Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@H:30]([C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][C:64]=1[Cl:65])[CH2:60]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@H:30]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:60][C:59]5[CH:62]=[CH:63][C:64]([Cl:65])=[C:57]([Cl:56])[CH:58]=5)=[CH:43][CH:44]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@@H:46]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (52 mg) was dissolved in 1 mL of DMF To this solution was added 3,4-dichlorobenzyl bromide (33 mg) and potassium carbonate. The mixture was stirred at room temperature for 6 hours and was poured onto ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 6-4-0.1) to provide (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (16 mg). LC/MS: m/z 894). 1H NMR (400 MHz, d6 acetone): 7.92-7.81 (m, 5H), 7.66 (s, 1H), 7.57 (m, 3H), 7.43 (m, 1H), 7.32-7.21 (m, 7H), 7.01-6.94 (m, 5H), 6.66 (s, 1H), 5.60 (s, 1H), 5.1 (s, 2H), 4.78 (m, 1H), 3.74 (s, 3H), 3.66 (m, 1H), 3.56 (d, 1H), 3.46 (m, 1H), 3.35 (s, 3H), 3.34 (d, 1H), 3.02-2.98 (m, 2H), 2.27 (m, 2H), 1.90-1.66 (m, 2H), 0.60 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
5-Chloro-3-(4-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) was dissolved in dry pyridine (15 ml) and the solution was cooled. After ethyl chlorocarbonate (1.5 g) was dropwise added to the solution, the resultant was stirred for 8 hours at 80° C. Pyridine was evaporated off under vacuum from the reaction mixture and the residue was recrystallized from a mixture of chloroform and ethanol to yield the title compound as colorless crystals (3.2 g). mp 196°-197° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:28]2[CH2:29][CH2:30][N:25]([C:23]([O:22][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:24])[CH2:26][CH2:27]2)[C@@H:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a solution of (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, mmol) and N-benzyloxycarbonyl-4-piperidone (1.2 g, 5 mmol) in methanol (8 mL) was added acetic acid (0.28 mL) and the solution was stirred at RT for 1 h. Sodium cyanoborohydride (310 mg, 5 mmol) was added and the reaction mixture was stirred at 45° C. overnight and then 1 N NaOH (5 mL) was added. The aqueous phase was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, concentrated under vacuum, and purified by silica gel chromatography (0-5% MeOH/DCM). Pure fractions were combined and concentrated under vacuum to provide the title intermediate (0.71 g, 30% yield) as a clear oil. (m/z): [M+H]+ calcd for C23H35N3O4 418.26 found 418.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:16]2=[CH:17][CH:18]=[N:19][CH:20]=[C:15]2[C:5]2[C:6]([OH:14])=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:14][C:6]1[C:5]2[C:15]3[C:16]([C:2]([CH3:1])([CH3:21])[O:3][C:4]=2[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=1)=[CH:17][CH:18]=[N:19][CH:20]=3)(=[O:24])[CH3:23]
Reactant: CCCCc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCc1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-n-butyl-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-n-butyl-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:12]([O:14]C)=[O:13])[CH:4]=[C:3]1[C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][CH:21]=1.[OH-].[Na+].O.Cl>C(O)C>[O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:12]([OH:14])=[O:13])[CH:4]=[C:3]1[C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(=O)n2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)c(=O)n2ccccc12

Procedure:
0.25 g of methyl 4-oxo-3-(α,α,α-trifluoro-m-tolyl)-4H-quinolizine-1-carboxylate was suspended in 3 ml of ethanol and treated with 3 ml of 1N sodium hydroxide solution. The mixture was heated to reflux until the reaction has finished. 13 ml of water were added and the mixture was acidified with 1N hydrochloric acid. The yellow crystals were removed by filtration and dried. After recrystallization from ethyl acetate, there was obtained 4-oxo-3-(α,α,α-trifluoro-m-tolyl)-4H-quinolizine-1-carboxylic acid as yellow crystals of m.p. 228°-229°.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([C:14]2([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:8]1([C:14]2([NH:20][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1(c2ccccc2)CCCCC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)NC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
Into a 200 ml four-necked flask, there were charged toluene (150 ml), 1-phenylcyclohexylamine (10.5 g) and pyridine (5.2 g), and trimethylacetyl chloride (7.2 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove pyridine hydrochloride. The toluene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 9.8 g of N-(1-phenylcyclohexyl)trimethylacetamide. M.P., 129°-130.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:4]([F:24])[CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[C:11]1[N:20]([CH3:23])[C:21](=[O:22])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:24])=[CH:9][C:10]2=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2F)cc2c3ccccc3n(C)c21
Product: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3F)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in preparation 1.9B above, with compound A 3-(4-chloro-2-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and acetyl chloride.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[C:9]([Cl:13])[CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[Cl:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[Cl:14])[C:5]1[N:28]([CH2:29][CH:30]([OH:32])[CH3:31])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: CC(O)CN
Reactant: O=CCC1Cc2cc(Cl)c(Cl)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1cc(Cl)c(Cl)cc1C2
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
A solution of 2.0 g of (RS)-2-(2-oxoethyl)-5,6-dichloro-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.47 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 4:1). 0.62 g (27%) of (RS)-1-(6,7-dichloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol was obtained as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:20][O:21][C:22](=[O:35])[CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH:32]=O)=[C:27]([CH3:34])[CH:26]=1>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=4)[CH:16]=[CH:17][C:18]=3[N:19]=2)=[C:27]([CH3:34])[CH:26]=1
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C)c(C)c4)cc3[nH]2)c(C)c1

Procedure:
The title compound was prepared from 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (from Example 6-17) analogous to Example 6-1. 1H NMR (Methanol-d4, 400 MHz): δ 8.32 (d, 1H), 7.91 (d, 1H), 7.79 (dd, 1H), 7.48 (s, 1H), 7.45 (dd, 1H), 7.15 (d, 1H), 7.08 (s, 2H), 3.67 (s, 3H), 2.97 (t, 2H), 2.71 (t, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.15 (s, 6H). MS (m/z) 456.1 (M+1); Retention time: 1.44 min (Method 10).
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:42][C:43]3[CH:48]=[CH:47][C:46]([N+:49]([O-])=O)=[CH:45][N:44]=3)[CH:38]=2)[O:33]1>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:42][C:43]3[N:44]=[CH:45][C:46]([NH2:49])=[CH:47][CH:48]=3)[CH:38]=2)[O:33]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2F)O3)nc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2F)O3)nc1

Procedure:
6-[2-(2-Fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 240 mg of 2-[2-(2-fluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 19(d)). 1H NMR (400 MHz, d6-DMSO) δ: 7.52 (m, 1H), 7.51 (d, 1H, J 3.0 Hz), 7.41 (m, 1H), 7.28-7.24 (m, 2H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.81-6.73 (m, 3H), 6.70 (d, 1H, J 8.6 Hz), 5.31 (dd, 1H, J 10.3, 2.2 Hz), 5.00 (s, 2H), 2.98 (m, 1H), 2.72 (m, 1H), 2.15 (m, 1H), 2.06 (m, 1H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Zn+2:12]>O>[C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Zn+2:12].[C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)C(=O)[O-]
Temperature: 4 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To 250 ml of water, warmed to 60°-70° C., was added 56.1 gm (0.55 mole) of pivalic acid (trimethylacetic acid). Then 31.25 gm (0.25 mole) of zinc carbonate was added portionwise over a period of 10 to 15 minutes and then the temperature was raised to 96°-98° C. After agitating the reaction mixture for 1 hour, the mixture was cooled to 4° C. with an ice bath for 30 minutes and the suspension filtered. The filter cake was washed once with 75 ml cold water and 3×50 ml cold acetone. The resulting product was dried at 60° C. for 16 hours in a draft oven to yield 58 gm (87%) of zinc pivaloate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][Si:28]([CH3:32])([CH3:31])[C:29]#[CH:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:30]#[C:29][Si:28]([CH3:32])([CH3:31])[CH3:27]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: C[Si](C)(C)C#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 66.1 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with 2-trimethylsilylacetylene (0.28 mL, 2 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (100:0 to 85:15 gradient over 40 min) to give the desired intermediate (247 mg, 81%). MS (ES+) m/z: 306 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC(C)(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a stirred solution of 2-((tert-butoxycarbonyl)amino)-2,4-dimethylpentanoic acid (1.6 g, 6.52 mmol) in tetrahydrofuran (40 mL) cooled to −10° C. under nitrogen atmosphere was added N-methylmorpholine (0.860 mL, 7.83 mmol) followed by isobutyl chloroformate (1.028 mL, 7.83 mmol) dropwise and the reaction mixture was stirred for 30 min. The reaction mixture was then filtered and the filtrate was added dropwise to a suspension of NaBH4 (0.494 g, 13.04 mmol) in water (20.0 mL). The reaction mixture was stirred for 10 min then diluted with ethyl acetate (30 mL). The organic layer was separated and washed with brine (2×20 mL), dried over (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate and pet ether) to afford tert-butyl(1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (1.1 g, 4.76 mmol, 73% yield) as an oil. 1H NMR (400 MHz, DMSO-d6) δ 6.09 (s, 1 H), 4.61 (t, J=7.6 Hz, 1 H), 3.35 (m, 2 H), 1.8-1.6 (m, 2 H), 1.44-1.35 (m, 10 H), 1.09 (s, 3 H), 0.86 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)N)=[CH:4][N:3]=1.[N:19]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C:22](=O)[CH2:21][CH2:20]2.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[C:21]3[CH2:20][N:19]4[CH2:27][CH2:26][CH:23]([C:22]2=3)[CH2:24][CH2:25]4)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N(N)CCc2ccc(Cl)nc2)cc1
Reactant: O=C1CCN2CCC1CC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)nc2)C2CCN(CC2)C1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In a 50 mL round-bottom flask were combined 2-chloro-5-(2-(1-p-tolylhydrazinyl)-ethyl)pyridine (0.272 g, 1.039 mmol; Example 117D), and 1-azabicyclo[3.2.2]nonan-4-one (0.188 g, 1.351 mmol; Example 2A) in dioxane (5 mL). After 10 minutes of warming to 50° C., the suspension cleared. Concentrated sulfuric acid (0.277 mL, 5.20 mmol) was added and the mixture was heated at 80° C. After 1.5 hours, the mixture was cooled and concentrated to about 3 mL. The residue was dissolved in water (75 mL), basified with concentrated sodium hydroxide (30 mmol), extracted with chloroform (4×25 mL), dried over magnesium sulfate, and concentrated. The residue was purified by reverse-phase HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 15 minutes] to give the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.63 (dddd, J=14.3, 9.3, 5.2, 2.4 Hz, 2H), 1.95 (ddt, J=13.6, 9.2, 5.2 Hz, 2H), 2.39 (s, 3H), 2.95 (m, 1H), 3.00 (m, 2H), 3.06 (t, J=6.4 Hz, 2H), 3.19 (ddd, J=14.1, 9.0, 5.2 Hz, 2H), 4.22 (s, 2H), 4.38 (t, J=6.4 Hz, 2H), 6.92 (dd, J=8.5, 1.4 Hz, 1H), 7.11 (br s, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.36 (dd, J=8.3, 2.4 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 366 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (4.0 mL) were added tert-butyl (3S)-3-(aminooxy)pyrrolidine-1-carboxylate 7 (0.164 g, 0.814 mmol, WO 2008/67481 A1), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 8 (0.22 g, 88%) as a white foam.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CN=C=O
Reactant: Nc1ccccc1
Solvent: CCOCC
Product: CNC(=O)Nc1ccccc1

Procedure:
1-Methyl-3-phenylurea was prepared by the dropwise addition of methylisocyanate (6 ml, 0.1 mole) over three hours to an ether solution (100 ml) containing aniline (9 ml, 0.1 mole) at 4° C. with stirring. 1-Methyl-3-phenylurea precipitated as purple crystals which were recrystallized from ethanol, m.p. 150° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[OH-].[K+].F[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:11]([N+:18]([O-:20])=[O:19])=[C:10]([CH:15]=1)[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: CN(C)CCO
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: COc1ccc([N+](=O)[O-])c(OCCN(C)C)c1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
N,N-Dimethylethanolamine (0.80 g, 9.0 mmol) was added to a mixture of powdered KOH (0.50 g, 9.0 mmol) and Aliquat 336 (0.36 g, 0.9 mmol) and the resulting mixture was stirred for 5 minutes at 80° C. Then 2-fluoro-4-methoxy-1-nitrobenzene (1.28 g, 7.5 mmol) was added, and stirring proceeded at this temperature for 30 minutes. The mixture was cooled and partitioned between methylene chloride (80 mL) and dilute aqueous HCl (50 mL), and the organic layer was extracted with dilute aqueous HCl (2×50 mL). The combined aqueous phases were washed with methylene chloride (3×75 mL), basified (3N NaOH), and extracted with methylene chloride (3×75 mL). The combined organic extracts were washed with water (3×100 mL), dried (MgSO4), and evaporated, providing 1.3 g as a yellow oil, in 74% yield: 1H NMR (CDCl3) δ 2.36 (s, 6H), 2.81 (t, J=5.8 Hz, 2H), 3.86 (s, 3H), 4.17 (t, J=5.8 Hz, 2H), 6.47-6.54 (m, 2H), 6.97 (d, J=9.0 Hz, 1H).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]>CN(C=O)C>[O:4]1[CH2:1][CH2:11][CH:10]([CH2:15][O:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:8]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC2CCOCC2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
K2CO3 (8.2 g, 59.2 mmol) was added to a stirred solution of methyl 3-hydroxybenzoate (11) (3.0 g, 19.72 mmol) sulfonate (10) (5.33 g, 19.72 mmol) in DMF (30 mL) and the reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh, 30% EtOAc in hexanes) gave methyl 3-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate (12) as a light yellow solid. Yield (4.8 g, 97%); 1H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J=7.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 3.88-3.82 (m, 7H), 3.32 (t, J=1.2 Hz, 2H), 2.02-1.96 (m, 1H), 1.69-1.66 (m, 2H), 1.38-1.28 (m, 2H).