Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C[Li])(C)C.[CH2:7]([NH:14][C:15]([C:17]1([C:21]([O:23]CC)=O)[CH2:20][CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:21]([C:17]1([C:15]([NH:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH2:18][CH2:19][CH2:20]1)(=[O:23])[CH3:1]
Reactant: CCOC(=O)C1(C(=O)NCc2ccccc2)CCC1
Reactant: [Li]C[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(=O)C1(C(=O)NCc2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
((Trimethylsilyl)methyl)lithium (1.0 M in pentane) (908 mL, 908 mmol) was added dropwise over 1 hr 20 min to a 0° C. solution of ethyl 1-(benzylcarbamoyl)cyclobutanecarboxylate (52.7 g, 202 mmol) in THF (703 mL) under N2. Stirring @ 0° C. was continued for 2 hrs during which time the solution became red. LC/MS after 1 hr looked the same as after 30 minutes, a complete reaction (m/e 232.1, M+H for desired product). While still @ 0° C., the reaction was quenched by the addition of anhydrous methanol (246 mL, over 45 minutes). There was solid formation which after ca. 30 minutes cleared up to form a turbid yellow solution. Note: methanol addition was dropwise; when further addition no longer caused extensive precipitation, the addition was accelerated to a slow stream. After 5 minutes, the ice bath was removed and stirring was continued for 30 minutes. Brine was added (800 mL), the layers were separated, the brine layer was extracted twice with EtOAc (300 mL each), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to yield 50.19 g of a yellow solid. The crude product was stirred and sonicated for 30 minutes in 400 mL of hexane. The product was collected by filtration and rinsed with hexane to yield ca. 40 g of a yellow solid with some sticky lumps. The solid was sonicated again for several minutes in 400 mL of hexane, collected by filtration, rinsed with hexane, and dried under vacuum to yield 35.82 g of an off-white solid. The combined hexane filtrate was concentrated under vacuum to yield 8.67 g of a yellow oil, which by LC/MS contained desired product. Flash chromatography of the filtrate on silica gel (Teledyne-Isco RediSep Rf 80 g column), eluting with 250 mL of hexane, 400 mL of 80:20, and 400 mL of 40:60 hexane:EtOAc yielded 5.15 g of an off-white solid. The chromatographed solid was similar in purity to the triturated solid, and the two solids were combined to afford 40.97 g of the title compound as an off-white solid. LC/MS: m/e 232.1 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.48-7.17 (m, 5H), 5.78 (br. s., 1H), 4.44 (d, J=5.9 Hz, 2H), 2.62-2.46 (m, 4H), 2.16 (s, 3H), 2.01-1.88 (m, 1H), 1.88-1.75 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:15][C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:19]#[N:20])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([CH3:24])=[C:16]([NH:15][C:7]2[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]3[CH:3]=[C:2]([F:1])[CH:26]=[CH:25][C:5]=3[N:6]=2)[CH:17]=1
Reactant: Cc1ccc(C#N)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CN)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Reaction time: 18 h

Procedure:
To a solution of 3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-2,6-naphthyridin-5-yl)amino]-4-methylbenzonitrile (40 mg, 0.12 mmol) in THF (1.1 mL) at 0° C. was added lithium aluminum hydride (0.4 mL, 1 M, 0.40 mmol). The reaction was stirred for 18 hours and then quenched by the addition of 0.02 mL water, then 0.02 mL 10% aq. NaOH and finally 0.05 mL water. The mixture was then poured into a separatory funnel with water and EtOAc. The mixture was extracted with EtOAc and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatographpy (0-10% MeOH/CH2Cl2 (with 1% NH4OH)) afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH2:20]([NH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([N:28]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: c1ccc(CCNc2ccncc2)cc1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(N(CCc2ccccc2)c2ccncc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(phenethylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: C(N(C1C2N=C([N:26]3[CH2:42][CH2:41][C:29]4([N:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:32][NH:31][C:30]4=[O:40])[CH2:28][CH2:27]3)N=C(N3CCOCC3)C=2N=CN=1)C)C1C=CC=CC=1.ClC1N=C(N2CCOCC2)C2N=CN=C(N(CC3C=CC=CC=3)C)C=2N=1>>[C:34]1([N:33]2[C:29]3([CH2:28][CH2:27][NH:26][CH2:42][CH2:41]3)[C:30](=[O:40])[NH:31][CH2:32]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCC4(CC3)C(=O)NCN4c3ccccc3)nc12
Agent: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: O=C1NCN(c2ccccc2)C12CCNCC2
Yield: 47 %

Procedure:
8-(N-benzyl-N-methyl-amino)-4-morpholino-2-(1-phenyl-1,3,8-triazaspiro [4,5]decan-4-on-8-yl)-pyrimido[5,4-d]pyrimidine From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one Yield: 47% of theory, Melting point: 203°-205° C. C31H35N9O2 (565.68)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]3[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:23]1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([NH:36][C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([N:24]4[CH2:25][CH2:26][CH:22]([N:21]([CH3:37])[CH3:20])[CH2:23]4)[S:28][C:29]=3[CH:35]=2)=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4ccc(Cl)c(Cl)c4)cc3s2)C1
Yield: 32.4 %

Procedure:
Combine 3,4-dichlorocinnamic acid (0.083 g, 0.381 mmol), CH2Cl2 (5.0 mL), and DMF (3 drops) with stirring. Add oxalyl chloride (0.10 mL, 1.14 mmol) and stir the mixture for 3 h at room temperature. Concentrate the mixture in vacuo, add hexane (approximately 10 mL), re-concentrate in vacuo, and add CH2Cl2 (5.0 mL). Transfer the mixture to a 40 mL reaction vial and add a mixture of 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (Example 1, step 3) in CH2Cl2 (5.0 mL). Shake the reaction vial overnight at room temperature. Dilute the reaction mixture with CH2Cl2 (30 mL), wash with saturated NaHCO3 (aqueous) (2×25 mL), dry over sodium sulfate, filter, and concentrate in vacuo. Purify the residue using silica gel chromatography (12 g column, 5-15% MeOH/CH2Cl2 over 45 min) to yield a yellow residue. Dilute the residue with CH2Cl2 (25 mL) and wash with 1 M NaOH (25 mL). Filter a yellow solid which precipitates in the separatory funnel. Concentrate the mother liquor in vacuo and filter, washing with cold CH2Cl2 to obtain a second crop. Combine the precipitate from the separatory funnel, and the second crop, to afford the title compound (57 mg, 32%). mass spectrum (m/e): 461.2 [M+1], 459.2 [M−1]. 1H NMR (400 MHz, CDCl3): δ8.31 (d, 1H, J=1.6 Hz), 7.65 (d, 1H, J=15.6 Hz), 7.64 (m, 1H), 7.52 (d, 1H, J=8.4 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.37 (m, 1H), 7.35 (m, 1H), 7.16 (dd, 1H, J=8.8, 2.4 Hz), 6.53 (d, 1H, J=15.6 Hz), 3.86 (t, 1H, J=9.2 Hz), 3.74 (t, 1H, J=9.2 Hz), 3.56 (m, 1H), 3.50-3.42 (m, 1H), 2.98 (m, 1H), 2.36 (s, 6H), 2.29 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C@H:20]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[NH:22]1[CH2:23][CH2:24][C@H:20]([CH2:19][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN(Cc2ccccc2)C(=O)OCc2ccccc2)C1
Solvent: CO
Solvent: CC(=O)Cl
Product: O=C(OCc1ccccc1)N(Cc1ccccc1)C[C@H]1CCNC1
Yield: 95.2 %

Procedure:
tert-Butyl (S)-3-[N-benzyl-N-(benzyloxycarbonyl)aminomethyl]pyrrolidine-1-carboxylate (Intermediate 167, 11 g) was added dropwise to a solution of acetyl chloride (15 g) in methanol (50 mL) and the resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was purified by HPLC (C18) to give benzyl N—((S)-pyrrolidin-3-ylmethyl)-N-benzylcarbamate (8.0 g) as an off white solid which was used without further characterisation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([O:24]C)=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([OH:24])=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Methyl 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate (710 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (3 mL) was added at 0° C. The mixture was stirred at 0° C. for 1 hr, and at room temperature for 2 hr, cooled again to 0° C., acidified with 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residual crystals were washed with a mixed solvent of isopropyl ether and hexane to give the title compound as colorless crystals (yield 577 mg, 83%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22]>O1CCOCC1>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1
Solvent: C1COCCO1
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
First, 11-(chloroacetyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one (5.0 g, 0.0174 mol) is dissolved in anhydrous dioxan (100 ml) and refluxed for 2 hours after the addition of 2-[(diethylamino)methyl]piperidine (6.0 g, 0.035 mol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[C:11]([I:13])[C:10]([OH:14])=[C:9]([I:15])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:16]=O.Cl>COCCOC>[OH:14][C:10]1[C:9]([I:15])=[C:8]2[C:7]([CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH:1][CH2:16]2)=[CH:12][C:11]=1[I:13]
Reactant: C=O
Reactant: N[C@@H](Cc1cc(I)c(O)c(I)c1)C(=O)O
Agent: Cl
Solvent: COCCOC
Product: O=C(O)[C@@H]1Cc2cc(I)c(O)c(I)c2CN1
Temperature: 72 °C
Yield: 45.4 %

Procedure:
A thick-walled reaction flask with a screw top was charged sequentially with (S)-2-amino-3-(4-hydroxy-3,5-diiodophenyl)propanoic acid (Chem-Impex Int'l Inc., 5.0 g, 12 mmol), 1,2-dimethoxyethane (5.0 mL), formaldehyde (37% wt. in H2O, 4.5 mL, 60 mmol), and conc. HCl (60.2 mL, 1981 mmol). The resulting tan slurry was sealed with a screw top and heated to 72° C. slowly over 30 min and then maintained at 72° C. for 12 h. The resulting brown reaction slurry was then cooled to 0° C., filtered while cold, and washed with small amounts of 1,2-dimethoxyethane to give the title compound (2.42 g, 5.45 mmol, 47%) as a white solid. 1H NMR (DMSO-d6) δ 9.93 (br s, 1H), 9.69 (br s, 1H), 7.75 (s, 1H), 4.34 (d, J=7.7 Hz, 1H), 4.21-3.94 (m, 2H), 3.93-3.47 (m, 1H), 3.33-3.16 (m, 1H), 3.15-2.97 (m, 1H); MS (ESI+) m/z 445.9 (M+H)+.
Reaction SMILES: [N+]([CH3:4])([O-])=O.[CH:5]1[CH:13]=[CH:12][C:11]2[C:7](=[N:8][O:9][N+:10]=2[O-:14])[CH:6]=1.CC1N=CN=C(C)C=1>O1CCCC1>[OH:9][N:8]1[C:7]2[CH:6]=[CH:5][CH:13]=[CH:12][C:11]=2[N+:10]([O-:14])=[CH:4]1
Reactant: C[N+](=O)[O-]
Reactant: [O-][n+]1onc2ccccc21
Agent: Cc1cc(C)ncn1
Solvent: C1CCOC1
Product: [O-][n+]1cn(O)c2ccccc21
Temperature: 25 °C

Procedure:
To a mixture containing nitromethane (7.4 g., 0.12 moles), benzofuroxan 13.6 g., 0.10 moles) and tetrahydrofuran (50 ml.) is slowly added dimethylpyrimidine (11.3 g.) dropwise. The heat of reaction causes the reaction temperature to rise sharply; therefore, an ice-bath is used to maintain a steady rate of reflux. Upon completion of addition, the resulting mixture is allowed to cool to room temperature whereupon the solid product which precipitates is filtered, washed with water, dried and recrystallized from a MeOH/NaOCH3 mixture which is subsequently acidified. The crystalline product has an M.P. 213° C. dec.
Reaction SMILES: [CH3:1][C:2]([NH2:8])([CH2:5][CH2:6][CH3:7])[CH2:3][NH2:4].[F:9][C:10]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:11]=1[CH2:12][O:13][C:14]1[C:15]2[N:16]([C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=2)[CH:17]=[C:18]([CH3:20])[CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:8][C:2]([CH3:1])([CH2:5][CH2:6][CH3:7])[CH2:3][NH:4][C:25]([C:21]1[N:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([O:13][CH2:12][C:11]3[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:10]=3[F:9])[C:15]2=[N:23][C:22]=1[CH3:24])=[O:26]
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: CCCC(C)(N)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCCC(C)(N)CNC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
77 mg (0.66 mmol) of rac-2-methylpentane-1,2-diamine were added to 200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid Example 21A, 203 mg (0.63 mmol) of TBTU and 0.27 ml (2.41 mmol) of 4-methylmorpholine in DMF (2.1 ml), and the reaction mixture was stirred at RT overnight. The mixture was diluted with water/TFA and purified by preparative RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fraction was concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. This gave 199 mg (76% of theory, purity 99%) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].CO>ClCCl.O>[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:25])[CH3:24]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 18 h

Procedure:
Combine 4-aminobenzophenone (500 g, 2.54 mol) and triethylamine (307 g,3.03 mol) in dichloromethane (2.54 L). Add acetic anhydride (313.9 g, 3.07 mol). After 18 hours, add methanol (100 mL) and evaporate in vacuo to give a residue. Combine the residue and water (8 L) and stir to give a solid. Collect the solid by filtration, rinse repeatedly with water, and dry to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:5][CH:4]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Product: COc1ccc(Oc2cccc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-methoxyphenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 459.2 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C(=O)C)=[C:20]([F:28])[CH:19]=2)=[N:16][N:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.S(=O)(=O)(O)O>C(O)C.CCCCCC>[CH2:3]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:28])[CH:19]=2)=[N:16][N:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCc1nnc(-c2ccc(OC(C)=O)c(F)c2)s1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: CCCCCCCCCCc1nnc(-c2ccc(O)c(F)c2)s1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
1.59 g (24.1 mM) of 85%-potassium hydroxide was dissolved in 50 ml of ethanol on an oil bath (bath temperature: about 70° C.). To the solution, 3.37 g (wet, 8.90 mM) of 2-decyl-5-(4-acetoxy-3-fluorophenyl)-1,3,4-thiadiazole was added, followed by stirring for 10 minutes at about 70° C. After the reaction, the reaction mixture was poured into iced water, followed by filtration under reduced pressure. The filtrate was condensed, followed by successive addition of about 100 ml of water, 2.3 ml of concentrated sulfuric acid and common salt and stirring at room temperature to precipitate a crystal. The crystal was dissolved in ethyl acetate and dried with anhydrous sodium sulfuric acid. The sodium sulfuric acid was recovered by filtration and the filtrate was condensed into a solid; n-hexane was added to the solid and stirred at room temperature, followed by filtration to obtain 2.78 g of 2-decyl-5-(3-fluoro-4-hydroxyphenyl)-1,3,4-thiadiazole (Yield: 92.8%, Yield through the steps iii) and iv): 82.7%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:28])=[C:13]([CH:27]=2)[O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]2)=[N:6][CH:7]=1.[F:29][CH:30]([F:47])[O:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][CH:30]([F:47])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:28])=[C:13]([CH:27]=3)[O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]3)=[N:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)C1CCN(CCOc2cc(Nc3ncc(Br)cn3)ccc2F)CC1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)C1CCN(CCOc2cc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)ccc2F)CC1
Temperature: 90 °C

Procedure:
To a solution of methyl 1-(2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate 47 (0.24 mmol) in 1,4-dioxane (2.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.28 mmol), 1.8M K2CO3 (0.5 mmol) and Pd(PPh3)4 (0.017 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 90° C. for 12 h. The reaction mixture is cooled to rt, diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer is separated, dried over Na2SO4 and concentrated. Purification by preparative HPLC (ACN gradient 20-70%) affords methyl 1-(2-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate 48 as white solid. MS (m/z) (M+1)+: 517.1.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C@@:7]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1)[CH:2]=C.[O:37]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([C@@H:14]([N:10]2[CH2:9][CH2:8][C@@:7]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)([CH2:6][CH2:5][O:4][CH2:1][CH2:2][OH:37])[O:12][C:11]2=[O:13])[CH3:15])=[CH:17][CH:18]=1
Reactant: C=CCOCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A solution of (S)-6-(2-(allyloxy)ethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.20 mmol) in CH2Cl2 (10 mL) was treated with O3 at −78° C. till the mixture was turned blue. Then NaBH4 (50 mg, 1.0 mmol) was added, and the mixture was stirred at rt overnight. The solution was concentrated and the residue was purified by preparative HPLC to give (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(2-hydroxyethoxy)ethyl)-1,3-oxazinan-2-one (40 mg, 30%). LC-MS Method 3 tR=1.41, min, m/z=500, 522; 1H NMR (CDCl3): 1.48-1.61 (d, 3H), 1.92-2.05 (m, 2H), 2.09-2.41 (m, 5H), 2.88-3.02 (m, 1H), 3.27-3.56 (m, 2H), 3.58-3.69 (m, 2H), 5.63-5.72 (m, 1H), 6.82-7.08 (m, 6H), 7.17-7.34 (m, 5H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(Cl)(Cl)(Cl)Cl.C(=O)=O.[CH3:36][C:37]([CH3:39])=[O:38]>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([C:37]([OH:38])([CH3:39])[CH3:36])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@]1(C(C)(C)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in tetrahydrofuran (45 mL) stirring at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (5.0 g, 21 mmol) in tetrahydrofuran (40 mL). The resulting golden mixture was warmed to −28° C. to −23° C. (CCl4/dry ice) and stirred for 30 min. The reaction solution was cooled down to −78° C. and anhydrous acetone (1.8 mL, 25 mmol) was added. After the addition, the reaction mixture was kept in a CCl4/dry ice bath and allowed to warm to room temperature overnight. The dark solution was quenched with saturated NH4Cl and extracted with ether three times. The combined extracts were dried, filtered, concentrated. The crude residue was purified by flash column chromatography (EtOAc/Hexane) to yield the desired product (1.4 g, 22k %).