Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][F:5].[C:7]([NH:10][C:11]([NH2:13])=[S:12])(=[O:9])[CH3:8]>CCO>[F:5][CH2:4][C:3]1[N:13]=[C:11]([NH:10][C:7](=[O:9])[CH3:8])[S:12][CH:2]=1
Reactant: CC(=O)NC(N)=S
Reactant: O=C(CF)CCl
Solvent: CCO
Product: CC(=O)Nc1nc(CF)cs1
Reaction time: 1.5 h
Yield: 8 %

Procedure:
A mixture of 1-chloro-3-fluoro-propan-2-one (Step 38.3) (1.14 g, 10.3 mmol) and N-acetyl-2-thiourea (1.22 g, 10.3 mmol) in EtOH (10 mL) is stirred for 1.5 h at reflux, allowed to cool and concentrated. The residue is dissolved in DCM/H2O and extracted with DCM. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:1) to afford 0.143 g of the title compound: ESI-MS: 173.1 [M−H]−; tR=1.98 min (System 1); TLC: Rf=0.21 (Hex/EtOAc, 1:1).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18]([C:44](=[O:46])[NH2:45])=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)[C:18]([C:44](=[O:46])[NH2:45])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of ((R)-benzyl 4-(4-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate) (4.71 g, 7.5 mmol) in CH2Cl2 (5 ml) was treated with 5 mL of TFA and stirred at rt for 5 h. The reaction mixture was concentrated and the residue was partitioned between 1N NaOH and CH2Cl2. The aqueous phase was extracted with CH2Cl2 and the combined organic layers were concentrated. The brown residue was purified by MPLC (ISCO, 8% NH4OH/MeOH/CH2Cl2, 120 g silica gel column) and the fractions containing product were combined and concentrated. The resulting solid was triturated with CH2Cl2 to obtain 1.9 g of (R)-benzyl 4-(4-(6-(3-aminopiperidin-1-yl)-3-carbamoylpyridin-2-ylamino) phenyl)piperazine-1-carboxylate as a white solid. A second trituration gave an additional 320 mg of product as a light yellow solid.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5[CH:36]=[C:35]([C:37](N)=O)[CH2:34][CH:33]=[CH:32]5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[CH:45]1([C:48](C2C=CC=CC=2)=[O:49])CC1.P([O-])([O-])([O-])=O.[OH-].[Na+]>C(OCC)C.CCCCCC.CC(O)C>[CH3:37][C:35]([CH3:36])=[CH:34][CH2:33][CH2:32][C@H:48]([OH:49])[CH3:45]
Reactant: O=C(c1ccccc1)C1CC1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)=CCC[C@@H](C)O
Temperature: 25 °C

Procedure:
A reaction mixture was formed by admixing (i) 50 mg NAD, (ii) 4 ml of 2-propanol and (iii) 5 mmoles of 6-methyl-5-hepten-2-one, Compound 10, in a liquid medium containing 1 gm of lyophilized PED alcohol dehydrogenase preparation, 75 ml of 50 mM phosphate buffer, pH 7.1, and 25 ml of hexane. The pH value of the reaction was maintained constant by addition of 1N NaOH. The reaction mixture was maintained at room temperature until product formation stopped. When product formation stopped, (R)-6-methyl-5-hepten-2-ol, Compound 10a, was isolated by removal of the hexane layer and extraction of the aqueous layer with ethyl ether (3×75 ml).
Reaction SMILES: Cl[C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=2[N:3]=1.C(O)(=[O:21])C>>[CH3:18][O:17][C:6]1[C:7]([O:15][CH3:16])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2](=[O:21])[N:14]1[NH:13][CH:12]=[N:11][C:10]=21
Reactant: CC(=O)O
Reactant: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Product: COc1cc2nc(=O)n3[nH]cnc3c2cc1OC

Procedure:
500 mg of 5-chloro-8,9-Dimethoxy-1,2,4-triazolo-[4,3-c]quinazoline is refluxed with 50 ml glacial acetic acid for 1 hour. The mixture is then evaporated in vacuo to dryness. The residue is treated with water/methylene chloride/diethyl ether and the solid material which is, 8,9-Dimethoxy-1,2,4-triazolo-[1,5-c]quinazoline-5-one is filtered off, washed well with water, then diethyl ether and dried, m.p. 320°-325° C.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][S:2]1(=[O:11])=[O:10].[Br:12]Br>[Fe].C(Cl)(Cl)(Cl)Cl>[Br:12][C:9]1[C:4]2[CH2:3][S:2](=[O:10])(=[O:11])[CH2:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: BrBr
Reactant: O=S1(=O)Cc2ccccc2C1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: O=S1(=O)Cc2cccc(Br)c2C1

Procedure:
1,3-Dihydrobenzo[c]thiophene 2,2-dioxide [Chem. & Ind., 1024 (1965)] is brominated according to the method described in Khim. Tadzh., 107 (1973), [C.A., 84, 89,930 (1976)], using bromine (1.1 equivalents) in refluxing carbon tetrachloride which contains iron until the bromine color is dissipated. Removal of the carbon tetrachloride and recrystallization from ethanol gives 4-bromo-1,3-dihydrobenzo[c]thiophene 2,2-dioxide.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:26][C@H:25]2[C@H:17]([CH2:18][C:19]3[C:24]2=[CH:23][C:22]([Br:27])=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15]1)C1C=CC=CC=1>C1COCC1>[CH2:5]([O:4][C:2]([N:14]1[CH2:26][C@H:25]2[C@H:17]([CH2:18][C:19]3[C:24]2=[CH:23][C:22]([Br:27])=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15]1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(Br)cc2c1C[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(Br)cc3[C@H]2C1
Temperature: 20 °C
Reaction time: 15 h
Yield: 42.2 %

Procedure:
To a solution of ethyl chloroformate (293 mg, 2.7 mmol) in THF (1.5 mL) was added a solution of cis-3-benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (320 mg, 0.90 mmol) in dry THF (1.5 mL) dropwise over 10 min at 0° C. The reaction mixture was warmed to 20° C., stirred for 15 h and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 7/3) to yield cis-6-bromo-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (130 mg, 0.38 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N+:20]([O-:22])=[O:21].COC1C(OC)=CC=CC=1OC1C=CC=C(F)C=1N.NC1SC=CN=1>COC1C(OC)=CC=CC=1OC1C=CC=C(F)C=1NC(NC1SC=CN=1)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1cccc(O)c1OC
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: COc1cccc(Oc2cccc(F)c2N)c1OC
Agent: COc1cccc(Oc2cccc(F)c2NC(=O)Nc2nccs2)c1OC
Agent: Nc1nccs1
Product: COc1cccc(Oc2cccc(F)c2[N+](=O)[O-])c1OC
Yield: 71.6 %

Procedure:
2-(2,3-Dimethoxyphenoxy)-6-fluoro-nitrobenzene (1.05 g, 72%) was prepared from 2,3-dimethoxyphenol (0.85 g, 5.5 mmol) and 2,6-difluoronitrobenzene (0.80 g, 5.0 mmol) following the general procedure A. This compound was reduced to 2-(2,3-dimethoxyphenoxy)-6-fluoroaniline (0.66 g, 70%) following the general procedure C N-[2-(2,3-Dimethoxyphenoxy)-6-fluorophenyl]-N′-(thiazol-2-yl)urea (136 mg, 70%) was prepared from 2-(2,3-dimethoxyphenoxy)-6-fluoroaniline (131 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[OH:9]N1C2C=CC=CC=2N=N1.[CH3:19][O:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:22]=1[C:23]([N:2]1[CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]1)=[O:24]
Reactant: O=C1CCCCN1
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCC(=O)CC2)c(OC)c1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Piperidone hydrochloride (3.0 g, 19.5 mmol) dissolved in DMF (25 ml), N,N-diiso-propylcarbodiimide (8.2 g, 65.1 mmol) and 1-hydroxybenzotriazole (8.8 g, 65.1 mmol) were added at 0° C. to a solution of 2,4-dimethoxybenzoic acid (11.8 g, 65.1 mmol) in DMF (25 ml) and the mixture was stirred at 0° C. for 3 h and subsequently at RT for 2 d. Aqueous 1M Na2CO3 solution (20 ml) was added to the reaction mixture and it was extracted with EA (3×20 ml). After drying of the combined organic phases, the solvent was removed and the residue was purified by means of column chromatography. The product 1-(2,4-dimethoxybenzoyl)piperidin-4-one was obtained in a yield of 2.7 g (39%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][OH:20]>>[CH3:19][O:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CO
Product: COc1nc(Nc2cc(C)[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 255 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][NH:11][C:10](=[S:13])[N:9]1[CH2:14][CH3:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCCC1.O.C(OCC)(=O)C>[C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][NH:11][C:10](=[S:13])[N:9]1[CH2:14][CH3:15])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1C(=S)NNC1c1ccccc1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=S)NNC1c1ccccc1NC(C)=O

Procedure:
A solution of 0.25 g of 5-(2-aminophenyl)-2,4-dihydro-4-ethyl-1H-[1,2,4]triazol-3-thione and 0.13 mL of acetic anhydride in 1.5 mL of tetrahydrofuran and 0.7 mL of water was stirred at 24° C. for 4 hours. The solution was diluted with 25 mL of ethyl acetate, washed with brine, and dried over MgSO4. The mixture was filtered and the filtrate was concentrated to dryness and then dissolved in 20 mL of 1N sodium hydroxide. The aqueous mixture was extracted twice with 20 mL portions of ethyl acetate. The extracts were combined, washed with brine, dried, and concentrated to dryness to give a solid. The solid was triturated with ethyl acetate:hexane (1:1 v/v) to give 140 mg of 5-(2-acetamidophenyl)-2,4-dihydro-4-ethyl-1H-[1,2,4]triazol-3-thione, mp 193°-194° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](CCl)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17]O.[CH3:19][CH:20]1[CH2:22][NH:21]1>O>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:17][N:21]2[CH2:22][CH:20]2[CH3:19])=[CH:7][CH:8]=1)=[CH2:1]
Reactant: CC1CN1
Reactant: CO
Reactant: C=Cc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccc(CN2CC2C)cc1
Yield: 87.1 %

Procedure:
The title compound was prepared in a manner analogous to Example 1. The components were ar-vinyl-benzyl chloride (approximately 95% para isomer, 0.249 mol.), potassium carbonate (50.0 g.), anhydrous methanol (1000 ml.) and 2-methylaziridine (70 ml.; 0.974 mol.). Distillation of the crude product (a brown oil) gave 7.6 g. of a water-white liquid boiling at about 85°C. under 0.2-0.3 mm. of Hg pressure. VPC analysis showed this fraction to contain 87.1% of the desired product. The product was obtained from the VPC fractionation and its structure confirmed by IR, NMR and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Br)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OCCCO2)=[C:18]([F:28])[C:17]=1[O:29][CH3:30].[F-].[K+]>C(#N)C.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:29][CH3:30])[C:18]=2[F:28])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: COC(=O)c1nc(Br)c(F)c(N)c1Cl
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
A stream of nitrogen was passed through a colorless mixture of methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate (2.8 g, 10 mmol) and 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (3.2 g, 13 mmol) in acetonitrile (CH3CN; 40 mL) and KF (1.7 g, 30 mmol) in H2O (20 mL) while heating to 50° C. (20-30 min). Dichloro-bis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2; 140 mg, 0.2 mmol) was added, and the mixture was heated to 65° C. The reaction was monitored by HPLC and was complete after 5 h. The reaction mixture was filtered hot through a short pad of Celite then was diluted with H2O (20 mL) and allowed to cool. The product was collected by filtration. The light tan solid was dried under vacuum to give methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (2.6 g, 72%): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 164.85 (s), 153.11 (d, J=252.5 Hz), 146.29 (s), 144.52 (d, J=4.3 Hz), 143.74 (s), 142.75 (dd, J=227.1, 14.0 Hz), 136.38 (d, J=13.4 Hz), 128.58 (d, J=3.2 Hz), 125.87 (s), 125.54 (d, J=3.5 Hz), 122.89 (dd, J=13.8, 4.0 Hz), 113.01 (d, J=3.0 Hz), 61.61 (d, J=4.2 Hz), 52.70 (s); ESIMS m/z 364 ([M+H]+). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:10]([F:13])([F:12])[F:11])=[CH:4][C:5](OCC)=[O:6].C[NH:15]N.Cl>O>[CH3:1][N:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[CH:4][C:5]([OH:6])=[N:15]1
Reactant: CCOC(=O)C=C(NC)C(F)(F)F
Reactant: CNN
Agent: Cl
Solvent: O
Product: Cn1nc(O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
A 50 ml. flask equipped with mechanical stirrer and reflux condenser was charged with 19.7 g of ethyl 3-methylamino-4,4,4-trifluoro-2-butenoate and 4.8 g of methylhydrazine and heated to 50°-65° C. for 2.75 hr., then to 40°-45° C. for 2 hr., and then allowed to cool to room temperature and stand overnight. The clear reaction mixture was taken up in 15 ml. of water and conc. hydrochloric acid added dropwise to pH 6.0-6.5 which required 5.2 ml. of acid. The precipitated product was collected by filtration and dried to obtain 7.06 g (42.5%) of product m.p. 127°-128.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].Cl.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.BrC1C=C(C)C([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=C(C)C=1>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:10]1[CH:9]=[C:18]([CH3:17])[C:3]([CH:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]([NH2:27])=[O:34])=[C:2]([CH3:5])[CH:1]=1)[CH2:13][CH2:12]2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Reactant: CC(C)(C)[O-]
Reactant: Fc1ccc2c(c1)CCNC2
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(F)ccc3C2)cc(C)c1C(C(N)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon for 30 minutes) and stirred for 30 minutes under argon. Potassium tert-butoxide (4.75 mg, 42.3 mmol), 6-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (3.2 g, 17.0 mmol), and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol) were then added, and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (5.11 g, 83%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:6](OC)=[O:7])#[N:2].C(O)C.[BH4-].[Li+]>O1CCCC1>[F:13][C:11]1[CH:12]=[C:3]([CH:4]=[C:5]([CH2:6][OH:7])[CH:10]=1)[C:1]#[N:2]
Reactant: COC(=O)c1cc(F)cc(C#N)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(F)cc(CO)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
(Step 2) To a mixed solution of methyl 3-cyano-5-fluorobenzoate (0.55 g) obtained in Step 1 in tetrahydrofuran:ethanol=10:1 (22 ml) was added lithium tetrahydroborate (0.10 g) at 0° C. After stirring at 55° C. for 1 hr, the reaction solution was quenched with ice and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 3-fluoro-5-(hydroxymethyl)benzonitrile (0.29 g).
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37]>ClCCl>[C:36]([O:39][CH2:40][C:41]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)=[O:42])(=[O:38])[CH3:37]
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (1.29 g, 3 mmol) was suspended in dichloromethane (25 ml) under nitrogen at ambient temperature. Triethylamine (1.06 g, 10.5 mmol) was added, to give a solution after 15 minutes. The mixture was cooled to 4°, and acetoxyacetyl chloride (410 mg, 3 mmol) was added dropwise. The mixture was stirred for 18 hours at ambient temperature, washed with water (2×20 ml), saturated brine (20 ml), and dried (magnesium sulfate). The residue was purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (1.16 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH2:32][N:33]([CH3:36])[O:34][CH:35]=1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:30][C:31]1[CH2:32][N:33]([CH3:36])[O:34][CH:35]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Reactant: CN1CC(CBr)=CO1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CN1CC(COc2ccc(C[C@@H]3CNCCO3)cc2Cl)=CO1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and 4-bromomethyl-2-methylisoxazole (55 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 20 as a colorless oil (19 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH2:19][OH:20])[CH:12]=1)(=[O:3])[CH3:2].O[C:27]1[C:28]([OH:37])=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N#N.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH2:19][O:20][C:34]2[CH:35]=[CH:36][CH:27]=[C:28]([OH:37])[C:29]=2[C:30]([O:32][CH3:33])=[O:31])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(O)c1O
Reactant: CCOC(=O)c1noc(-c2cccc(/C=C/CO)c2)c1COC(C)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1noc(-c2cccc(/C=C/COc3cccc(O)c3C(=O)OC)c2)c1COC(C)=O
Reaction time: 16 h
Yield: 42.8 %

Procedure:
To a solution of ethyl 4-((acetyloxy)methyl)-5-{3-((1E)-3-hydroxyprop-1-enyl)phenyl}isoxazole-3-carboxylate (960 mg, 2.78 mmol) in THF (14 mL) was added methyl dihydroxybenzoate (934 mg, 5.57 mmol) and PPh3 (1.46 g, 5.57 mmol). After purging the vessel with N2, diethyazodicarboxylate (968 mg, 5.57 mmol) was added. The mixture was stirred for 16 hours, concentrated under vacuo and the residue purified by column chromatography (0–40% ethyl acetate in hexanes) to provide the titled compound (590 mg, 43%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:8].[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH3:30])[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[O:28]=[C:27]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C@@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](NC(=O)c1cccn1N)c1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)N[C@@H](C)c1ccccc1
Yield: 94.3 %

Procedure:
The title compound was prepared from (S)-1-amino-N-(1-phenylethyl)-1H-pyrrole-2-carboxamide (3.50 g, 15.3 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (2.89 g, 15.3 mmol) following the experimental procedure described in Preparation 73a. 5.78 g (92% yield) of the desired compound were obtained.