Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20].CN(C)C>O1CCOCC1.O>[C:1]([NH:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: CN(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.22 g lauroylchloride dissolved in 46 ml dioxane were slowly added to 6.72 g glutamine and 13.94 g trimethylamine in 92 ml water and 92 ml dioxane, the temperature being 0° C. After stirring at room temperature for 1 hour, the dioxane was evaporated and the remaining solution was acidified to pH 1 with HCl. The crystals were filtered off and recrystallized from acetone and then from methanol: 9.9 g white needles.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([OH:19])[C@@H:11]([OH:18])[C@H:12]([OH:17])[C:13](=[O:16])[CH2:14][OH:15])=O)(C)(C)C.O.[ClH:21]>C(O)CC>[ClH:21].[NH2:8][CH2:9][C@H:10]([OH:19])[C@@H:11]([OH:18])[C@H:12]([OH:17])[C:13](=[O:16])[CH2:14][OH:15]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Agent: Cl
Solvent: O
Solvent: CCCO
Product: NC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO

Procedure:
20 g of N-tert.-butoxycarbonyl-6-amino-6-desoxy-L-sorbose were introduced in portions into a mixture of 6.4 ml of H2O and 13.2 ml of concentrated hydrochloric acid, whilst stirring and cooling. The batch was subsequently stirred for 2 hours, without cooling, and 120 ml of n-propanol were then added in the course of 2 hours. The resulting suspension of crystals was then stirred at 0° C. for 1 hour and filtered on a suction filter. The crystals were washed with a little n-propanol and dried at room temperature in a vacuum drying cabinet.
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[OH:42][CH2:43][CH2:44][NH2:45]>>[CH3:34][N:33]1[C:29]([C:27]([NH:26][C:22]2[CH:21]=[C:20]([C:19]#[C:18][C:16]3[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=3)[C:10]([N:9]=[S@@:7]([CH2:3][C:4]([NH:45][CH2:44][CH2:43][OH:42])=[O:5])(=[O:8])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:11])[CH:25]=[CH:24][CH:23]=2)=[O:28])=[CH:30][C:31]([CH3:35])=[N:32]1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Reactant: NCCO
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CC(=O)NCCO)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and 2-hydroxyethylamine were reacted to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:39]([OH:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])[C:3]([NH:5][C@:6]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH:36]([CH3:38])[CH3:37])[CH:29]=1)([C:14]1[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.B.[H][H]>C1COCC1>[NH2:1][CH:2]([CH2:3][NH:5][C@:6]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH:36]([CH3:38])[CH3:37])[CH:29]=1)([C:14]1[CH:19]=[C:18]([O:20][C:21]([F:25])([F:26])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:39]([C:44]([F:45])([F:46])[F:47])([OH:48])[C:40]([F:43])([F:42])[F:41]
Reactant: [H][H]
Reactant: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C(N)C(O)(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: B
Solvent: C1CCOC1
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NCC(N)C(O)(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 100 °C
Yield: 20 %

Procedure:
To a solution of 2-amino-4,4,4-trifluoro-N—((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamide, prepared as described in Example 293, (20 mg, 0.028 mmol) in THF (0.5 mL) was added borane (0.2 mL, 1.0 M solution in THF). After hydrogen evolution ceased, the solution was heated in a sealed microwave vial under microwave irradiation at 100° C. for 5 min. The solvents were removed under a stream of nitrogen then THF (0.5 mL) was added to the residue followed by BF3Et2O (30 mg, 0.21 mmol) and LAH (0.2 mL, 1.0 M solution in THF). After evolution of hydrogen gas had ceased, the sealed microwave vial was heated at 100° C. for 10 min. The solvents were removed under a stream of nitrogen and the residue dissolved in NH4OH (ca. 10 mL). LiCl (10%, ca. 10 mL) was added and the aqueous extracted with DCM (3×10 mL). The combined organic portions were concentrated under reduced pressure and purified by preparative TLC (25×25 mm, silica gel 1 mm elution with hexane:EtOAc 4:1). 3-Amino-1,1,1-trifluoro-4-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylamino)-2-(trifluoromethyl)butan-2-ol (Example 327, 5 mg, 20% yield) was isolated as a colorless oil at Rf of 0.5. LCMS: RT=3.88 min [M+H] 693.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.88 min, Purity 91% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) 7.15 ppm, 3H, m; 7.05 ppm, 1H, m; 6.86 ppm, 2H, d, J=8.0 Hz; 6.83 ppm, 3H, m; 6.61 ppm, 2H, d, J=8.0 Hz; 5.87 ppm, 1H, t, t, J=52.0 Hz and J=4.0 Hz; 4.41 ppm, 1H, sept, J=8.0 Hz; 3.57 ppm, 1H, d, J=12.0 Hz; 3.48 ppm, 1H, d, J=12.0 Hz; 2.99 ppm, 2H, m; 2.53 ppm, 1H, brt; 1.27 ppm, 3H, d, J=8.0 Hz; 1.25 ppm, 3H, d, J=8.0 Hz.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH:13]([C:22]2[C:23]([CH3:34])=[N:24][O:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[N:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([O:37][C:38](=[O:58])[CH2:39][C:40]1([C:43]2[CH:48]=[CH:47][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][CH:44]=2)[CH2:42][CH2:41]1)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:58])[CH2:39][C:40]1([C:43]2[CH:48]=[CH:47][C:46]([C:30]3[CH:31]=[CH:32][C:27]([C:26]4[O:25][N:24]=[C:23]([CH3:34])[C:22]=4[CH:13]([C:10]4[O:9][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:12][N:11]=4)[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:28][CH:29]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41]1)[CH3:36]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O[Si](C)(C)C(C)(C)C)c1nnc(Cc2ccccc2)o1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O[Si](C)(C)C(C)(C)C)c4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2-benzyl-5-[[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(tert-butyl-dimethyl-silanyloxy)-methyl]-[1,3,4]oxadiazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C1CCCCCCC1.N(OC(C)(C)C)=O.ON1[C:21](=O)[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(=NO)CCCCCCC1.[N+](C1CCCCCCC1)([O-])=O>C(O)(=O)C>[C:18]1(=[O:27])[CH2:19][CH2:26][CH2:25][CH2:24][CH2:23][CH2:20][CH2:21]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)(C)ON=O
Agent: O=[N+]([O-])C1CCCCCCC1
Agent: ON=C1CCCCCCC1
Solvent: CC(=O)O
Solvent: C1CCCCCCC1
Product: O=C1CCCCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclooctane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclooctanone oxime, nitrocyclooctane, and cyclooctanone were formed in yields of 55%, 5%, and 4%, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C(NC(C)C)(C)C.[C:20](=[O:22])=[O:21].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:20]([OH:22])=[O:21]
Reactant: Fc1cccnc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
3-Fluoropyridine (25 g, 257 mmol) was added to a solution of butyllithium (270 mmol) and diisopropylamine (27.4 g, 271 mmol) in tetrahydrofuran (600 mL) at −78° C. After stirring for one hour, crushed dry ice was added to the solution and the solution was warmed to room temperature during one hour. Aqueous hydrogen chloride was added to the solution to acidify the solution to pH 5. The resulting precipitate was filtered and dried. The title compound (25.2 g, 179 mmol, 70%) was obtained as colorless crystal.
Reaction SMILES: [O:1]=[S:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>CN(C)C=O.O>[O:1]=[S:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccccc1F
Reactant: O=S1(=O)CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1N1CCCCS1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
Added to a solution of 1,1-dioxo[1,2]thiazinane (3.37 g, 25 mmol) in dimethylformamide (35 mL) was sodium hydride (0.675 g, 25 mmol, 95%) and the mixture stirred at room temperature for 15 min. 2-Fluorobenzonitrile (3.37 mL, 31.3 mmol) was added and the mixture stirred at 80° C. for 18 h. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, then dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (SiO2) eluting with 10%-100% ethyl acetate/hexane. The isolated solid was recrystallized from hot ethyl acetate/hexane (2:1) to give the title compound as white crystals (4.15 g, 70% yield). 1H-NMR (300 MHz, CDCl3) δ ppm: 7.70 (1H, dd, J=7.7, 1.1 Hz), 7.64–7.53 (2H, m), 7.41 (1H, td, J=7.3, 1.6 Hz), 3.72 (2H, t, J=5.5 Hz), 3.32 (2H, t, J=6.0 Hz), 2.40–2.32 (2H, m), 2.05–1.97 (2H, m). LCMS [M+H]+ calcd for C11H12N2O2S: 237.06; found: 237.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:56]=[CH:55][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=2)=[O:47])=[CH:44][C:43]=1[CH3:57]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:56]=[CH:55][C:45]([C:46]([NH:48][C:49]6[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=6)=[O:47])=[CH:44][C:43]=5[CH3:57])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)Nc2ccncc2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)Nc4ccncc4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and 4-bromo-3-methyl-N-pyridin-4-yl-benzamide (41 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-N-pyridin-4-yl-benzamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-258) as a pale yellow powder (22 mg, 9%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:33](Br)[CH:34]=[CH2:35]>>[CH2:35]([N:21]([CH2:20][CH2:19][C:18]1[CH:29]=[CH:30][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:31])[F:32])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:34]=[CH2:33]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: C=CCBr
Product: C=CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared as described in Example 102 using tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) and allyl bromide and isolated as a yellow oil (0.144 g, 99%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.15-8.08 (m, 2H), 7.85-7.76 (m, 2H), 7.39 (dq, J=7.8, 1.0 Hz, 2H), 7.30 (s, 2H), 5.76 (s, 1H), 5.12 (s, 2H), 3.76 (d, J=45.8 Hz, 2H), 3.42 (s, 2H), 2.89 (d, J=0.7 Hz, 2H), 1.47 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 489 ([M+H]+).
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:19][C:18]([C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[C:25]([C:29]([OH:31])=O)[NH:26]4)=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:19][C:18]([C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[C:25]([C:29]([N:65]5[CH2:70][CH2:69][O:68][CH2:67][CH2:66]5)=[O:31])[NH:26]4)=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3cc(C(=O)O)[nH]c3c2)o1)C1CCCCC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3cc(C(=O)N4CCOCC4)[nH]c3c2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-{5-[((S)-cyclohexyl-methylcarbamoyl-methyl)-carbamoyl]-furan-2-yl}-1H-indole-2-carboxylic acid (20 mg, 0.047 mmol) is added subsequently HATU (10 mg, 0.052 mmol), DIEA (0.026 mL, 0.142 mmol), and morpholine (4.5 mg, 0.052 mmol). The reaction is stirred at room temperature for 2 h and is directly purified by reversed phase (HPLC). 7.0 mg, 30%, LC/MS ESI m/z (M+H)+=493.43.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11](CBr)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].C(OC([C:24]1[CH:25](C2C=CC=C(Cl)C=2)[N:26]=[C:27](OC)[NH:28][C:29]=1C)=O)(C)C.N1CCCCC1.N1C=CC=NC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[NH:28]1[CH:29]=[CH:24][CH:25]=[N:26][CH2:27]1.[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC1=NC(c2cccc(Cl)c2)C(C(=O)OC(C)C)=C(C)N1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: C1=CNCN=C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1
Reaction time: 0.33 h
Yield: 29 %

Procedure:
Tetrabutyl ammonium iodide (0.39 mmol) was added to a solution of N-Boc 4-bromomethyl piperidine (0.58 mmol; prepared as described in Bioorganic and Medicinal Chemistry Letters, 9, 2615, (1999)) in dimethylformamide (1 ml) at ambient temperature for 20 minutes. In a second vessel, NaH (0.47 mmol) was added to a solution of 2-methoxy-6-methyl-4-(3-chloro-phenyl)-1,4-dihydro-pyrimidine-5-carboxylic acid isopropyl ester (0.39 mmol) in dimethylformamide (1 ml) at ambient temperature and stirred for 20 minutes. The piperidine solution was then added to the dihydropyrimidine solution and stirred for approximately 2 hours. The reaction was quenched by addition of water, diluted with ethyl acetate, and subsequently washed with water and brine solution. The acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting material was purified via silica gel chromatography utilizing 20% ethyl acetate/hexanes eluent affording the corresponding N Boc piperidine dihydropyrimidine intermediate 195A in 29% yield.
Reaction SMILES: N[C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].N([O-])=[O:14].[Na+]>CC(O)=O.OS(O)(=O)=O.O>[OH:14][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1cccc(N)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(O)cccc1C(=O)O
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A solution of 20.6 g (0.125 mol) of methyl 3-amino-2-methylbenzoate in 150 mL of HOAc and 25 mL of conc. H2SO4 was cooled in ice and diazotized by the dropwise addition of a solution of 8.7 g (0.125 mol) of NaNO2 in 50 mL of H2O. After stirring for 15 minutes, the diazonium solution was added dropwise to a boiling solution of 200 mL of 50% H2SO4, and the refluxing continued for 15 minutes after the addition was complete. The mixture was diluted with H2O and extracted twice with Et2O. The Et2O was washed 5 times with H2O, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 17.98 g (94.4% yield) of the product as a tan solid, mp 137-140° C. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:21](Cl)[C:22]1[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:27][O:26][C:25]1[CH:28]=[CH:29][C:22]([CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 50 °C

Procedure:
To a stirred solution of ethyl 4-hydroxybenzoate (530 g, 3.19 mol) in DMF (6 L) were added K2CO3 powder (1102 g, 7.97 mol, 2.5 eq.), NaI (1195 g, 7.97 mol, 2.5 eq.) and PMB-Cl (599.4 g, 3.83 mol, 1.2 eq.) at ambient temperature. The reaction mixture was heated at 50° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and ice-water (9 L) was added to the reaction mixture. The resulting solid was filtered and washed with water (5 L), dried at 40° C. under vacuum to obtain product.
Reaction SMILES: [Na].CCOCC.C[C:8]([CH3:18])([CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[C:9]#N.[Cl-].[NH4+]>C(O)C.O1CCCC1>[CH3:18][C:8]1([CH3:9])[CH2:11][CH2:12][C:13]([CH3:16])([CH3:17])[CH:14]1[NH2:15]
Reactant: CC(C)(C#N)CCC(C)(C)C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: CC1(C)CCC(C)(C)C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A flask was charged with 35 g. (0.61 mole) of 40% sodium dispersion in mineral oil. The oil was removed by washing with ethyl ether and decantation. The sodium was then mixed with 400 ml. of ether and a mixture of 32.8 g (0.20 mole) 2,2,5,5-tetramethyladiponitrile, prepared by the method of Coffman et al., J. Am. Chem. Soc., 80, 2868 (1957), and 400 ml. of tetrahydrofuran was added slowly. The resulting mixture was stirred at room temperature for 4 hours, the excess sodium decomposed by dropwise addition of saturated aqueous ammonium chloride, the organic layer washed with water, dried (Na2SO4) and evaporated to afford 25.1 g. of crude 2,2,5,5-tetramethylcyclopentylimine. The imine was dissolved in 75 ml. of ethanol and added dropwise to a flask containing 23.3 g. (1 mole) sodium shot. An additional 75 ml. ethanol was added and the mixture heated at reflux until the remaining sodium metal was consumed. The reaction mixture was diluted with water, acidified to pH 1 with concentrated hydrochloric acid, the aqueous phase washed with ether then made strongly basic by addition of sodium hydroxide. The organic layer was extracted with ether, washed with brine, dried (Na2SO4) and evaporated to dryness. The residue was distilled in vacuo to afford 6.6 g. (23%) of the desired amine, B.P. 60°-61° C. (20 mm.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([Cl:18])=[C:6]([O:8][C:9]2[C:14]([F:15])=[C:13]([CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])[CH:7]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([Cl:18])=[C:6]([O:8][C:9]2[C:14]([F:15])=[C:13]([CH2:16][Br:27])[CH:12]=[CH:11][C:10]=2[Cl:17])[CH:7]=1
Reactant: Cc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(Br)cc(Oc2c(Cl)ccc(CBr)c2F)c1Cl
Yield: 62.4 %

Procedure:
2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (13.25 g, 36.0 mmol) and NBS (6.41 g, 36.0 mmol) were combined in carbon tetrachloride (150 mL) with a catalytic amount of AIBN (0.296 g, 1.800 mmol) and stirred at reflux for 16 h. The reaction mixture was washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by chromatography on 330 g silica gel eluted with 0 to 10% Et2O in hexanes to give the desired product, 2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-(bromomethyl)-1-chloro-3-fluorobenzene (10.04 g, 22.47 mmol, 62.4% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.53-7.67 (m, 3H), 6.78 (s, 1H), 4.75 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[OH:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].ClC(Cl)(Cl)C(O)=O.[CH:40]([O:42][CH2:43][CH3:44])=[CH2:41]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[CH2:40]([O:42][CH:43]([O:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32])[CH3:44])[CH3:41]
Reactant: C=COCC
Reactant: O=C1CCCN1CO
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(C)OCN1CCCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4 g of dl-5-hydroxymethyl-2-pyrrolidone are dissolved in 20 ml of chloroform, and 0.1 g of trichloroacetic acid and 16 ml of vinylethylether are added thereto. The solution is stirred at room temperature for 4 hours. After the reaction, the solution is cooled with ice-water, and washed with an aqueous sodium bicarbonate solution. The washings is extracted with chloroform. Then, the reaction solution and chloroform extract are combined, and the combined mixture is washed with water saturated with ammonium sulfate, dried and evaporated to remove solvent. The residue thus obtained is distilled under reduced pressure. dl-5-[1-(Ethoxy)ethoxy-methyl]-2-pyrrolidone is obtained as pale yellow oil. Yield: 6.45 g. B.p. 137°-138° C./1.5 mmHg