Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=1>CN(C)C=O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:14][CH:12]2[CH2:13][N:10]([CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11]2)=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: Fc1ccc(Cl)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A stirred slurry of 41.3 g (1.03 mole) of 60% sodium hydride (in mineral oil) in 500 ml of dry dimethylformamide under nitrogen atmosphere was heated to 50° C. and 22.5 g (0.94 mole) of 1-diphenylmethyl-3-azetidinol in 700 ml of dry dimethylformamide was added dropwise at a rate which maintained the temperature between 70°-80° C. and allowed a gentle evolution of hydrogen. After the addition was complete, the reaction mixture was stirred for 2 hr at 90° C., then 125 g (0.94 mole) of 1-chloro-4-fluorobenzene was added dropwise. The reaction mixture was stirred at 90° C. under nitrogen for 24 hr, then stirred an additional 24 hr while the reaction mixture cooled to ambient temperature. The reaction mixture was poured into 6 liter of ice water and the solid which formed was collected by filtration to yield 271 g of wet crude product. A sample was recrystallized for elemental analysis from ethanol, yielding a fine tan crystalline product in 82.4% yield, m.p. 113°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[O:12][CH2:11][CH2:10][N:9]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1>C(OC(C)C)(=O)C.C(#N)C>[CH2:15]([N:9]1[CH:10]=[CH:11][O:12][C:13](=[O:14])[C@@H:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1OCCN(Cc2ccccc2)C1c1ccc(F)cc1
Solvent: CC(=O)OC(C)C
Solvent: CC#N
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a solution of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-4-fluorophenyl-1,4-oxazin-2-one) (10 g) in isopropyl acetate (110 ml) at room temperature was added a solution of (-)-3-bromocamphor-8-sulphonic acid ((-)-3BCS) (12 g) in acetonitrile (24 ml). Crystallisation began after 2-3 min. The slurry was stirred for 1 h at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture stirred at 65° C. for 3 days. The mixture was cooled to 0°-5° C., aged for 1 h. and the solid collected, washed with isopropyl acetate and dried in vacuo at 40° C., to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 17.24 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 79%(R), 21%(S). The liquors were stirred at 65° C. for 3 days, then cooled to 0°-5° C. The solid was collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 0.84 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 64%(R), 36%(S). The liquors were stripped in vacuo and the residue was dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at 65° C. for 20 h. The mixture was cooled to 0°-5° C. for 1 h and the solid collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 2.2 g, ee 99.2% (S) isomer. Total weight of (-)-3BCS salt: 20.28 g, 97% yield. A sample (0.5 g) of the (-)-3BCS salt was retained and the remainder converted back to free base. The salt was partitioned between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonia soln. (3 ml). The layers were separated and the aqueous phase extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to residue and flushed with isopropyl acetate to give the 3-(S)-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one) as the free base: yield 8.7 g, 93% recovery, ee 98.4% (S) isomer.
Reaction SMILES: [OH-].[K+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1>C(O)C>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([O-:15])=[O:14])=[CH:6][CH:5]=1.[K+:2]
Reactant: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Aqueous potassium hydroxide (1 mL of 0.1 N, 0.1 mmol) was added to a solution of 2-(bis-(4-hydroxyphenyl)-methyl)-benzoic acid [32 mg, 0.1 mmol, Adamczyk, M. and Grote, J. Organic Preparations and Procedures International, 2001, 33(1), 95] in 5 mL of ethanol and the mixture was stirred for additional 2 h at room temperature. The mixture was evaporated to dryness under reduced pressure to give 36 mg (100% yield) of the desired compound as a white solid, mp>300° C. 1H NMR (D2O, 300 MHz): δ6.41 [s, 1H, —CH], 6.66 [d, 4H, J=8.8 Hz, Ar—H], 6.80 [d, 4H, J=8.8 Hz, Ar—H], 7.03 [d, 1H, J=7.7 Hz, Ar—H], 7.35 [t, 1H, J=7.7 Hz, Ar—H], 7.44 [t, 1H, J=7.7 Hz, Ar—H], 7.74 [dd, 1H, =7.7 Hz, J2=2.2 Hz, Ar—H].
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH2:12])[C:5]=2[CH:4]=1.[CH3:19][N:20]1[CH2:25][CH2:24]N[CH2:22][CH2:21]1.[CH:26](N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:2][C:3]1[C:18]([CH3:26])=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([N:12]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:5]=2[CH:4]=1
Reactant: Cc1ccc2c(c1)C(N)=Nc1ccccc1N2
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C)C(N1CCN(C)CC1)=Nc1ccccc1N2
Temperature: 110 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
Combine 2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (600.0 mg, 2.31 mmol), N-methylpiperazine (1.39 g, 13.86 mmol), N,N-diisopropylethylamine (298.6 mg, 2.31 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 110° C. After 48 hours, cool the mixture to ambient temperature and stir it overnight. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 550.5 mg (78%) of a tan foam: mp 170°–177°, dec; mass spectrum (ion spray): m/z=307.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][CH:36]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53].Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH3:43])=[CH:39][CH:40]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][O:34][S:52]([CH3:51])(=[O:54])=[O:53])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCOS(C)(=O)=O)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Reaction time: 0.5 h

Procedure:
To a methylene chloride (2 mL) solution containing tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (0.693 mmol), triethylamine (290 μL, 2.08 mmol) and methanesulfonyl chloride (80 μL, 1.04 mmol) were added with ice-cooling, and the mixture was stirred for 30 min. After the reaction, 1 mol/L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:12][CH:13]([F:43])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[N:26]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)[C:29]([CH3:31])=[CH:30][C:25]2=[N:24][C:23]=1[CH3:42]>C(Cl)Cl>[F:43][CH:13]([F:12])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[N:26]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([NH:41][C:1](=[O:3])[CH3:2])(=[O:39])=[O:40])=[CH:34][CH:33]=3)[C:29]([CH3:31])=[CH:30][C:25]2=[N:24][C:23]=1[CH3:42]
Reactant: Cc1cc2nc(C)c(Cc3ccccc3OC(F)F)n2cc1-c1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cn3c(Cc4ccccc4OC(F)F)c(C)nc3cc2C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 14.6 %

Procedure:
Acetyl chloride (24 μL, 0.34 mmol) and triethylamine (47 μL, 0.34 mmol) were added to a solution of Example 78 (154 mg, 0.34 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2.5 h. Further acetyl chloride (12 μL, 0.17 mmol) and triethylamine (23 μL, 0.17 mmol) were added, and the mixture was stirred at room temperature for 24 h. Further acetyl chloride (49 μL, 0.68 mmol) and triethylamine (94 μL, 0.34 mmol) were added, and the mixture was stirred for 3 days. The solvent was removed and the mixture was purified by silica gel chromatography, eluting with a 0-5% gradient of 7M ammonia/methanol in DCM, to afford the title compound (24.8 mg, 14%) as a white solid. δH (250 MHz, CDCl3) 8.09 (d, J 8.4 Hz, 2H), 7.64 (d, J 19.1 Hz, 2H), 7.42 (s, 1H), 7.35 (d, J 8.3 Hz, 2H), 7.26 (m, 1H), 7.07 (td, J 8.4, 2.1 Hz, 2H), 6.94-6.24 (m, 2H), 4.24 (s, 2H), 2.49 (s, 3H), 2.25 (s, 3H), 2.09 (s, 3H). Method A HPLC-MS: MH+ m/z 500, RT 1.96 minutes (100%).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:20]([C:22]1([OH:26])[CH2:25][O:24][CH2:23]1)#[CH:21]>>[F:19][C:3]1[C:2]([C:21]#[C:20][C:22]2([OH:26])[CH2:25][O:24][CH2:23]2)=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC1(O)COC1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)COC3)c(F)cc1OCC2
Yield: 83 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-ethynyloxetan-3-ol to give the titled compound as a light brown solid (140 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([NH2:14])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:15][C:16]1[N:17]([CH:25]([CH3:29])[C:26](O)=[O:27])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([NH:14][C:26](=[O:27])[CH:25]([N:17]3[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[N:20]=[C:16]3[CH3:15])[CH3:29])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Reactant: Cc1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-methylpyrazol-4-amine (0.03 g, 0.16 mmol) in DMF (1.0 mL) was added 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.035 g, 0.16 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.067 g, 0.18 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.038 mmol, 24%). 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.93 (s, 1H), 7.81 (d, J=1.3 Hz, 1H), 7.42-7.32 (m, 2H), 7.24-7.14 (m, 2H), 5.35 (q, J=6.8 Hz, 1H), 2.48 (s, 3H), 2.19 (s, 3H), 1.86 (d, J=7.0 Hz, 3H); MS: (ES) m/z calculated for C18H17F4N5O [M+H]+ 396.1, found 396.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]2[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[NH:21][C:20]([C:30]3[S:31][CH:32]=[CH:33][N:34]=3)=[N:19]2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.C1C(=O)N([Br:42])C(=O)C1>>[Br:42][CH2:29][C:22]1[NH:21][C:20]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[N:19][CH:18]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=2[C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Yield: 60 %

Procedure:
Ethyl 4-(5-fluoro-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (5 g, 10.2 mmol) was reacted with NBS (2.2 g, 12.2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.48 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:5][C:6](=[O:48])[C@@H:7]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH2:17].[C:54]([O:58][C:59]([NH:61][C@H:62]([C:72]([OH:74])=O)[CH2:63][O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)=[O:60])([CH3:57])(C)C.ON1[C:80]2C=CC=C[C:79]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:49][CH:50]([CH3:51])[CH3:52])[NH:5][C:6](=[O:48])[C@@H:7]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH:17][C:72](=[O:74])[C@H:62]([CH2:63][O:64][CH2:65][C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)[NH:61][C:59]([O:58][CH2:54][CH2:57][CH2:79][CH3:80])=[O:60]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCCCOC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C

Procedure:
L-Tryptophyl-L-seryl-L-tyrosyl-D-phenylalanyl-L-leucine methyl ester, 1.53 g., is dissolved in 35 ml. of dimethylformamide, the solution cooled in ice and treated with 620 mg. of Nα -t-butoxycarbonyl-O-benzyl-L-serine, 311 mg. of 1-hydroxybenztriazole and 475 mg. of dicyclohexylcarbodiimide (10% excess). The reaction is stirred overnight to room temperature and twenty-four hours additional at room temperature. The mixture is filtered and the filtrate evaporated under reduced pressure. The residue is dissolved in 500 ml. of ethyl acetate and washed with 0.1N hydrochloric acid, saturated salt solution, 5% sodium bicarbonate solution, saturated salt solution and water. The ethyl acetate solution is dried over magnesium sulfate and evaporated. The residual solid is dried under reduced pressure; 2.29 g.; m.p. 200°-202° C.; [α]D23 -19.5° (c 1.03, methanol); ultraviolet in methanol λmax 289.5 E11 52; λmax 280 E11 68.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:9][CH:8]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][CH2:4][CH:5]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:11][CH:12]=1)(=[O:31])=[O:30]
Reactant: N#Cc1ccc(C(CCCO)Oc2ccc(OC3CCCCO3)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Yield: 100 %

Procedure:
A solution of 4-{4-hydroxy-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenoxy]butyl}benzonitrile (see step (ii) above; 2.37 g, 6.45 mmol) and TEA (1.35 mL, 9.68 mmol) in DCM (10 mL) was cooled to −5° C. Methanesulfonyl chloride (0.65 mL, 8.38 mmol) in DCM (5 mL) was added slowly. After addition was complete, the temperature was maintained below 5° C. for 1 h before DCM and water were added. The organic layer was washed with water, dried (Na2SO4) and then evaporated to yield 2.87 g (100%) of the sub-title compound. This was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])([O:3][CH2:4][CH3:5])=[O:2].[CH3:29]NC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2CC)[C@H](O)[C@@H]1O.ClCCC(OCC)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH2:25][CH3:29])[C@H:12]([OH:26])[C@@H:11]1[OH:27])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CNC)[C@@H](O)[C@H]1O
Agent: CCOC(=O)CCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(CC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 13b was prepared by the same procedure as described for the preparation of 13a using 4b (260 mg, 0.84 mmol), ethyl 3-chloropropionate (138 mg, 1.0 mmol), DIEA (53 mg, 0.07 mL, 0.41 mmol), and DMF (4 mL). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH), a glassy sticky solid was obtained: yield 153 mg (44%), MS: m/z 409 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.10 (bs, 2H, 6-NH2), 5.71 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.32 (bd, 1H, OH-2′, J2′-2′OH=5.0 Hz), 5.16 (bd, 1H, OH-3′, J3′-3′OH=5.1 Hz), 5.12 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=5.7 Hz, J2′-2′OH=5.0 Hz), 4.14 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.1 Hz, J3′-3′OH=5.1 Hz), 4.01 (q, 2H, OCH2CH3), 3.91-3.98 (m, 1H, H-4′), 2.87 (q, 2H, CH2 of 8-Et), 2.71-2.79 (m, 1H, 5′-CH2), 2.51-2.65 (m, 3H, 5′-CH2, CO—CH2), 2.38 (t, 2H, N(CH3)—CH2), 2.16 (bs, 3H, N—CH3), 1.30 (t, 3H, CH3 of 8-Et), 1.15 (t, 3H, OCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]I)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH3:18]>CC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:23][C:22]2[CH:24]=[CH:25][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:4][N:3]=1
Reactant: CCc1ccc(N)cc1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A heterogeneous mixture of 2,4-dichloro-5-(iodomethyl)pyrimidine (31.07 g, 107.3 mmol) (from Example 1c supra) and potassium carbonate (74 g, 536.5 mmol) in acetone (535 mL) was treated with 4-ethylaniline (13.3 mL, 107.3 mmol) (Aldrich). The mixture was stirred at room temperature overnight, then diluted with water (500 mL) and extracted with ethyl acetate. The combined organic layers were successively washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The crude mixture was purified by flash chromatography (20% ethyl acetate in hexanes) to give (2,4-dichloro-pyrimidin-5-yl-methyl)-(4-ethyl-phenyl)-amine as a beige solid. (Yield 21.4 g, 70%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:28])[CH2:13][C:14]([CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])=O)[CH3:10].[CH2:29]([O:31][C:32](=[O:37])/[CH:33]=[C:34](\[NH2:36])/[CH3:35])[CH3:30]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:33]([C:32]([O:31][CH2:29][CH3:30])=[O:37])=[C:34]([CH3:35])[NH:36][C:14]=1[CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])=[O:28])[CH3:10]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 10.6 g of benzaldehyde, 28 g of phthalimidoacetoacetic acid ethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 150 ccs of ethanol is heated under reflux for 2×24 hours, the mixture is stirred overnight at room temperature and the precipitate is filtered off and washed with alcohol and ether. Light yellow crystals of melting point 169°-170° C. are obtained in 75% yield.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:28](OCC)=[O:29])=[N:6][C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][OH:27])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])([O-])=O.ClC1N=C([C:40](OCC)=[O:41])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.[NH2:57]C1C=CC=CC=1CO.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:27][CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:7]1[N:8]=[C:9]2[C:4]([NH:1][C:40](=[O:41])[N:10]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[C:5]([C:28]([NH2:57])=[O:29])[N:6]=1
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(Nc2ccccc2CO)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: Nc1ccccc1CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3CO)nc21
Yield: 86 %

Procedure:
Ethyl 5-nitro-2-(2-(hydroxymethyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (0.300 g, 0.852 mmol), 2-aminobenzyl alcohol (0.125 g, 1.2 mmol) and diisopropylethylamine (0.296 g) were reacted according to General Procedure C, except at room temperature and in dimethylformamide (5 ml). The crude reaction mixture was condensed and purified using Biotage chromatography (60 to 100% EtOAc in hexanes) to afford the title compound (0.323 g, 86%). MS (ESI) m/z 440.5 [M+1]+.