Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)([O:3][CH3:4])=[O:2].[Br-].[C:14]([C:18]1[CH:19]=[C:20]([CH:41]=[CH:42][CH:43]=1)[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:21][C:20]2[CH:41]=[CH:42][CH:43]=[C:18]([C:14]([O:16][CH3:17])=[O:15])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: COC(=O)c1cccc(C=Cc2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a mixture of 49.2 g (0.3 mole) of m-carbomethoxybenzaldehyde, 221 g (0.45 mole) of m-carbomethoxybenzyl triphenyl phosphonium bromide and 1.0 g of tetrabutyl ammonium iodide in 500 ml of dichloromethane, 500 ml of 50% solution of potassium carbonate was added. The mixture was stirred at room temperature for 3 hr. The alkaline layer was separated, extracted with dichloromethane and the combined organic solvent was washed with plenty of water and dried. Evaporation of the solvent and recrystallization of the residue from ether gave 73.2 g of white needles of predominantly transisomer. Yield 82%. m.p. softens at 64° C. and melts at 105°-107° C. The infrared spectrum showed absorption at 1720 cm-1 (COOCH3), 1675 cm-1 (trans c=c), 965 cm-1 (trans c=c) and 670 cm-1 (weak cis c=c). NMR (CDCl3) showed 3.9-4.0 (d. COOCH3, 6) 67-72 (d, CH=CH, 2) and 7.3-8.4 (m, aromatic, 8). Anal. calcd. for C18H16O4 : C, 72.97%, H, 5.40. Found: C, 73.02%, H, 5.41%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH3:11])[NH2:10].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[CH:15][N:14]=1.N>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:10][C:13]1[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:11]
Reactant: CC(N)c1c(Cl)cccc1Cl
Reactant: N#Cc1cccnc1Cl
Agent: N
Solvent: CC(=O)N(C)C
Product: CC(Nc1ncccc1C#N)c1c(Cl)cccc1Cl
Temperature: 90 °C
Reaction time: 20 h
Yield: 41.1 %

Procedure:
A mixture of 2,6-dichloro-α-methylbenzenemethanamine (0.03 mol) and 2-chloro-3-pyridinecarbonitrile (0.03 mol) in N,N-dimethylacetamide (few drops) was stirred for 20 hours at 90° C. The reaction mixture was cooled and poured out into aqueous ammonia. The mixture was extracted twice with CH2Cl2. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /hexane 50/50). The pure fractions were collected and the solvent was evaporated, yielding 3.6 g (±)-2-[[1-(2,6-dichlorophenyl)ethyl]amino]-3-pyridinecarbonitrile (41.4%); mp. 84.4° C. (comp. 9).
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].N([O-])=[O:12].[Na+].N(O)=O.NC(N)=O>OS(O)(=O)=O.O>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([OH:12])[C:8]([OH:10])=[O:9]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=NO
Agent: O=S(=O)(O)O
Solvent: O
Product: NCCCC[C@H](O)C(=O)O
Reaction time: 4.5 h
Yield: 56 %

Procedure:
The crude L-lysine.2H2SO4 was taken up in 10% H2SO4 (250 ml) and treated dropwise with a solution of sodium nitrite (25.9 gm, 0.36 mole) in water (100 ml) at 45°-50° C. (bath temperature) over a period of 2 hours. When the addition was complete, the mixture was stirred at 45°-50° C. for an additional 4.5 hours, the excess nitrous acid decomposed with urea and the mixture poured onto an AG-50-X8 ion exchange column (H+ form, 200 ml bed volume). The column was eluted with water and then aqueous NH4OH (conc. NH4OH--H2O; 1:3) to elute the product. The ninhydrin positive fractions were combined and evaporated to give a pink semi-solid which was recrystallized from H2O--EtOH to give title compound (8.20 gm, 56%) as white crystals, m.p. 197°-199° C. [α]D =-12.2° (c=1.2, H2O)[Lit m.p. 203°-206° C., [α]D =-12.1° (c=1.16, H2O)]. TLC (i-iPrOH-conc. NH4OH--H2O; 7:2:1) Rf =0.16 (contains trace of lysine, Rf =0.02).
Reaction SMILES: C[NH:2][C:3](=[O:22])[CH:4]([C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1>CO.[OH-].[Na+].CO.O.[H][H]>[CH3:20][NH:19][CH2:18][C:17]([CH:4]([CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)[C:3]([NH2:2])=[O:22])=[O:21]
Reactant: [H][H]
Reactant: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)NC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(N)=O
Reaction time: 1 h
Yield: 90 %

Procedure:
N-Methylglycylbiotinamide methyl ester was hydrolyzed in a mixture of 31 mL MeOH and 10 mL of 1N NaOH at room temperature with stirring for 1 hour. The mixture was diluted with 50 mL 50% MeOH/water and neutralized with cation exchange resin, hydrogen form (AG MP-50, BioRad). The solution was filtered, the resin washed (3×50 mL) with 50% MeOH/water, and the solvents removed by rotary evaporation to yield 1.6 g (90%) of N-methylglycylbiotinamide acid as an off-white solid. 1H-NMR. (Ref. Wilbur, D. S., Bioconj. Chem., v8 pp572-584)
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=2)=[C:8]([F:23])[CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:32]([CH:34]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=1)[C:35](OC)=O)=[O:33].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:23][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]([F:20])([F:22])[F:21])=[N:17][CH:18]=1)[CH2:5][CH2:4][O:3][C:1]1[NH:2][CH:35]=[C:34]([CH2:39][C:40]2[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=2)[C:32](=[O:33])[N:24]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)cn1
Temperature: 100 °C

Procedure:
To the solution of 3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethyl carbamimidate, trifluoroacetate (50 mg, 0.109 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (30 mg, 0.134 mmol) in 1,4-dioxane (1 mL) was added K2CO3 (60 mg, 0.434 mmol). The mixture was heated with a microwave reactor at 100° C. for 0.5 h. Purification via MDAP then afforded the title compound (13.5 mg, 23.82 yield). LCMS: rt=2.97 min, [M+H+]=519
Reaction SMILES: Cl.[CH2:2]([S:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)[C@@H:13]([NH2:15])[CH3:14])=[CH:8][CH:7]=1)[CH3:3].C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH2:2]([S:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:21]=[CH:20]3)[C@@H:13]([NH:15][C:37](=[O:36])[CH2:38][OH:39])[CH3:14])=[CH:10][CH:11]=1)[CH3:3]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCSCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Agent: Cl
Product: CCSCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CO)cc1

Procedure:
The title compound was prepared analogous to the method described in Example 21 starting from (1R,2S)-1-(4-(ethylthiomethyl)phenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine hydrochloride (25a) (50 mg, 0.11 mmol), and acetoxyacetyl chloride (13 μL, 0.12 mmol). Yield 33 mg (63%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:17])[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[NH:5][C:4]1=[O:16].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>N1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:18][N:19]([CH3:23])[C:20]([O:16][C:4]1[C:3]([CH2:2][O:1][C:20](=[O:21])[N:19]([CH3:23])[CH3:18])([CH3:17])[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=1)=[O:21]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(N2CC(C)(CO)C(=O)N2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(N2CC(C)(COC(=O)N(C)C)C(OC(=O)N(C)C)=N2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
4-hydroxymethyl-4-methyl-1-(4-methoxyphenyl)pyrazolidinone [1.2 g] and dimethylcarbamoyl chloride [0.8 mL] were combined in 10 mL pyridine and 3 mL triethylamine. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution (30 mL), dried over MgSO4, and evaporated. The resulting crude material was taken up in 20 mL anhydrous methanol and sodium methoxide [0.4 g] was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with methylene chloride (50 mL), washed with saturated ammonium chloride solution (30 mL), dried over MgSO4, and evaporated. This crude oil was dissolved in 10 mL pyridine and 3 mL triethylamine. Dimethylcarbamoyl chloride [0.45 mL] was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution (30 mL), dried over MgSO4, and evaporated. Chromatography on silica gel gave 0.86 g (45%) of pure 3-(N,N-dimethylcarbamoyloxy)-4-(N,N-dimethylcarbamoyloxymethyl)-4-methyl-1-(4-methoxyphenyl)-2-pyrazoline as a light yellow oil. 1H NMR: 7.1 (4H, dd, j=7,2), 3.8 (4H, m), 3.2 (6H, s), 3.1 (6H, s), 2.0 (3H, s), 1.4 (3H, s).
Reaction SMILES: N[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([CH:14]([CH3:16])[CH3:15])[C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.N([O-])=[O:18].[Na+].N>F[B-](F)(F)F.[H+]>[CH:14]([C:5]1[C:6]([O:12][CH3:13])=[CH:7][CH:8]=[C:9]2[C:4]=1[NH:3][C:2](=[O:18])[N:11]=[CH:10]2)([CH3:16])[CH3:15]
Reactant: COc1ccc2cnc(N)nc2c1C(C)C
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: N
Agent: [H+]
Product: COc1ccc2cnc(=O)[nH]c2c1C(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a solution of 2-amino-7-methoxy-8-(2-propyl)quinazoline (1.3 g) in tetrafluoroboric acid (50 mL), sodium nitrite solution (2.6 g in 10 mL of water) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 18 hours. The reaction mixture was cooled in an ice bath and neutralized with 30% ammonia solution. The product was extracted with ethyl acetate (3×50 mL), combined organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound as an off-white solid (1.2 g, 92.3%). mp 188–190° C. (decom); 1H NMR (CDCl3): δ 1.32 (d, 6H, 2×CH3), 3.44 (m, 1H, CH), 3.97 (s, 3H, OCH3), 6.88 (d, 1H, Ar-H, J=8.8 Hz), 7.59 (d, 1H, Ar-H, 8.8 Hz), 9.0 (s, 1H, Ar-H), 9.1 (brs, 1H, NH).
Reaction SMILES: CON(C)[C:4](=[O:18])[C@H:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])(O)(=O)=O.[K+]>CCOCC>[C:14]([O:13][C:11]([NH:10][C@H:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:18])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCC[C@H](C=O)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepareded according to the procedure described in Example 1, Step C, except using N-methoxy-N-methyl 2(R)-tert-butoxycarbonylaminohexanamide (4.08 g, 14.89 mmol), lithium aluminum hydride (0.621 g, 16.37 mmol), in ether (200 mL), followed by potassium hydrogen sulfate (4.05 g, 29.78 mmol) workup. The title compound was obtained as a clear oil, 3.28 g. NMR (CDCl3, 300 MHz) δ 9.6 (1H, s), 5.04 (1H, bs), 4.23 (1H, m), 1.15-2.0 (15H, m), 0.9 (3H, m).
Reaction SMILES: C(O)=O.OS([O-])(=O)=O.[K+].[Cl:10][C:11]1[CH:12]=[C:13]2[N:36](COCC[Si](C)(C)C)[C:35]([O:45][C@H:46]3[C@H:50]4[O:51][CH2:52][C@@H:53]([OH:54])[C@H:49]4[O:48][CH2:47]3)=[N:34][C:14]2=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.[OH-].[Na+]>O>[Cl:10][C:11]1[CH:12]=[C:13]2[NH:36][C:35]([O:45][C@H:46]3[C@H:50]4[O:51][CH2:52][C@@H:53]([OH:54])[C@H:49]4[O:48][CH2:47]3)=[N:34][C:14]2=[N:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccc(-n5cncn5)cc4)cc3)c(Cl)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccc(-n5cncn5)cc4)cc3)c(Cl)cc2[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of formic acid (3 mL, 68.8 mmol), saturated aqueous KHSO4 (0.33 mL, 1.777 mmol), and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (1.15 g, 1.777 mmol). The reaction mixture was stirred at 60° C. overnight, and then cooled to 0° C. in an ice bath. The pH of the reaction mixture was adjusted to pH>11 through the addition of NaOH (2.75 g, 68.8 mmol) in water (5 mL). THE (5 mL) was added to the reaction mixture, and the reaction was removed from the ice bath and allowed to warm to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to pH 6 through the addition of concentrated HCl. The biphasic mixture was separated. The organic layer and the resulting white precipitate that had formed were concentrated under reduced pressure, redissolved in DMSO, and filtered before being purified by preparative HPLC Reverse phase (C-18), using a 19×100 mm Sunfire™ column and eluting with a 10%-90% acetonitrile/water gradient+0.05% TFA followed by a 90% acetonitrile/water+0.05% TFA flush. The desired fractions were combined, and evaporated under reduced pressure. The resulting residue was washed with MeOH and lyophilized from acetonitrile and water to afford the title compound as a white solid. LC-MS: calculated for C26H21ClN6O4 516.13 observed m/e: 516.85 (M+H)+ (Rt 1.11/2 min); 1H NMR δ (ppm) (CD3OD): 9.17 (s, 1H), 8.21 (s, 1H), 7.82-7.97 (m, 4H), 7.78-7.80 (m, 5H), 5.56 (qt, J=5.5 Hz, 1H), 4.98 (t, J=5.3 Hz, 1H), 4.49 (t, J=5 Hz, 11H), 4.28-4.32 (m, 1H), 4.19 (dd, J=6.0 Hz, 10.0 Hz, 1H), 4.12 (dd, J=5.0 Hz, 10.0 Hz, 1H), 3.92 (dd, J=7.0 Hz, 8.0 Hz, 1H), 3.62 (t, J=8.8 Hz, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[O:3].[NH2:16][C:17]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]1.[OH-].[Na+]>CC(C)=O.C(OCC)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([NH:1][C:2]([NH:16][C:17]2([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]2)=[O:3])=[CH:5][C:6]=1[C:12]([F:13])([F:14])[F:15])#[N:9]
Reactant: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Reactant: NC1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: N#Cc1ccc(NC(=O)NC2(C(=O)O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (4.56 g, 21.5 mmol) in acetone (12 ml) is added dropwise to 1-aminocyclopropane carboxylic acid (2.02 g, 20 mmol) dissolved in an aqueous solution of sodium hydroxide (12 ml, 0.8 g, 20 mmol). The reaction medium is stirred for 1 hour at ambient temperature then poured into an aqueous solution of sodium hydroxide (1N, 40 ml). The solution obtained is washed with ethyl acetate (30 ml) then acidified by the addition of an aqueous solution of sulphuric acid (2M, 30 ml) and extracted with ethyl acetate (2×50 ml). The organic phase thus obtained is washed with water then with a saturated aqueous solution of sodium chloride, dried over Na2SO4 and filtered. The solvent is evaporated off under reduced pressure. The residue obtained is taken up in ethyl ether in order to produce a white solid, after filtration, with a yield of 50% (3.16 g).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[CH:13]2[NH:16][CH:10]([CH2:11][CH2:12]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH2:1]([N:8]1[CH2:14][CH:13]2[NH:16][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCC(N2)C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: c1ccc(CN2CC3CCC(C2)N3)cc1
Reaction time: 30 h
Yield: 52 %

Procedure:
A solution of 3-benzyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione LXVI (0.00108 mol, 250 mg) in dry ether (2 mL) was added to a stirred suspension of LiAlH4 (122 mg, 0.00315 mol) in dry ether (8 mL) at 0° C. under nitrogen atmosphere. The reaction bath was allowed to return at room temperature and stirring was continued for 30 h. After completion of the reaction (checked by TLC), the reaction mixture was quenched with chilled water and then stirred for 1 h. The reaction mixture was diluted with ether (20 mL) and the organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 60-120 mesh; EA-Hexane, 1:1) to afford the product LXVII in 52% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:26])[C:11](OS(C(F)(F)F)(=O)=O)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:27]2[CH2:29][CH2:28]2)[CH:7]=1)=[O:5])[CH3:2].[CH:30]([Sn](CCCC)(CCCC)CCCC)=[CH2:31].[Li+].[Cl-].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[F-].[NH+]1C=CC=CC=1>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:26])[C:11]([CH:30]=[CH2:31])=[C:12]([F:17])[CH:13]=2)[N:8]([CH:27]2[CH2:28][CH2:29]2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(OS(=O)(=O)C(F)(F)F)c(F)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=Cc1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Into a properly equipped flask was added 2.0 g (4.52 mmoles) Compound 3 and 24 ml dry THF. While flushing with nitrogen, 1.36 ml (4.68 mmoles) of vinyltributyltin was added along with 0.58 g (13.56 mmoles) LiCl and, 0.070 g (0.10 mmoles) Pd(PPh3)2Cl2. A couple crystals of 2,6-di-tert-butyl4-methyl phenol was also added just before heating. The reaction was heated to 60°-65° C. for 21 hours after which it turned black and a black precipitate was present. The reaction was cooled to room temperature and 1 ml of pyridine and 2 ml of pyridinium fluoride were added and the reaction allowed to stir overnight. THF was added and the reaction filtered through a celite pad and poured into water. The precipitate formed was collected to give 2.0 g of crude product which was taken up in CH2Cl2 and run through a short silica gel column eluting with dichloromethane to start and slowly increasing polarity to 1% methanol in dichloromethane. The fractions containing product were evaporated in vacuo to give 1.07 g of (4), 74% yield.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[OH-].[K+].[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]>O>[OH:2][CH2:1][CH2:3][NH:4][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)NCCO
Reaction time: 18 h
Yield: 50.8 %

Procedure:
To a stirred 4° aqueous solution containing ethanolamine (610 mg, 10 mmol), KOH (840 mg, 15 mmol) and H2O (15 mL) was added pivaloyl chloride (1.44 g, 12 mmol) whereupon the reaction was allowed to slowly warm to 20°. After stirring for 18 hr, the solution was extracted 4× with EtOAc,. The combined organic layers were washed with brine, dried over Na2SO4 prior to concentration using a rotary evaporator to yield 737 mg of a clear oil.
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH2:13]3)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:28].CCOCC>CO>[ClH:28].[ClH:28].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)=[O:11])=[CH:26][CH:27]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[1-(4-(1H-Imidazol-1-yl)benzoyl]-4-piperidinyl]carbamic acid, 1,1-dimethylethyl ester (131.6 g, 355 mmol) is dissolved in methanol (800 mL) at 0° C., and the solution is saturated with HCl gas. The mixture is stirred for 3 hr at room temperature, after which ether is added to give a turbid solution. The resulting precipitate is collected and air dried to afford the title compound.
Reaction SMILES: C([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7]C1(C)C)(=O)CC.Cl.[OH-].[Na+]>C(Cl)Cl.O>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([C@@H:8]([OH:7])[C@H:9]([NH2:5])[CH2:10][F:11])=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: CCC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Temperature: 95 °C

Procedure:
Methylene chloride (450 mL) distills from a solution of (4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound IX: R1 is methylsulfonyl, R2 and R3 are methyl and R4 is ethyl) (50.0 g, 0.1456 moles) after addition of water (300 mL) containing 20% hydrochloric acid and heating to 90-100° C. for 2-4 hours. Adjusting the pH to greater than 12 by addition of sodium hydroxide and extraction with methylene chloride (350 mL) yields a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (Compound Xa). Methanol (150 mL) replaces methylene chloride which distills off. Addition of methyl dichloroacetate (52.0 g, 0.3640 moles) and triethylamine (11.0 g, 0.1092 moles) with agitation for 12-16 hours at 20-25° C. then addition of water (150 mL) and toluene (100 mL) precipitates the crude product. Filtration, washing with water (75 mL) and toluene (125 mL) then dissolution in water (50 mL) and isopropanol (100 mL) at reflux, cooling to 20-25° C., filtration of the solids, washing with 1 to 1 water/isopropanol (50 mL) then drying gives pure (1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol (Florfenicol).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH2:9][CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][C:23]=2[O:22]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C.O.C(OCC)(=O)C>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][C:31]4[O:32][CH2:21][O:22][C:23]=4[CH:24]=3)[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(OCC2CCNC2)c2ccccc2)cc1
Reactant: BrCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: c1ccc(C(OCC2CCN(CCc3ccc4c(c3)OCO4)C2)c2ccccc2)cc1
Yield: 52.3 %

Procedure:
A mixture of 3-(diphenylmethoxymethyl)pyrrolidine (267 mg) (Preparation 7), 3,4-methylenedioxyphenethyl bromide (250 mg), sodium carbonate (1.0 g) and sodium iodide (100 mg) in acetonitrile (30 ml) was heated under reflux for 24 hours, diluted with water and ethyl acetate and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatogrpahy on silica using dichloromethane plus 0-20% ethyl acetate followed by dichloromethane plus 20% ethyl acetate plus 1-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (217 mg) as a colourless oil which was characterised containing 0.25 equivalents of water.