Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[N:6][CH:7]=1.N([O-])=O.[Na+].[Na+].[I-:20]>Cl.O>[I:20][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[N:6][CH:7]=1
Reactant: Nc1ccc(-n2ccccc2=O)nc1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1ccccn1-c1ccc(I)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of 1-(5-aminopyridin-2-yl)pyridin-2(1H)-one (316 mg, 1.69 mmol) in concentrated HCl (8 mL) cooled in an ice bath, a solution of NaNO2 (117 mg, 1.69 mmol) in H2O (3 mL) was added dropwise. After 30 min of stirring, NaI (1.03 g, 6.87 mmol) in H2O (4 mL) was added. The mixture was stirred at 0° C. for 1 h. It was then allowed to warm up to room temperature and stirred at room temperature overnight. The mixture was extracted with EtOAc. The EtOAc solution was washed with 5% NaHCO3, then with Na2S2O3, dried over Na2SO4, and concentrated in vacuo to give 1-(5-iodopyridin-2-yl)pyridin-2(1H)-one (189 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C(O)CCC>[Cl:1][C:2]1[NH:3][C:4]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2
Reactant: COc1ccc(N)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: COc1ccc(Nc2[nH]c(Cl)nc3ncnc2-3)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
189 mg of 2,6-dichloropurine, 4 ml of butanol and 135 mg (1.1 mol) of 4-methoxybenzenamine are mixed at room temperature and the medium is heated at a temperature of 75° C. for 5 hours and then left at room temperature overnight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=3[F:32])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=c1[nH]c(=O)n(-c2ccc(F)cc2)o1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2ccc(F)cc2)c1=O
Reaction time: 24 h

Procedure:
2-(4-Fluorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(4-fluorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1.ClCCl>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][CH2:11][CH2:10][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[N:15]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCCn1ccc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1cncc(OCCn2ccc3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
K-t-BuO (0.67 g, 5.93 mmol) was added to a stirred solution of the product obtained in step 1 above (0.67 g, 5.93 mmol) in dioxane (20 mL) at 0° C. (ice-bath). After being stirred for 7 min at 0° C. and 5 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (2.62 g, 17.6 mmol) was added. The yellowish reaction mixture was stirred at 0° C. for 20 min and at room temperature for 10 min and then diluted with dichloromethane. Drying (K2CO3), filtration, and concentration in vacuo furnished a beige oil. This material was purified by chromatography on silica gel (13×4 cm) using n-hexane/ethyl acetate (80:20). This furnished 1.39 g (94%) of the title compound as an oil that solidified upon standing. HRMS m/z calcd for C14H12ClN3O (M)+ 273.0669, found 273.0671. Anal. (C14H12ClN3O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl-].[Mg+2].[Cl-].[CH2:12]=[O:13].C(N(CC)CC)C.Cl>C(#N)C>[Br:1][C:2]1[C:3]([OH:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:12]=[O:13]
Reactant: C=O
Reactant: Oc1ccccc1Br
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1cccc(Br)c1O
Temperature: 0 °C

Procedure:
20.0 g (115.6 mmol) of 2-bromophenol are introduced into 500 ml of dry acetonitrile. 16.84 g (176.87 mmol) of dry magnesium chloride, 23.4 g of paraformaldehyde granules and 41.9 ml (300.6 mmol) of triethylamine are added. The reaction mixture is heated under reflux for 4 h and, after cooling to 0° C., 300 ml of 2N hydrochloric acid are added. The aqueous phase is extracted three times with 200 ml of diethyl ether each time. The organic phase is dried over magnesium sulphate, and the solvent is removed in vacuo. 24 g (64% of theory, 62% pure according to HPLC) of the title compound are isolated and reacted further without further purification.
Reaction SMILES: [C:1]([S:4][CH:5]([C:21]1[N:22]=[CH:23][N:24](C(OC(C)(C)C)=O)[CH:25]=1)[CH2:6][C:7]([N:9]1[CH2:20][CH2:19][CH2:18][C@H:10]1[C:11]([O:13]C(C)(C)C)=[O:12])=[O:8])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.[ClH:41]>C(Cl)Cl>[ClH:41].[C:1]([S:4][CH:5]([C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[CH2:6][C:7]([N:9]1[CH2:20][CH2:19][CH2:18][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)c1cn(C(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)c1c[nH]cn1
Reaction time: 5 h

Procedure:
A solution of 2.8 g (5.99 mmol) of (±)-1-[3-(acetylthio)-3-[1-[(1,1-dimethylethoxy)carbonyl]-1H-imidazol-4-yl]-1-oxopropyl]-L-proline, 1,1-dimethylethyl ester in 125 ml of CH2Cl2 and 6.5 ml (59.9 mmol) of anisole is cooled in an ice-water bath under nitrogen and saturated with HCl. The cold bath is removed and the stoppered flask is kept at ambient temperature for five hours. The reaction mixture is then concentrated in vacuo and the residue partitioned between 40 ml of water and 40 ml of diethyl ether. The organic solution is extracted with 20 ml more of water and the combined aqueous extracts lyophillized to afford 1.9 g of a glassy solid. This material is chromatographed on about 600 ml of LH-20 eluted with water. Pooling of the product fractions (R=0.36 on silica gel; 4:1:1:1, n-butanol:pyridine:acetic acid:water) yielded 1.9 g of product (±)-1-[3-(acetylthio)-3-(1H-imidazol-4-yl)-1-oxopropyl]-L-proline, hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=O)[CH3:18].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[N:21][OH:22])[CH3:18]
Reactant: CC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccccc1Nc1c(Cl)ccc(C)c1Cl

Procedure:
1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]ethanone (0.8 g, 2.7 mmol) and hydroxylamine hydrochloride (0.8 g, 10.8 mmol) are dissolved in 15 ml of pyridine under argon at room temperature for 12 hours. The pyridine is evaporated, and the residue partitioned between methylene chloride and water. The organic layer is washed twice with 100 ml of water and dried over magnesium sulfate. The solution is concentrated on the rotovap and passed through a silica gel pad which is then eluted with methylene chloride. The solvent is evaporated and 1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]ethanone oxime is recrystallized from H2O/MeOH. Yield 0.2 g (24%); mp 116°-118° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Reactant: O=[N+]([O-])c1cccc(Br)c1
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cccc([N+](=O)[O-])c1)OCC

Procedure:
Analogously to the process described under Example 6A/Step 1, 1.0 g (3.62 mmol) of the compound of Example 4A and 804 mg (3.98 mmol) of 1-bromo-3-nitrobenzene gave 1.26 g (87% of theory) of the title compound. In this case, chromatographic isolation of the product was by MPLC (mobile phase cyclohexane/ethyl acetate 1:2); subsequent trituration with diisopropyl ether was dispensed with.
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[F:19]>C(O)(C)C>[ClH:12].[F:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Fc1cnccc1Cl
Reactant: Nn1ccc2ccccc21
Agent: Cl
Solvent: CC(C)O
Product: Fc1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 4-chloro-3-fluoropyridine hydrochloride in isopropanol at 90° C. for 4 hours in substantially the same manner as in Example 1, m.p. >250° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:5]([NH2:7])=[O:6])[CH3:3].[C:18](Cl)(=[O:20])[CH3:19]>C(N(CC)CC)C>[CH3:5][N:4]([CH3:8])[CH2:2][CH2:1][NH:7][C:5](=[O:6])[N:4]([CH:2]([CH3:1])[CH3:3])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=1
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(N)=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(OCCN(C(=O)NCCN(C)C)C(C)C)cc1

Procedure:
The title compound is prepared by reacting the compound of Example 64: N'-[2-dimethylamino)ethyl]-N-(1-methylethyl)-N-[2-(4-aminophenoxy)ethyl]urea with acetyl chloride in triethylamine.
Reaction SMILES: [F:1][C:2]([F:15])([CH:6]([O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.[F:31][C:32]([F:36])([F:35])[CH2:33]O.Cl>ClCCl.CN(C1C=CN=CC=1)C>[F:31][C:32]([F:36])([F:35])[CH2:33][O:4][C:3](=[O:5])[C:2]([F:15])([F:1])[CH:6]([O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[CH2:7][CH3:8]
Reactant: OCC(F)(F)F
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
After a reaction vessel which had been sufficiently dried inside by vacuum heating was replaced with dry nitrogen, 100 mL of a solution of 22.22 g (0.1 mol) of 2,2-difluoro-3-(methacryloyloxy)pentanoic acid in dichloromethane was added into the reaction vessel, and the mixture was cooled to an ice temperature. Thereto was added 100 mL of a solution of 22.70 g (0.11 mol) of DCC in dichloromethane over 10 min, and 0.61 g (5 mmol) of DMAP and 10.40 g (0.105 mol) of 2,2,2-trifluoroethanol were further added. Thereafter, the temperature of the reaction vessel was elevated to the room temperature, followed by stirring the mixture for 2 hrs, and 300 g of 1 N aqueous hydrochloric acid was added while intimately stirring. Subsequently, dichloromethane was separated by a separatory funnel, and the aqueous layer was extracted again with dichloromethane to obtain an extraction liquid. After the extraction liquid was combined with the dichloromethane layer and washed with 1 N aqueous hydrochloric acid, the solvent of the dichloromethane layer was distilled off with an evaporator, followed by purification by column chromatography to give 21.60 g of 2,2,2-trifluoroethyl-2,2-difluoro-3-(methacryloyloxy)pentanoate (M-5) (yield: 71%).
Reaction SMILES: C([C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:7][CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][NH:10][CH2:9]1)=[O:6])C.[N:28]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[C:4]1([C:5]([NH:7][CH:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=3)[CH2:11][N:10]([C:29]([NH:28][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[O:30])[CH2:9]2)=[O:6])[CH:3]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCc1ccccc1C(=O)NC1CNCC(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=C=Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Nc2ccncc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80 mg (0.23 mmol) of ethyl-N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 2 ml of THF, and 28 mg (0.23 mmol) of 4-isocyanatopyridine and 35 μl (0.25 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 75 mg (70% of theory)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[NH2:4].[CH:11]12[CH2:16][CH:15]1[C:14](=O)[O:13][C:12]2=[O:18]>CN(C)C=O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:4]=[C:14]([C@H:15]2[CH2:16][C@H:11]2[C:12]([OH:18])=[O:13])[O:1][N:2]=1
Reactant: NC(=NO)c1ccccn1
Reactant: O=C1OC(=O)C2CC12
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1C[C@@H]1c1nc(-c2ccccn2)no1
Yield: 86.6 %

Procedure:
N′-hydroxy-2-pyridinecarboximidamide (0.137 g) with 3-oxabicyclo[3.1.0]hexane-2,4-dione (0.112 g) in dimethylformamide (2 drops) was heated for 4 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W to leave a fused mass. The reaction was allowed to cool and triturated with diethyl ether and filtered to leave cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid (0.200 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]#[N:26])=[CH:4][N:3]=1.[NH2:27][OH:28].C(N(CC)CC)C>CCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:21])([CH3:22])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]([NH:27][OH:28])=[NH:26])=[CH:4][N:3]=1
Reactant: Cc1cn(-c2ccc3c(N)ncc(C#N)c3c2)c2c1C(=O)CC(C)(C)C2
Reactant: NO
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc3c(N)ncc(C(=N)NO)c3c2)c2c1C(=O)CC(C)(C)C2
Reaction time: 48 h
Yield: 45 %

Procedure:
A suspension of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile (0.035 g, 0.1 mmol), hydroxylamine (7 mg, 0.1 mmol) and triethylamine (0.01 mL, 0.1 mmol) in EtOH (2 mL) is placed in an oil bath at 100° C. and stirred for 2 days. The solvent is evaporated under reduced pressure, and the residue is purified using a Biotage column (0-20% MeOH/CH2Cl2) to afford 0.017 g (48%) of 1-amino-N-hydroxy-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carboxamidine. LC/MS m/z=378 [M+H]+, RT=1.82 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C>[N:10]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN=[N+]=[N-]
Yield: 96.2 %

Procedure:
Ethyl 4-bromobutanoate (17.11 g, 87.7 mmol) and NaN3 (28.50 g, 438.5 mmol) was dissolved in 70 mL DMF and reacted at 77° C. for 30 hours. 250 mL of 4:1 EtOAc/hexanes was added, and was washed twice with 250 mL saturated aqueous sodium bicarbonate, and once with 200 mL water. Organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 4-azidobutanoate 6 (13.26 g, 96%). Ethyl 4-azidobutanoate 6 (6.18 g, 39.29 mmol) was then saponified using excess KOH in 12:10 methanol/water at 0° C. for 5 minutes and then ambient temperature for 11 hours, followed by acid workup to yield 4-Azidobutanoic acid 7 (4.69 g, 92%). 1H NMR (400 MHz, cdcl3) δ 1.71-1.98 (2H, m), 2.45 (2H, t, J=7.2 Hz), 3.35 (2H, t, J=6.7 Hz), 11.21 (1H, s) ppm.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[NH2:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1NC1CCCCC1
Yield: 100 %

Procedure:
32 g (0.11 mol) of N-cyclohexyl-2-nitro-4-trifluoromethylaniline dissolved in 250 ml of methanol were hydrogenated under a pressure of about 1 bar of hydrogen in the presence of 1.5 g of palladium/active carbon (10% by weight Pd) at room temperature. The reaction mixture was filtered. Conventional workup of the filtrate gave a 100% yield of the abovementioned compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH:12]=[CH:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([N:32]2[CH2:37][CH2:36][C@:35]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:34][C:33]2=[O:49])[CH3:31])=[CH:26][CH:25]=1>>[OH:48][C:45]([CH3:46])([CH3:47])[CH2:44][C@@:35]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:34][C:33](=[O:49])[N:32]([C@H:30]([C:27]2[CH:26]=[CH:25][C:24]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]4=[O:21])[N:14]=3)=[CH:29][CH:28]=2)[CH3:31])[CH2:37][CH2:36]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC1(C)OB(c2cccc(N3CCCCC3=O)n2)OC1(C)C
Product: C[C@@H](c1ccc(-c2cccc(N3CCCCC3=O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 1-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperidin-2-one (purchased from CombiPhos Catalysts Inc., Princeton, N.J., USA) and (S)-3-[(S)-1-(4-bromophenyl)ethyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 35. LC (method 5): tR=1.62 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Product: CC(=O)Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Yield: 50 %

Procedure:
Using an analogous procedure to that described in Example 11, 6-amino-4-(3'-chloroanilino)quinazoline was reacted with acetic anhydride to give 6-acetamido-4-(3'-chloroanilino)quinazoline in 50% yield, m.p. 260°-262° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[NH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C)C=O>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11][C@H:7]2[CH2:6][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:33])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCNCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.0 g) in dimethylformamide (90 ml) was added piperazine (2.0 g) and the mixture was stirred at 80°-90° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(piperazin-1-yl)methyl-4-(triphenylmethylthio)pyrrolidine (2.52 g).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:30])[CH:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=1)[NH2:17])[CH3:13].C(N(CC)CC)C>O1CCOCC1>[CH2:12]([O:14][C:15](=[O:30])[CH:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:20]=1)[NH:17][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(N)Cc1cccc(NS(C)(=O)=O)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1cccc(NS(C)(=O)=O)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 10°-15° C., add benzylchloroformate (15.5 mL) dropwise to a heterogeneous mixture of 3-methanesulfonamido-D,L-phenylalanine ethyl ester (25.00 g) and triethylamine (15 mL) in dioxane (400 mL). Warm to room temperature, stir overnight, and remove the dioxane in vacuo. Partition the mixture between EtOAc (200 mL)/water (500 mL). Wash the EtOAc solution with water (500 mL), 1N HCl (500 mL), 5% NaHCO3 (500 mL), and brine (500 mL). Concentrate the dried (MgSO4) EtOAc solution in vacuo to a residue. Chromatograph the residue on silica gel (40μ, 2200 mL) using EtOAc:hexane (3:7) as eluant to give N-benzyloxycarbonyl-3-methanesulfonamido-D,L-phenylalanine ethyl ester.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([NH:12]N)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].O=[C:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16]1.CC(O)=O>O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:9]([C:20]3[CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16][C:15]=3[NH:12]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(NN)c1
Reactant: CC(=O)NC1CCCC(=O)C1
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
A mixture of 0.2 mol of 3-n-butyloxyphenylhydrazine, 0.2 mol of N-(3-oxocyclohexyl)acetamide, and 350 ml of glacial HOAc was stirred at room temperature for 3 hr and then refluxed for 2 hr. After pouring into 2.5 l of H2O and stirring overnight, the insoluble material had partly crystallized. The crystalline material was filtered, washed with H2O, and dried (23 g, Fraction A). The remaining insoluble semi-solid was taken up in EtOAc, washed with H2O, dried, and evaporated. The dark residue was triturated with Et2O and filtered (b 6.7 g, mp 181°-183°, Fraction B). Additional product was extracted from Fraction A by stirring with two 4 l. portions of Et2O. The combined extracts were evaporated and the resulting residue combined with Fraction B and recrystallized twice from Me2CO to yield 10.2 g of the title compound, mp 182°-184°.