Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH2:11][C@@H:12]([C:14](O)=[O:15])[NH2:13])=[CH:3]1.S(C)C.B>C1COCC1>[NH2:13][CH:12]([CH2:11][C:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:2][CH:3]=1)[CH2:14][OH:15]
Reactant: N[C@@H](Cc1c[nH]c2ncccc12)C(=O)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: NC(CO)Cc1c[nH]c2ncccc12
Yield: 51.2 %

Procedure:
To a stirred solution of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)alanine monohydrate (10.0 g, 50.0 mmol) in THF (140 mL) at 0° C. was slowly added BF3.Et2O complex (7.0 mL, 60.0 mmol) followed by BH3.Me2S complex (10M in THF, 14.5 mL, 145.0 mmol). The reaction mixture was stirred at r.t. for 16 h and on completion the excess borane was quenched by the addition of MeOH (5 mL) at 0° C. The reaction mixture was concentrated, dissolved in EtOAc (120 mL) and washed with aqueous 20% NaOH solution (2×60 mL). The organic layer was then extracted into aqueous 2M HCl (2×150 mL). The combined acidic aqueous layers were then basified to pH 14 (addition of solid NaOH) and re-extracted with EtOAc (2×100 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a white solid (4.9 g, 52%). δH (MeOD-d3) 12.13 (1H, br. s), 8.97 (1H, dd, J 4.7 and 1.5 Hz), 8.06 (1H, s), 7.82 (1H, m), 4.12 (1H, dd, J 10.3 and 4.9 Hz), 4.01 (1H, dd, J 10.3 and 6.5 Hz), 3.75 (1H, m), 3.59 (1H, dd, J 14.0 and 5.5 Hz), 3.37 (1H, dd, J 14.0 and 7.3 Hz). Exchangeable protons were not observed.
Reaction SMILES: Br[CH:2]1[CH2:10][CH2:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]1=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([NH2:21])=[S:20].CCOC(C)=O.CO>CC(C)=O>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[S:20][C:2]2[CH2:10][CH2:9][C:8]3[NH:7][N:6]=[CH:5][C:4]=3[C:3]=2[N:21]=1
Reactant: NC(=S)Nc1ccccn1
Reactant: O=C1c2cn[nH]c2CCC1Br
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: c1ccc(Nc2nc3c(s2)CCc2[nH]ncc2-3)nc1
Yield: 56.9 %

Procedure:
According to Scheme 1 Step 4: A solution of 5-bromo-6,7-dihydro-1H-indazol-4(5H)-one (23.3 mmol, 5.00 g) and of 1-(pyridin-2-yl)thiourea (20.9 mmol, 3.21 g) in acetone (60 mL) was stirred at 60° C. for 5 hours. The precipitate formed was filtered and partitioned between AcOEt and a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was dried over Na2SO4 and concentrated to yield a grey solid. The crude residue was purified by flash chromatography over silica gel using DCM/MeOH (95:5) as eluent and by two recristallizations with AcOEt/MeOH (50:50) to yield N-(pyridin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (11.9 mmol, 3.20 g, 51%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH3:28])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]([CH3:28])[CH2:2][CH2:3][CH:4]2[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[O:5]2)=[CH:21][CH:20]=1
Reactant: CNCCc1ccc(OC)cc1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(CCN(C)CCC2CN(C)C(=S)c3cccnc3O2)cc1
Reaction time: 8 h

Procedure:
To 40 ml of absolute ethanol was added 5.0 g (0.0195 mole) of 2-(2-chloroethyl-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione and 3.65 g (0.022 mole) of 4-methoxy-N-methylbenzene-ethanamine and 2.5 g (0.0195 mole) of diisopropylethylamine. After ~6 hr heating at reflux 3.15 g (0.022 mole) of 4-methoxy-N-methylbenzeneethanamine was added and heating was continued overnight. After removing the solvent by rotary evaporation, the residue was taken up in 100 ml of methylene chloride and the solution was washed with 2×50 ml of 1N sodium hydroxide and 50 ml of water, dried over sodium sulfate and filtered. The solution was then treated with 10 ml of acetic anhydride overnight. The methylene chlordide was extracted with 3×100 ml of hydrochloric acid. The combined aqueous extracts were washed with 2×100 ml of chloroform made basic with concentrated sodium hydroxide and extracted into 3×100 ml of chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 2.8 g (37%) of yellow, analytically pure crystals, m.p. 75°-78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)=O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of maleic acid (0.58 g) in acetone (35 ml) with stirring at room temperature. The mixture is stirred for 3 hours at room temperature and concentrated at vacuum to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2.CCCCCC.C([Li])CCC.[CH2:29]([O:31]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH:29]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2)=[O:31]
Reactant: CCOCC
Reactant: Brc1ccc2c(c1)CCC2OC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.1 g of 5-bromo-1-(tetrahydropyran-2-yloxy)indane was dissolved in 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. To the solution was dropwise added 20 ml of a 1.5N n-butyllithiumhexan solution at -65° C. in 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes. Thereto was added 2.3 ml of anhydrous N,N-dimethylformaide. The reaction mixture was heated to room temperature and added to a mixture of 100 ml of ice water, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=15/1) to obtain 6.5 g of 5-formyl-1-(tetrahydropyran-2-yloxy)indane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13].[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1O
Reactant: O=C(O)c1ccncc1F
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1F
Temperature: 80 °C
Yield: 65.9 %

Procedure:
A mixture of 2.0 g of 2-amino-5-chloro-4-trifluoromethylphenol, 1.33 g of 3-fluoroisonicotinic acid, 2.36 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for 3.5 hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.08 g of 3-fluoro-N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:17][CH2:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=3)[CH:37]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2CC(C)(C)C)c1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1cccc(OCc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 86.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of (6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methanol (100 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (73 mg) in toluene (4.7 mL) were added 1,1′-(azodicarbonyl)dipiperidine (133 mg) and tributylphosphine (130 μL), and the mixture was stirred at room temperature for 60 hr. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (144 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17](Cl)=[N:16][CH:15]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH:24][CH2:23][CH2:22][NH2:25])=[N:16][CH:15]=1
Reactant: Nc1cc(C(F)(F)F)ccc1NC(=O)c1ccc(Cl)nc1
Reactant: NCCN
Product: NCCNc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2N)cn1
Yield: 47 %

Procedure:
N-(2-Amino-4-trifluoromethylphenyl)-6-chloronicotinamide (316 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (159 mg, 47% yield) as a brown solid. LC-MS (m/z) 340 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:30][CH:31]=O)[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:33][C:34]1[C:39]([NH2:40])=[CH:38][CH:37]=[C:36]([N:41]2[CH2:45][CH2:44][C@@H:43]([N:46]3[CH2:50][CH2:49][CH2:48][C@@H:47]3[CH3:51])[CH2:42]2)[N:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:30][CH2:31][NH:40][C:39]2[C:34]([CH3:33])=[N:35][C:36]([N:41]3[CH2:45][CH2:44][C@@H:43]([N:46]4[CH2:50][CH2:49][CH2:48][C@@H:47]4[CH3:51])[CH2:42]3)=[CH:37][CH:38]=2)[CH2:7][CH2:8][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC=O)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Product: CCOC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 1 of Example 1, by condensing 4-(tert-butyl-diphenyl-silanyloxy)-1-(2-oxo-ethyl)-cyclohexanecarboxylic acid ethyl ester (100 mg, 0.22 mmol) and 2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine to obtain 132 mg of a crude solid, which was used in the next reaction without further purification.
Reaction SMILES: C(OC(ON1C2C(=CC([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=CC=2)CC(NC(=O)OC(C)(C)C)C1=O)=O)(C)(C)C.[C:36]1([C:42]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[N:43][C@H:44]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:45][C:46]2[C:51]([N+:52]([O-:54])=[O:53])=[CH:50][CH:49]=[C:48](F)[CH:47]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.ClC1C=CC=CC=1O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][C:48]1[CH:47]=[C:46]([C:51]([N+:52]([O-:54])=[O:53])=[CH:50][CH:49]=1)[CH2:45][C@@H:44]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[N:43]=[C:42]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1cc(F)ccc1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Oc3ccccc3Cl)ccc2N(OC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1Cl
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H](Cc1cc(Oc2ccccc2Cl)ccc1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
tert-Butyl {1-[(tert-butoxycarbonyl)oxy]-6-(2-chlorophenoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}carbamate (83) A mixture of tert-butyl N-(diphenylmethylene)-3-fluoro-6-nitro-L-phenylalaninate (which can be prepared according to the general method described in Example 12) (148 mg, 0.33 mmol), 2-chlorophenol (51 mg, 0.40 mmol), and Cs2CO3 (160 mg, 0.50 mmol) in anhydrous MeCN (5 mL) under N2 was heated to 70° C. for 20 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was dissolved in EtOAc (20 mL) and water (20 mL), and the separated aqueous phase was washed with EtOAc (20 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to yield tert-butyl 3-(2-chlorophenoxy)-N-(diphenylmethylene)-6-nitrophenylalaninate as a brown oil (180 mg). This residue was dissolved in a solution of HCl in dioxane (4 M, 10 mL), and the resulting solution was heated to 100° C. for 1 h. The reaction mixture was concentrated in vacuo to yield 3-(2-chlorophenoxy)-6-nitrophenylalanine (79 mg) as a solid. This product was converted to the title compound following the general procedure described in Example 9. The product was obtained as a gum (51 mg, 48%). LCMS m/z 505.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.56 (br s, 9H), 2.94 (br dd, J=14, 14 Hz, 1H), 3.37 (v br d, J=15 Hz, 1H), 4.48-4.58 (m, 1H), 5.60 (br s, 1H), 6.79 (br s, 1H), 6.88-6.93 (m, 1H), 6.9-7.1 (v br s, 1H), 7.01 (br d, J=8 Hz, 1H), 7.13 (br dd, J=8, 8 Hz, 1H), 7.26 (br dd, J=8, 8 Hz, 1H), 7.47 (br d, J=8 Hz, 1H).
Reaction SMILES: ClCl.[CH3:3][S:4][CH2:5][C:6]#[N:7].[NH2:8][C:9]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:19][C:20]([O:23][CH3:24])=[CH:21][C:22]=1[CH:5]([S:4][CH3:3])[C:6]#[N:7]
Reactant: COc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: CSCC#N
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2ccccc2)c(N)c(C(C#N)SC)c1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.0 ml (0.088 mole) of chlorine in 200 ml of methylene chloride cooled to -70° C. is added dropwise a solution of 7.65 g (0.088 mole) of methylthioacetonitrile in 1 liter of methylene chloride while maintaining the temperature below -65° C. After several minutes a solution containing 0.2 mole of 2-amino-5-methoxybenzophenone in 100 ml of methylene chloride is added dropwise over a 30 min period. The mixture is stirred at -70° C. for about 1.5 hr and 18 g (0.18 mole) of triethylamine is added. The mixture is stirred for about an hour at -70° C. and then allowed to warm to ambient temperature. The mixture is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from a suitable solvent, e.g., 2-propanol, to give the title product.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[CH:7][CH:6]=1)#[N:4].[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22]Br>CN(C)C=O>[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22][N:11]([C:12]1[CH:17]=[N:16][CH:15]=[N:14][CH:13]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1ccc(CBr)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(F)c(Br)c2)c2cncnc2)cc1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a suspension of 0.04 g of sodium hydride (60% in a mineral oil) in 2 ml of N,N-dimethylformamide was added 0.2 g of 5-[N-(4-cyanophenyl)amino]pyrimidine at room temperature, followed by stirring at that temperature for 1 hour. To the solution was added 0.27 g of 3-bromo-4-fluorobenzyl bromide while cooling with ice, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and water was added to the residue, followed by extraction with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to collect crude crystals from the chloroform eluate. The crude crystals were recrystallized from a mixed solvent of ethyl acetate and ethyl ether to obtain 0.25 g of 5-[N-(3-bromo-4-fluorobenzyl)-N-(4cyanophenyl)amino]pyrimidine.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]>O.CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26][O:4][C:1](=[O:3])[CH3:2])=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26][OH:3])=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CO)cc(Cl)c1O2
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)COC(C)=O)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 6 h
Yield: 2 %
Yield: 1 %

Procedure:
Sodium acetate (0.054 g, 0.658 mmol) in water (5 mL) was added to solution of compound of Example 4 (0.18 g, 0.405 mmol) in DMF (5 mL) at 25° C. and then the reaction mixture was stirred at 80° C. for 6 h. The solvent was removed under vacuum, water (15 mL) was added and extracted using ethyl acetate (3×30 mL). Combined organic layer was washed with water (2×100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and crude product was purified by column chromatography (silica gel) to obtain the title compound (B) (1% methanol in chloroform) and compound (A) (2% methanol in chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.CCOC(C)=O>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]([N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[CH:5]=[CH:6][CH:7]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: COCCN(C(=O)OC(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COCCN(C(=O)OC(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)c1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A suspension of tert-butyl 1-(3-aminophenyl)-2-(tert-butyldimethylsilyloxy)ethyl(2-methoxyethyl)carbamate (0.5 g, 1.95 mmol) and 4-bromobenzenesulfonyl chloride (0.99 g) in chloroform (20 mL) was stirred under nitrogen at room temperature. N,N-Diisopropyl ethyl amine (1 mL) was added and the mixture was stirred for 16 hours at 60° C. The solution was diluted with EtOAc (50 mL), washed with water (2×20 mL), 1 M HCl (20 mL) and brine (20 mL) and dried over Na2SO4. Evaporation of the solvents gave a brown oil which was purified by column chromatography (30% EtOAc in hexane) to give the title compound as a light yellow oil (0.3 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][C:34]=2[F:47])[C:19](=[O:31])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:3][C:4](=[O:7])[O:5][N:46]=3)=[CH:35][C:34]=2[F:47])[C:19](=[O:31])[C:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)c(-c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)c(-c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.02 g), sodium hydrogen carbonate (1.45 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-5-(4-fluorophenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.51 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.41 g, 73%).