Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]1=[O:16].C([N-]C(C)C)(C)C.[Li+].[C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=[O:30])#[N:26].O>O1CCCC1>[NH:26]=[C:25]1[O:30][CH:29]([C:10]2[S:11][C:5]3[N:4]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:3](=[O:16])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=3[CH:9]=2)[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]1=2
Reactant: N#Cc1ccccc1C=O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C3OC(=N)c4ccccc43)sc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (500 mg) in tetrahydrofuran (10 ml) at −78° C. was added lithium diisopropylamide (1M, 3.1 ml). After 5 minutes a solution of o-cyanobenzaldehyde in tetrahydrofuran (2 ml) was added and the reaction was allowed to stir for 2 h. Water (10 ml) was the added and the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate. The organic layer was separated and dried over magnesium sulfate, then concentrated in vacuo and purified by normal phase HPLC to yield the title compound (15 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([C:11]#[C:12][CH3:13])[C:3]=1[CH:4]=O.[NH3:14].CO>>[F:10][C:8]1[CH:7]=[C:6]2[C:3](=[C:2]([F:1])[CH:9]=1)[CH:4]=[N:14][C:12]([CH3:13])=[CH:11]2
Reactant: N
Reactant: CC#Cc1cc(F)cc(F)c1C=O
Solvent: CO
Product: Cc1cc2cc(F)cc(F)c2cn1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of 2,4-difluoro-6-prop-1-ynylbenzaldehyde (Description 71, 8.7 g; 48.8 mmol) and 2.0M ammonia in methanol (244 ml; 488 mmol) were heated together at 80° C. in a Parr apparatus (approx 35 psi achieved) for 5 hours. The cooled mixture was evaporated and the residue purified by column chromatography on silica-elution with 100% dichloromethane to give the title compound (5.2 g, 59%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH3:36])[C:20]1=[O:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH3:36])[C:20]2=[O:37])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (prepared as described in Bock M. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber, D. F.; Freidinger, R. M.; Hirshfield, J.; Springer, J. P. J. Org. Chem. 1987, 52, 3232), the title compound was prepared as a solid having a melting point of 152-160° C. The reaction was monitored by tlc on silica gel (Rf=0.15 in 50% ethyl acetate/hexanes) and purification was by silica gel chromatography.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26]O>>[C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([O:23][CH3:26])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(=O)O)c[nH]2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1c[nH]c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)n1
Reaction time: 2 h

Procedure:
A solution of crude 2-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-4-carboxyimidazole ◯1 (30 g.) in methanol (600 ml.) is heated to reflux, and then heating is discontinued as hydrogen chloride is bubbled rapidly through the solution with stirring for a half hour, followed by two and a half hours at reflux. Bubbling of hydrogen chloride is continued for another two hours followed by another hour at reflux and then the reaction mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate is then concentrated to dryness under reduced pressure. The residue is dissolved in water (150 ml.) and the pH is adjusted to 8 with saturated sodium carbonate solution. The basic mixture is extracted with ethyl acetate and the extracts are dried, filtered, and concentrated under reduced pressure to yield a solid which is recrystallized from acetonitrile to yield the methyl 2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-imidazole-4-carboxylate as a cream-colored solid, m.p. 168°-172° C.
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[N:6][C:5]1=[O:27].[OH-].[Na+].[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[CH:24]([C:21]1[CH:20]=[CH:19][C:18]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]#[CH:17])[CH:9]=3)[N:4]([CH2:3][CH:2]([O:1][C:36](=[O:38])[CH3:37])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:5](=[O:27])[N:6]=2)=[CH:23][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CC(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CC(OC(C)=O)c1ccccc1

Procedure:
A solution of 100 mg (0.228 mmol) 1-(2-hydroxy-2-phenyl-ethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in 1 ml acetic anhydride is heated at 100° C. for 18 h. The reaction mixture is poured onto 1 M aqueous NaOH and extracted with ether. The product is purified by preparative reversed phase HPLC.
Reaction SMILES: [C:1]([C:4]1[C:14]([F:15])=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(C)=O>[C:1]([C:4]1[C:14]([F:15])=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(cc1F)OCC(=O)N2
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(C(C)=O)cc21
Temperature: 80 °C
Yield: 74.4 %

Procedure:
To a mixture of 6-acetyl-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (12 g, 57.4 mmol) and K2CO3 (11.89 g, 86 mmol) in acetone (120 mL) was added ethyl 2-bromopropanoate (23.6 mL, 172 mmol) and the mixture was stirred and heated at 80° C. for 16 h. The mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give ethyl 2-(6-acetyl-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoate as a gray solid (13.2 g, 74.4%). 1H-NMR (CDCl3, 400 MHz): δ 7.40 (d, J=6.4 Hz, 1H), 6.80 (d, J=10.8 Hz, 1H), 5.24 (q, J=11.2 Hz, 1H), 4.66 (q, J=15.2 Hz, 2H), 4.23 (m, 2H), 2.60 (d, J=5.2 Hz, 3H), 1.63 (d, J=7.2 Hz, 3H), 1.23 (t, 3H).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:31][C@H:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:31][C@H:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:33]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5]1)=[O:34]
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.82 mmol) in CH2Cl2 (6 mL) was added triethylamine (227 μL, 1.63 mmol) followed by the addition of (R)-2-hydroxy-4-methylpentanoic acid (140 mg, 1.06 mmol) and HATU (403 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one (265 mg, 77%). LC/MS: m/z 421.30 (M+H)+ at 2.57 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J=8.3, 1.7 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H) 7.88 (m, 2H), 7.57 (m, 1H), 7.40 (m, 1H), 6.96 (m, 2H), 4.92 (d, J=7.2 Hz, 1H), 4.39 (m, 1H), 3.95 (m, 4H), 3.76 (m, 4H), 1.80 (m, 1H), 1.43 (m, 2H), 0.92 (q, J=3.8 Hz, 6H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>ClCCl>[OH:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:13](=[O:15])[CH3:14])[CH:2]([CH3:1])[CH2:11]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(O)c2ccccc2N1
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2C(O)CC1C
Yield: 92 %

Procedure:
A solution of 1,2,3,4-tetrahydro-2-methyl-4-quinolinol (5.9 g, 36.4 mmol) and acetic anhydride (37.1 g, 364 mmol) in dichloromethane (100 ml) was stirred for one hour. The solvents were evaporated and the crude product was purified on silica (ethyl acetate:heptane 1:1) to obtain the sub-titled product (33.5 mmol).
Reaction SMILES: [OH:1]O.[F:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:17])[C:8]=2[CH:7]=[CH:6][C:5]=1B(O)O.O>COC(C)(C)C>[F:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:17])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: OB(O)c1ccc2c(c1F)Cc1c(F)cccc1-2
Reactant: OO
Solvent: COC(C)(C)C
Solvent: O
Product: Oc1ccc2c(c1F)Cc1c(F)cccc1-2
Reaction time: 4 h

Procedure:
40 ml of hydrogen peroxide (35 percent) is added dropwise at room temperature to a suspension of 54 mmol of 1,8-difluorofluorene-2-boronic acid in 120 ml of tert-butyl methyl ether and the mixture is subsequently heated to boiling for 4 h. After cooling, the mixture is admixed with 150 ml of water, the phases are separated and the organic phase is washed twice each with water and saturated sodium sulfite solution and also with saturated sodium chloride solution, so that no more peroxide can be detected. The organic phase is dried over sodium sulfate and the solvent is removed on a rotary evaporator. Recrystallization from heptane provides 1,8-difluorofluoren-2-ol.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][CH2:8][P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11])=[O:6])[CH3:4].[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:28]([NH:2][C@H:3]([C:5]([NH:7][CH2:8][P:9](=[O:14])([O:10][CH3:11])[O:12][CH3:13])=[O:6])[CH3:4])=[O:29])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COP(=O)(CNC(=O)[C@H](C)N)OC
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COP(=O)(CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1)OC
Reaction time: 8 h

Procedure:
24.65 g of dimethyl (L-alanylamino)-methylphosphonate hydrochloride and 32.0 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine were stirred in 200 ml of dry dimethylformamide while 14 ml of dry triethylamine were added dropwise at 20° C. The mixture was stirred overnight and then the triethylamine hydrochloride filtered off and washed with a small amount of dimethylformamide. The filtrate was evaporated under an oil-pump vacuum, the residue treated with 150 ml of water and then extracted with four 125 ml portions of chloroform. The combined chloroform layers were washed with a 20 % potassium carbonate solution, separated and dried over sodium sulphate. The sodium sulphate was filtered off, the filtrate evaporated firstly under a water-pump vacuum and then under an oil-pump vacuum and the residue taken up in 100 ml of ethyl acetate. About 100 ml of ether were added to faint turbidity when crystallization began. After refrigeration overnight, the solid was filtered off, washed successively with ethyl acetate/ether (1:1) and ether and then dried in vacuo. Recrystallization from 200 ml of boiling ethyl acetate by the addition of 200 ml of ether gave 27.8 g of dimethyl [(N-benzyloxycarbonyl-L-alanyl-L-alanyl)amino] -methylphosphonate of melting point 106°-108° C; [α]D20 =- 37.4° (c =1% in glacial acetic acid).
Reaction SMILES: I[CH:2]([O:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:3].[NH2:11][C:12]1[S:13][CH:14]=[C:15](/[C:17](=[N:38]/[O:39][CH3:40])/[C:18]([NH:20][C@@H:21]2[C:36](=[O:37])[N:23]3[C:24]([C:33]([O-:35])=[O:34])=[C:25]([C@@H:28]4[CH2:32][CH2:31][CH2:30][O:29]4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:16]=1.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:11][C:12]1[S:13][CH:14]=[C:15](/[C:17](=[N:38]/[O:39][CH3:40])/[C:18]([NH:20][C@@H:21]2[C:36](=[O:37])[N:23]3[C:24]([C:33]([O:35][CH:2]([O:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:3])=[O:34])=[C:25]([C@@H:28]4[CH2:32][CH2:31][CH2:30][O:29]4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:16]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)OC(=O)OC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(=O)OC(C)C)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 19.9 %

Procedure:
A solution of (RS)-1-iodo-1-(propan-2-yl)oxycarbonyloxyethane (516mg) in 1-methyl-2-pyrrolidinone (2ml) was added dropwise over 45 mins to an ice-cold mixture of sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S) -tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (237mg) and finely powdered potassium carbonate (276mg) in 1-methyl-2-pyrrolidinone (5ml). The mixture was stirred for an additional 15 mins, diluted with ethyl acetate, washed with water, brine, dried (magnesium sulphate), concentrated and flash chromatographed on silica gel eluting with 50, 60, 70, 80% ethyl acetate in hexane to give the title compound as a foam (58mg); vmax (CHCl3) 2960, 1787, 1760, 1682, 1633, 1519 and 1377cm-1 ; δ(CDCl3, 250MHz) 1.20-2.50 (13H, m), 3.35-3.80 (2H, m), 3.80-4.20 (2H, m), 4.22 (3H, s), 4.83-5.10 (2H, m), 5.85-6.00 (1H, m), 6.85-7.08 (1H, m), 7.27 (1H, s) and 7.76 (1H, br, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (606)].
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[Br:8][C:9]1[C:13]2=[N:14][C:15]([CH2:18][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][CH:17]=[C:12]2[S:11][CH:10]=1.[CH:38]([C:40]1[CH:41]=[C:42]([C@H:46]([S:59][CH2:60][C:61]2([CH2:64][C:65]([O:67][CH3:68])=[O:66])[CH2:63][CH2:62]2)[CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=1)=O>C1COCC1>[Br:8][C:9]1[C:13]2=[N:14][C:15]([CH:18]=[CH:38][C:40]3[CH:41]=[C:42]([C@H:46]([S:59][CH2:60][C:61]4([CH2:64][C:65]([O:67][CH3:68])=[O:66])[CH2:62][CH2:63]4)[CH2:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=3)=[CH:16][CH:17]=[C:12]2[S:11][CH:10]=1
Reactant: Brc1csc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=O)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=Cc3ccc4scc(Br)c4n3)c2)CC1
Reaction time: 0.33 h

Procedure:
A 1 molar solution of potassium t-butoxide (0.57 mL, 0.57 mmol) was added to a -78° C. suspension of the phosphonium salt (0.290 g, 0.55 mmol) of Step 4, in 3 mL of THF. The temperature was brought to 0° C. for 20 min then lowered back to -78° C. followed by the addition of a 0.5 molar solution of methyl 1-(((1(R)-(3-formylphenyl)3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetate (1.47 mL, 0.44 mmol) of Step 17 of Example 1. The bath was brought to 0° C. for 1 hr and the reaction mixture was quenched with a 25% aqueous NH4OAc. The organic solvents were evaporated and the title product was purified by flash chromatography on silica with EtOAc:hexane 30:70 to yield 0.270 g (94%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Al](C)C.C[O:28][C:29](=O)[NH:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:39][CH3:40])[N:32]=1>C(Cl)Cl>[Cl:1][C:2]1[C:11]([S:12]([NH:15][C:29]([NH:30][C:31]2[N:32]=[C:33]([O:39][CH3:40])[N:34]=[C:35]([O:37][CH3:38])[N:36]=2)=[O:28])(=[O:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1c(Cl)ccc2cccnc12
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2c(Cl)ccc3cccnc23)nc(OC)n1
Reaction time: 0.75 h
Yield: 27.5 %

Procedure:
To a stirred mixture of 7-chloro-8-quinolinesulfonamide (1.5 g) in 75 ml methylene chloride is added a 2 M toluene solution of trimethyl aluminum (4.7 ml). The resulting solution is stirred under N2 for 45 min. Solid methyl(4,6-dimethoxy-1,3,5-triazin-2-yl)carbamate (1.1 g) is added and the mixture is heated at reflux for 60 h. The reaction is quenched sequentially with acetic acid (1 ml), 6 N HCl (2.5 ml) and water (13 ml). The organic solution is retained, dried with MgSO4, and is concentrated to an oil-solid mixture. Filtration afforded 0.6 g yellow solid m.p. 169°-191° C. (dec). The infrared spectrum showed characteristic absorption bands at 3300 and 1700 cm-1.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[C:18]1([CH:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[OH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[OH:25][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:26]1[CH2:27][CH2:28][N:29]([C:14](=[O:16])[C:13]([NH:12][C:10]2[CH:9]=[CH:8][C:6]3[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=3[CH:11]=2)=[O:17])[CH2:30][CH2:31]1
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: OC(c1ccccc1)C1CCNCC1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(C(O)c4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and phenyl-piperidine-4-yl-methanol [J. Amer. Chem. Soc.,52, 4006. (1930)] according to the method described in Example 1c. Melting Point: 195-197° C. (diethylether)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc(C)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc(C)c1OC)C(F)(F)F
Temperature: 35 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
20 g (71.90) of ethyl-4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate and 12.3 g (86.28 mmol) of (trifluoromethyl)trimethylsilane are introduced into 117 ml of tetrahydrofuran. At room temperature, 180 mg of tetrabutylammonium fluoride is added (heating to about 35° C.). After stirring overnight, 22.7 g (71.90 mmol) of tetrabutylammonium fluoride is added, and the batch is stirred for three hours at room temperature. After dilution with methyl tert-butyl ether, the organic phase is washed three times with water and once with brine. After the solvent is dried and spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 16.33 g (65.2%) of the desired compound is isolated.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[C:9]([C:11](=[CH:17][NH:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:12](OCC)=[O:13])#[N:10]>O1CCCC1>[CH3:25][C:24]1[C:19]2=[N:18][CH:17]=[C:11]([C:9]3[NH:10][N:7]=[N:6][N:5]=3)[C:12](=[O:13])[N:20]2[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C#N)=CNc1ncccc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Yield: 50.7 %

Procedure:
Aluminum chloride (3.51 g., 0.0263 mole) was added to cold (-30°) tetrahydrofuran (180 ml.). Sodium azide (5.12 g., 0.0788 mole) was added and the mixture heated under reflux for 30 minutes. The mixture was cooled to 5°. Ethyl 2-cyano-3-(3-methyl-2-pyridylamino)acrylate (5.0 g., 0.0216 mole) was added and the mixture heated under reflux for 18 hours. The tetrahydrofuran was removed under reduced pressure. The residue was treated with ice water (100 ml.) and acidified to pH 3 with 6N hydrochloric acid. The mixture was filtered and the collected solid recrystallized from N,N-dimethylformamide to give the title compound (2.5 g., 50.7%), m.p. 310°-311° (decomp).