl
Reactant: NC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Temperature: 72.5 °C
Reaction time: 4.5 h
Yield: 23.8 %

Procedure:
(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (20.0 g, 92.9 mmol) was added to toluene (75 ml), and 1,3-dichloroacetone (22.0 g, 173.3 mmol) and toluene (25 ml) were added. The mixture was subjected to refluxing azeotropic dehydration for 9 hours. The reaction mixture was divided into two equal portions and one of them was concentrated under reduced pressure. To the residue were added dimethyl sulfoxide (100 ml), sodium acetate trihydrate (15.9 g, 116.8 mmol) and water (20 ml). The mixture was stirred at 70-75° C. for 4.5 hours. 2N-Aqueous sodium hydroxide solution (60 ml) was added at the same temperature and the mixture was stirred for 1 hour. After allowing to cool to room temperature, toluene (400 ml) and water (400 ml) were added and the mixture was partitioned. After washing with 5% brine (200 ml), the organic layer was concentrated under reduced pressure. To the residue was added methanol (10 ml) and the mixture was heated to 60° C. to allow dissolution. After allowing to cool to room temperature and stirring, the mixture was stirred for 1 hour under ice-cooling. The precipitated crystals were collected by filtration, washed with cold-methanol (5 ml) and dried under reduced pressure to give 4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole (5.96 g, 22.1 mmol, yield 48%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:7]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[CH:20][C:8]=2[S:9][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1)=[O:12]>ClCCl.C(OCC)(=O)C>[Cl:5][C:6]1[C:7]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[C:20]([N+:1]([O-:4])=[O:2])[C:8]=2[S:9][C:10]=1[C:11]([N:13]1[CH2:14][CH2:15][CH:16]([OH:19])[CH2:17][CH2:18]1)=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1sc2cc(O)c(O)cc2c1Cl)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl)N1CCC(O)CC1
Reaction time: 3 h

Procedure:
A solution of 1 M HNO3 in dichloromethane (0.67 ml) was added to a solution of (3-chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidin-1-yl)-methanone (0.17 g) in ethyl acetate (10 ml). Stirring was continued at 60° C. for 3 hours and then at room temperature overnight. The mixture was concentrated to smaller volume and the precipitate filtered and washed with water. The crude product was recrystallized from N,N-dimethylformamide/ethanol (25:75).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:22]([CH3:25])=[N:23][N:24]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([CH2:20]O)[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:6]=2[CH:7]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[C:3]2[N:4]([C:22]([CH3:25])=[N:23][N:24]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([CH2:20][N:28]4[CH2:29][CH2:30][CH2:27][CH2:26]4)[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(cc(Br)c3nnc(C)n32)n1Cc1cc(Cl)cc(CO)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1CCNC1
Product: Cc1cc2c(cc(Br)c3nnc(C)n32)n1Cc1cc(Cl)cc(CN2CCCC2)c1
Reaction time: 0.5 h

Procedure:
A solution of {3-[(4-bromo-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]-5-chlorophenyl}methanol (0.360 g, 0.858 mmol, from Step 4) in DCM (50. mL) was treated with triethylamine (510 μL, 3.6 mmol) and methanesulfonyl chloride (220 μL, 2.9 mmol, Aldrich). After 30 minutes, the solvent was removed in vacuo, and the residue was dissolved in a mixture of THF (20. mL) and methanol (20. mL). The solution was added to a mixture of pyrrolidine (0.42 mL, 5 mmol, aldrich) and triethylamine (0.61 mL, 4.3 mmol) in THF (10 mL). The reaction was stirred for 1 hour, and then the solvent was removed in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-10% MeOH in DCM, was used to purify product. Yield: (0.30 g, 74%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10]([O:12]C)=O)(=[O:7])=[O:6].[CH3:21][NH:22][CH3:23].CC(C)([O-])C.[K+]>CO.C(O)(C)(C)C>[CH3:21][N:22]([CH3:23])[C:10](=[O:12])[C:9]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:8]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:6])=[O:7]
Reactant: CNC
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CO
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reaction time: 96 h
Yield: 87.7 %

Procedure:
A solution of methyl 2-[N-(2-hydroxyethyl)aminosulfonyl]-6-nitrobenzoate (4.58 g, 15.1 mmol) in absolute MeOH (50 ml) was added to a solution of dimethylamine (6.8 g, 0.15 mol) and potassium tertbutoxide (0.68 ml of a 0.262 M soluton in tertbutanol) in absolute MeOH (100 ml). After stirring at 20-25° for 4 days, solvents were removed under reduced pressure. The residue was dissolved in EtOAc and washed with 0.5N HCl followed by a saturated aqueous NaCl solution. The EtOAc extract was dried (Na2SO4), filtered and concentrated to give 4.2 g (88%) of product.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23].[OH:25][C:26]1[C:27]([CH3:40])=[C:28]([C:31]([O:36][CH2:37][CH2:38][OH:39])=[C:32]([CH3:35])[C:33]=1[CH3:34])[CH2:29][Cl:30]>CN(C)C=O>[ClH:30].[OH:25][C:26]1[C:27]([CH3:40])=[C:28]([C:31]([O:36][CH2:37][CH2:38][OH:39])=[C:32]([CH3:35])[C:33]=1[CH3:34])[CH2:29][N:10]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23])[CH3:9]
Reactant: CNCCOc1cc(C)c(O)cc1C(C)C
Reactant: Cc1c(C)c(OCCO)c(CCl)c(C)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCCN(C)Cc2c(C)c(O)c(C)c(C)c2OCCO)c(C(C)C)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
Triethylamine (2.8 ml) was added dropwise to a solution of N-methyl-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethylamine hydrochloride (2.60 g) and 3-hydroxy-6-(2-hydroxyethoxy)-2,4,5-trimethylbenzyl chloride (2.45 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction mixture was poured on ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 3.8 g of a pale brown oil. The oil was dissolved in a small amount of methanol and conc. hydrochloric acid (1.2 ml) was added. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol-diethyl ether to give 2.9 g of the title compound (colorless crystals).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[O:13]C(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl.C(OCC)(=O)C>[OH:13][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:12])[CH2:11][C:2]1([CH3:17])[CH3:1]
Reactant: CC(=O)OC1c2ccccc2C(=O)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC(=O)c2ccccc2C1O
Reaction time: 8 h

Procedure:
To a solution of acetic acid 2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl ester (4.03 g, 16.7 mmol) in methanol (50 mL) and dichloromethane (10 mL) is added potassium carbonate (2.33 g, 16.66 mmol). The reaction is permitted to stir for 8 hours at which time it is diluted with ethyl acetate and the resulting solution is washed successively with water and brine. The aqueous phases are then back-extracted with dichloromethane and the organic phases are then combined, dried over magnesium sulfate, filtered, and concentrated to furnish 4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-naphthalen-1-one; 1H NMR (400 MHz, CDCl3) δ ppm 1.04 (s, 3 H), 1.11 (s, 3 H), 2.07 (d, J=6.1 Hz, 1 H), 2.46 (d, J=16. 7 Hz, 1 H), 2.78 (d, J=16.7 Hz, 1 H), 4.64 (d, J=5.8 Hz, 1 H), 7.38-7.46 (m, 1 H), 7.59-7.63 (m, 2 H), 8.02 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:6]([F:19])[CH:5]=1)[CH3:3].Cl[C:21]1[N:26]=[C:25]([N:27]2[C@@H:31]([CH:32]([CH3:34])[CH3:33])[CH2:30][O:29][C:28]2=[O:35])[C:24]([F:36])=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:11]1([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[CH:18][C:4]([C@@H:2]([NH:1][C:21]3[N:26]=[C:25]([N:27]4[C@@H:31]([CH:32]([CH3:33])[CH3:34])[CH2:30][O:29][C:28]4=[O:35])[C:24]([F:36])=[CH:23][N:22]=3)[CH3:3])=[CH:5][C:6]=2[F:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[C@H](N)c1ccc(C(=O)NC2CCCCC2)c(F)c1
Reactant: CC(C)[C@H]1COC(=O)N1c1nc(Cl)ncc1F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1nc(N[C@@H](C)c2ccc(C(=O)NC3CCCCC3)c(F)c2)ncc1F
Temperature: 125 °C
Yield: 8.4 %

Procedure:
To (S)-4-(1-aminoethyl)-N-cyclohexyl-2-fluorobenzamide (16 mg, 0.061 mmol) was added (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (31.4 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). The reaction was heated at 125° C. for 4 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 2.5 mg of N-cyclohexyl-2-fluoro-4-((S)-1-(5-fluoro-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 488.2 (M+H)+, Rt 0.99 min.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)[NH2:26])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].CCN(CC)CC.[NH2:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]([O:48][C:49]2[CH:50]=[C:51]3[C:56](=[CH:57][CH:58]=2)[NH:55][CH2:54][CH2:53][CH2:52]3)[CH:43]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:13]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]2[CH:24]=[C:25]([NH:26][C:2]([N:55]3[C:56]4[C:51](=[CH:50][C:49]([O:48][C:44]5[CH:43]=[C:42]([NH2:41])[N:47]=[CH:46][N:45]=5)=[CH:58][CH:57]=4)[CH2:52][CH2:53][CH2:54]3)=[O:4])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)[CH2:20][CH2:21]1)([CH3:15])[CH3:14]
Reactant: Nc1cc(Oc2ccc3c(c2)CCCN3)ncn1
Reactant: CC(C)N1CCN(Cc2cc(N)cc(C(F)(F)F)c2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(Cc2cc(NC(=O)N3CCCc4cc(Oc5cc(N)ncn5)ccc43)cc(C(F)(F)F)c2)CC1
Temperature: 2 °C
Reaction time: 0.05 h

Procedure:
A solution of 83 mg (0.28 mMol) of triphosgene in 10 ml of CH2Cl2 is cooled to 2° C. Then a solution of 260 mg (0.86 mMol) of 3-(4-isopropylpiperazin-1-ylmethyl)-5-trifluoromethyl-aniline and 171 μl (1-23 mMol) Et3N in 4 ml CH2Cl2 is added during 5 min. The mixture is stirred for 3 min at 2° C. and then warmed up to rt in a water bath. A solution of 200 mg (0.82 mMol) of 6-amino-4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrimidine (Step 1.3) and 114 μl (0.82 mMol) Et3N in 4 ml of CH2Cl2 is added during 5 min and stirring continued for 2 h at rt. EtOAc and a diluted solution of Na2CO3 is added to the reaction mixture. The aqueous phase is separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc/EtOH/Et3N 90:10:0→90:10:1) gives the title compound: TLC(EtOAc/EtOH/Et3N 90:10:1): Rf=0.15; MS: [M+1]+=570; Anal.: C,H,N,F.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>CCOCC>[Br:34][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1)[CH3:12]
Reactant: CC(C)Cc1cccc(C(C)O)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)Cc1cccc(C(C)Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of 1-(3-isobutylphenyl)ethanol (1.1 g), triphenylphosphine (3.24 g) and carbon tetrabromide (4.09 g) in ether (20 ml) was stirred at 25° C. for 1 hour. The precipitates were filtered off, and the filtrate was evaporated to give 1-(1-bromoethyl)-3-isobutylbenzene (1.49 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1>>[NH2:37][C:36]1[CH:38]=[CH:39][C:33]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH3:24])=[O:22])=[CH:16][CH:15]=3)[N:3]=2)=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CCOCC3)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Yield: 45 %

Procedure:
The title compound was prepared by following the procedure of Example 462 step 4 using 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g, 45% yield.
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[K+]>CN1CCCC1=O.O.[I-].[K+]>[C:17]([O:20][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: COC=C(C(=O)OC)c1ccc(CBr)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC=C(C(=O)OC)c1ccc(OC(C)=O)cc1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
3 g (10.5 mmol) of methyl 2-(p-bromomethylphenyl)-3-methoxyacrylate (prepared similarly to EP 226 917), 1.1 g (11.2 mmol) of potassium acetate and 50 mg of potassium iodide in 70 ml of N-methylpyrrolidone are stirred for 3 hours at 70°-80° C. The reaction mixture is diluted with water and extracted three times with ether. The combined ether phases are washed with water, dried over MgSO4 and evaporated down. Purification of the residue by column chromatography gives 2.3 g (8.7 mmol, 83%) of the title compound as colorless crystals (mp.= 69°-70° C.).