Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S([N:11]2[CH2:16][C@H:15]3[CH2:17][C@@H:12]2[CH2:13][N:14]3[CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=O)=O)=CC=1.[BrH:25].C(O)(=O)C>C(O)(=O)C>[BrH:25].[BrH:25].[BrH:25].[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][N:14]2[CH2:13][C@H:12]3[CH2:17][C@@H:15]2[CH2:16][NH:11]3)[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3Cc2cccnc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: c1cncc(CN2C[C@H]3C[C@@H]2CN3)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
The product from Example 20A (320 mg, 0.9 mmol) in acetic acid (3.4 mL) and 33% HBr/acetic acid (7 mL) was heated to 70° C. for 18 hours. After cooling to ambient temperature, the precipitate was filtered, washed with ether, and dried. The resulting solids were recrystallized from EtOH/EtOAc to provide the title compound (332 mg, 80%). 1H NMR (DMSO-d6, 300 MHz) δ 2.22 (m, 1H), 2.47 (m, 1H), 3.29-3.48 (m, 2H), 3.35 (m, 1H), 3.69 (m, 1H), 4.19-4.53 (m, 2H), 5.59 (m, 2H), 8.05 (m, 1H), 8.62 (m, 1H), 8.78-8.88 (m, 2H); MS (DCI/NH3) m/z 190 (M+H)+; Anal. Calcd. for C11H15N3.3.0 HBr.0.1H2O: C, 30.46; H, 4.23; N, 9.69. Found: C, 30.83; H, 4.25; N, 9.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=O)[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=[CH:29][N+:26]([O-:28])=[O:27])[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc2c(n1)c(C=O)c1n2Cc2ccccc2-1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2Cc2ccccc2-1

Procedure:
600 mg (2.27 mmol) of the compound obtained in Step E dissolved in 25 ml of nitromethane are heated at 120° C., for 3 hours in the presence of 440 mg (5.67 mmol) of ammonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation of the organic phase yields the title compound in the form of a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH2:25][CH3:26])=[C:18]([N+:21]([O-])=O)[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:27]#[N:28])[CH:6]=[CH:7][C:8]=1[F:9].[Cl-].[NH4+].CO>O.[Fe]>[NH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH2:25][CH3:26])[N:14]=[CH:13][C:12]([C:27]#[N:28])=[C:11]2[NH:10][C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([Cl:2])[CH:4]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reaction time: 4 h

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-ethoxy-6-nitro-quinoline-3-carbonitrile hydrochloride (38.6 g 91.2 mmol) was mixed with 35.7 g (638 mmol) of iron powder. A solution of 43.9 g (820 mmol) of ammonium chloride in 280 ml of water was added followed by 985 ml of methanol. The mixture was reflux with mechanical stirring under nitrogen for 4 hr at which time TLC indicated complete reduction. The reaction mixture was filtered hot and solids were washed with 500 ml of boiling methanol. After the combined filtrate was evaporated, the residue was partitioned between 1.5L of warm ethyl acetate and 700 ml of saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, treated with Norite, filtered and evaporated to give a solid which was recrystallized from CHCl3-hexanes giving 29.0 g (89%) of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile as a light green solid.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].S(Cl)([Cl:15])=O>CN(C)C=O>[N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13.7 g of p-aminobenzoic acid was dispersed in a solution of 100 cc of water and 30 cc of 30% hydrochloric acid in an ordinary manner and the dispersion was cooled with ice. A solution of 8.3 g of sodium nitrite in 50 cc of water was added dropwise to the dispersion to effect the diazotization reaction. A solution of 10.1 g of sodium azide in 70 cc of water was added dropwise to the mixture, stirred for about one hour, filtered and vacuum-dried to obtain p-azidobenzoic acid. 5.4 g of the thus obtained p-azidobenzoic acid was dissolved in 10 cc of dimethylformamide and 25 g of thionyl chloride was added dropwise to the solution. The mixture was stirred for about one hour and the product was added dropwise to ice-water. After filtration followed by washing with water and vacuum drying, p-azidobenzoyl chloride was obtained.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25]>O>[N+:24]([C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: C1CCCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Hexahydro-1H-azepine (682 μl, 6.05 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 2 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (506 mg, 2.42 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for one hour. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=7/1). Thus, hexahydro-1-[2-nitro-4-(trifluoromethyl)phenyl]-1H-azepine (680 mg, 97.5%) was yielded as an orange-colored solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:12])[C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:12])[C:9]=1[O:10][CH3:11])[CH2:5][NH:6][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COc1c(Cl)cc(CN)cc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(Cl)cc(CNc2ccccc2[N+](=O)[O-])cc1Cl
Yield: 86.1 %

Procedure:
A mixture of 3,5-dichloro-4-methoxybenzylamine (6 g, 29.2 mmole), 2-fluoronitrobenzene (2 g, 14.2 mmole) and ammonium acetate (1.0 g) was heated at 80° for 1 hour. The cooled mixture was taken up into ethyl acetate and washed sequentially with aqueous 3N HCl, water, aqueous 5% sodium bicarbonate, brine, dried (Na2SO4), and concentrated to give the title compound 4.0 g (78%) as orange crystals, mp 128°.
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5]([O:7]C)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)C(c1ccc(Cl)cc1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.6 %

Procedure:
A mixture of 13.0 grams (0.058 mole) of methyl 2-cyclopropyl-2-(4-chlorophenyl)acetate and 5.0 grams of an aqueous, 50% sodium hydroxide solution in 50 mL of methanol was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with 150 mL of water, and the solution was decanted from a solid residue. The liquid portion was washed with three portions of diethyl ether. The combined ether washes were, in turn, washed with an aqueous, dilute sodium hydroxide solution. The combined aqueous layers were made acidic by the slow addition of aqueous, 10% hydrochloric acid. The acidified mixture was extracted with five portions of methylene chloride. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 7.4 grams of 2-cyclopropyl-2-(4-chlorophenyl)acetic acid as a solid, m.p. 95°-96° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[F:39]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)c(Cl)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chloro-4-fluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=614.1)=95%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([NH2:23])=[O:22])=[N:4][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N[C:25]1C(C(OC)=O)=NC(C2C=NC=CC=2)=NC=1NC1C=CC=CC=1.N>CO>[C:9]1([N:8]2[CH:25]=[N:1][C:2]3[C:7]2=[N:6][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:4][C:3]=3[C:21]([NH2:23])=[O:22])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(-c2cccnc2)nc(Nc2ccccc2)c1N
Reactant: NC(=O)c1nc(-c2cccnc2)nc(Nc2ccccc2)c1N
Agent: N
Solvent: CO
Product: NC(=O)c1nc(-c2cccnc2)nc2c1ncn2-c1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
5-Amino-6-(phenylamino)-2-(3-pyridyl)pyrimidine-4-carboxamide. A solution of methyl 5-amino-6-(phenylamino)-2-(3-pyridyl)pyrimidine-4-carboxylate (0.123 g, 0.383 mmol) in anhydrous methanol (15 mL) was chilled to −78° C. The solution was then saturated with ammonia gas. The reaction vessel was sealed at −78° C. and allowed to warm to room temperature. After 18 hours the reaction was chilled to −78° C. and opened to atmosphere. The volatiles were evaporated and the resulting solids dried under vacuum to provide the title compound (0.117 g, 0.383 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.50 (d, J=1.6, 1H), 8.93 (s, 1H), 8.67 (dt, J=8.0, 2.0, 1H), 8.58 (dd, J=4.8, 1.6, 1H), 8.43 (s, 1H), 7.85 (d, J=8.4, 2H), 7.63 (s, 1H), 7.42-7.47 (m, 3H) 7.23 (s, 2H), 7.11 (t, J=7.6, 1H); MS (ESI) m/z 307.3 [M+1]+; mp 285-288° C.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=[O:21].[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C1(C)C=CC=CC=1>[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([C:15]2[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=2)[CH:20]=[O:21])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc(N2CCN(Cc3ccccc3)CC2)ccc1O
Reaction time: 0.33 h

Procedure:
0.6 g of bis(dibenzylideneacetone)palladium and 0.16 g of tri-tert-butylphosphine are added under nitrogen to 200 ml of toluene, and the resultant dark-red solution is stirred at 20° for 20 minutes. 10 g of 5-bromo-2-hydroxybenzaldehyde, 9.7 g of 1-benzylpiperazine and 7.2 g of sodium tert-butoxide are then added. The mixture is stirred at 60° for 24 hours and cooled, 800 ml of water are added, and the mixture is extracted with 2×500 ml of ethyl acetate. The organic phases are combined and washed with 300 ml of water, and the solvent is removed at 30° under reduced pressure. The dark-orange oil which remains (9.7 g) is purified by chromatography (300 g of silica gel; MTB ether/heptane 5:1; 1.5 litres). 9.9 g of pale-yellow crystals remain (67%), m.p. 101-103°; MS 296 (M+), 205, 119, 91 (100%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([C:16]([O:18][CH:19](Cl)[CH3:20])=[O:17])[C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=12.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([C:16]([O:18][CH:19]([O:29][C:26](=[O:28])[CH3:27])[CH3:20])=[O:17])[C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=12
Reactant: CC(Cl)OC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)OC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21

Procedure:
The product from Step 2 (4 g) and sodium acetate (6 g) were refluxed together in glacial acetic acid (60 ml) for 1 hour. The mixture was cooled, diluted with ethyl acetate (300 ml) and washed with water (3×100 ml), then with aqueous sodium bicarbonate and again with water, dried and evaporated down. The residue was chromatographed on a column of silica gel eluting with a 1:9 mixture of ethyl acetate-hexane to afford, after trituration in ether and filtration, the pure title compound (1.2 g), m.p. 195°-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][O:24][CH3:25].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:9][C:10]([N:23]([O:24][CH3:25])[CH3:22])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccc(F)cc1
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 66 h

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)-N-(4-fluorobenzyl)glycine (10.5 g, 37.2 mmol) in CH2Cl2 (37 mL) was added N,O-dimethylhydroxylamine hydrochloride (3.62 g, 37.2 mmol). The resulting suspension was treated with N-methylmorpholine (4.08 mL, 37.2 mmol) and cooled to 0° C. The mixture was then treated with a 1 M solution of N,N′-dicyclohexylcarbodiimide in CH2Cl2 (37.2 mL, 37.2 mmol) and was then allowed to warm to ambient temperature under inert atmosphere. After stirring for 66 h, the mixture was filtered, washing the solid residue with excess CH2Cl2. The filtrate was concentrated in vacuo and resuspended in EtOAc. After stirring for 1 h, the mixture was filtered, washing the solids with excess EtOAc. The filtrate was again concentrated in vacuo to give an orange oil. Purification by silica gel chromatography (20% to 60% EtOAc/hexanes) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.27-7.20 (m, 2H), 7.03-7.01 (m, 2H), 4.52 (d, J=13.6 Hz, 2H), 4.09 (s, 1H), 3.95 (s, 1H), 3.63 (d, J=20.4 Hz, 3H), 3.18 (s, 3H), 1.47 (s, 9H). ES MS (M+1)=327.17.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:11][C:10](=[O:12])[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:4][CH2:3]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([N:4]1[CH2:3][C:2]([CH3:13])([CH3:1])[NH:11][C:10](=[O:12])[C:5]21[CH2:9][CH2:8][CH2:7][CH2:6]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)CNC2(CCCC2)C(=O)N1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(Cc2ccccc2)C2(CCCC2)C(=O)N1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 6.72 g of 8,8-dimethyl-6,9-diaza-spiro[4.5]decan-10-one in 35 ml of DMF were added 4.8 ml of benzyl bromide and 6.9 ml of Hünig's base. The reaction was stirred at r.t overnight. The precipitated product was isolated by suction and washed with DMF and EtOAc. The filtrate was concentrated and the resulting residue was dissolved in EtOAc, washed with water, dried over Na2SO4, filtered and concentrated to yield a second fraction of the product. 9.62 g (96%) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:18][C:19]([F:27])([F:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[O:21].O.O.O.FC(F)(F)C(C(F)(F)F)=O.S(=O)(=O)(O)O.Cl>ClCCl>[OH:21][C:20]([C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=2[O:6][C:2]=1[CH3:1])([C:22]([F:25])([F:24])[F:23])[C:19]([F:27])([F:26])[F:18]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1cc2cccc([N+](=O)[O-])c2o1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: O
Solvent: ClCCl
Product: Cc1oc2c([N+](=O)[O-])cccc2c1C(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a mixture of 2-methyl-7-nitrobenzo[b]furan (200 mg) and aluminum chloride (301 mg) in dichloromethane was passed hexafluoroacetone gas which was made from hexafluoroacetone trihydrate (4.7 ml) and conc. sulfuric acid (15 ml). The mixture was stirred at ambient temperature for 4 hours and then, cooled to 4° C. To the mixture was added 1N-hydrochloric acid dropwise. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from n-hexane to give 3-(1-hydroxy-2,2,2-trifluoro-1-trifluoromethylethyl)-2-methyl-7-nitrobenzo[b]furan (265 mg).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=3[F:29])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][S:37]([CH2:40][CH2:41][OH:42])(=[O:39])=[O:38]>[Cu](I)I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:24][C:23]=3[F:29])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Nc2ccc(I)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: CS(=O)(=O)CCO
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(Nc2ccc(OCCS(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 3 %

Procedure:
General procedure of coupling alcohol to aryl halides: A mixture of 4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (103 mg, 0.2 mmole), cesium carbonate (130 mg, 0.4 mmole), copper iodide (8 mg, 0.04 mmole), and 1, 10-phenanthroline (14 mg, 0.08 mmole) in 2-methanesulfonyl-ethanol (3 mL) was heated under microwave irradiation at 150° C. for 1 hour. The crude mixture was purified by HPLC to provide Compound A95 as a yellow solid (3 mg, 3%). Exact mass calculated for C23H31FN4O6S 510.2, found 511.3 (MH+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH:9]([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>>[CH:9]([S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)([CH3:11])[CH3:10]
Reactant: Sc1ccncc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Sc1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
A mixture of 4-mercaptopyridine (7 g, 63 mmol), 2-bromopropane (7.0 ml, 75.6 mmol), and potassium carbonate (10.2 g, 73.7 mmol) was stirred at room temperature for 6 hours and left overnight. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (i-hexane:ethyl acetate) to give the title product (7.4 g, 63%). The hydrochloride salt was prepared by treatment of the title compound with ethereal HCl.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]1>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)[N:3]=1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(F)ccc(OC)c2F)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Solvent: CC(C)O
Product: COc1ccc(F)c(C(=O)c2cnc(NC3CCN(C(C)=O)CC3)nc2N)c1F

Procedure:
A suspension of (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(2,6-difluoro-3-methoxy-phenyl)-methanone (20.0 mg, 0.056 mmol, Example 89) and 1-(4-amino-piperidin-1-yl)-ethanone (21.1 mg, 0.148 mmol, prepared as described in U.S. Pat. No. 5,817,828) in isopropyl alcohol (2.5 mL) was heated at 120° C. in a sealed tube under microwave conditions for 0.3 to 1 hour. The resulting reaction mixture was evaporated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 1-[4-[4-amino-5-(2,6-difluoro-3-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid (18.3 mg). MS (M+H)+, 406.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][N:19]=1)[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O.[CH2:20]([NH:22][CH2:23][CH2:24][NH2:25])[CH3:21]>O1CCCC1>[CH2:20]([NH:22][CH2:23][CH2:24][NH:25][C:5](=[O:7])[C:4]1[CH:17]=[CH:18][N:19]=[C:2]([F:1])[CH:3]=1)[CH3:21]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccnc(F)c1
Reactant: CCNCCN
Solvent: C1CCOC1
Product: CCNCCNC(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.9 %

Procedure:
To a solution of compound 35 (4.60 g, 17.5 mmol) in anhydrous tetrahydrofuran (185 mL) was added, under argon, N-ethylethylenediamine (1.80 mL, 17.5 mmol). The mixture was stirred at room temperature for 24 h. The solvent was evaporated under vacuum and the residue was suspended in dichloromethane (95 mL). A 1.0 N aqueous sodium hydroxide solution (140 mL) was added to the mixture. The solution was decanted and the aqueous layer was extracted with dichloromethane (6×120 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 36 (3.37 g, 15.9 mmol) as a yellow solid. Yield 91%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.16; mp 51-52° C.; IR (KBr) ν 1300, 1416, 1554, 1675, 2700-3050, 3100-3600 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.07 (t, 3H, J=7.1 Hz), 2.63 (q, 2H, J=7.1 Hz), 2.76 (se, 1H), 2.83 (t, 2H, J=5.8 Hz), 3.50 (m, 2H), 7.33 (s, 1H), 7.54 (m, 1H), 7.74 (se, 1H), 8.24 (d, 1H, J=5.1 Hz); MS m/z 212 (M+H+, 1), 124 (8), 96 (15), 71 (19), 58 (100).