Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)C1C=CC=CC=1>C(O)C.[Pd]>[N:19]1([CH2:18][CH:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:16][CH2:17][NH:8]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: c1ccc(CN2CCc3ccccc3C2CN2CCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc2c(c1)CCNC2CN1CCCC1
Yield: 97.4 %

Procedure:
8 g of 2-benzyl-1-(1-pyrrolidinylmethyl)-1,2,3,4-tetrahydroisoquinoline were dissolved in 200 ml of 95% ethanol and hydrogenated on 1.5 g of 5% Pd on charcoal at 40° C. and room temperature. After 7 hr the catalyst was filtered off, and the solvent evaporated i.v. 5.5 g of crude product were obtained, sufficiently pure for the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Cl)c2cccnc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(OCc2ccccc2)c2ncccc12
Yield: 79.5 %

Procedure:
10.0 mmol of 5-chloro-8-hydroxyquinoline (ALDRICH) are dissolved, with stirring, in 20 ml of dry DMF, in a 50 ml round-bottomed flask provided with stirring and a thermometer. Then 11 mmol of potassium carbonate and 10% by weight of potassium iodide are added. A solution of 11 mmol of benzyl chloride (JANSSEN) in 5 ml of DMF is added dropwise over 5 minutes, at room temperature and with stirring. After 18 hours of reaction at 50° C., the reaction mixture, supplemented with 100 ml of water is extracted with 4×50 ml of tert-butyl methyl ether. The organic phases are combined, then washed with 3×50 ml of 1N HCl. The aqueous phases are combined, alkalized to pH=9 and extracted with 2×50 ml of ethyl acetate. After drying the organic phase over MgSO4, the solvent is evaporated under reduced pressure. The desired product is obtained after recrystallization from ethanol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[N:14]=[CH:15][CH:16]=[CH:17][C:8]2=1)=O.[NH2:18][C:19]([NH2:21])=[S:20]>CCO>[N:14]1[C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH:17]=[CH:16][CH:15]=1)=[CH:6][C:5]([C:3]1[N:18]=[C:19]([NH2:21])[S:20][CH:2]=1)=[CH:13][CH:12]=3
Reactant: O=C(CBr)c1ccc2[nH]c3ncccc3c2c1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2ccc3[nH]c4ncccc4c3c2)cs1
Temperature: 70 °C
Yield: 99 %

Procedure:
To a stirred suspension of 2-Bromo-1-(9H-pyrido[2,3-b]indol-6-yl)ethanone (100 mg, 0.346 mmol) in EtOH (2 mL) was added thiourea (26 mg, 1 equiv.) and the mixture was heated at 70° C. for 2 h. After cooling to room temperature, the solvent was evaporated to dryness. The resulting solid was stirred in a mixture of EtOAc/saturated aqueous NaHCO3 solution (2:1) until dissolution, and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Compound 13 was obtained as a white powder in 99% yield after trituration of the crude product in MeOH and filtration; 1H-NMR (300 MHz; DMSO-d6): δ 12.07 (bs, 1H), 8.57-8.45 (m, 2H), 8.47 (dd, 1H, J=1.5, 4.9 Hz), 7.85 (dd, 1H, J=1.7, 8.5 Hz), 7.57 (d, 1H, J=8.5 Hz), 7.28 (dd, 1H, J=5.0, 7.7 Hz), 7.08 (s, 1H); 13C-NMR (75 MHz; DMSO-d6): δ 170.1 (C), 150.9 (C), 145.1 (CH), 140.3 (C), 139.2 (C), 130.0 (CH), 125.0 (CH), 121.1 (C), 120.4 (C), 119.2 (CH), 116.0 (C), 115.6 (CH), 112.0 (CH), 100.7 (CH); MS (ESI) m/z 267.1 [M+H+]; HRMS (ESI): Calcd for C14H10N4S: 267.0704. Found: 267.0703
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)C)[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:13]>C(O)C>[ClH:13].[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[NH2:9]
Reactant: CC(=O)Nc1cc(F)cc(Br)c1
Agent: Cl
Solvent: CCO
Product: Nc1cc(F)cc(Br)c1
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of N-(3-bromo-5-fluorophenyl)acetamide (3.5 g, 15.13 mmole) in absolute ethanol (40 mL) was added HCl (50 mL of a 11% aqueous solution). The reaction mixture was stirred while refluxing in an oil bath set at 110° C. overnight. Conc hydrochloric acid (5 mL) was added and stirred for an additional 5 h prior to concentrating under reduce pressure. The resulting 3-bromo-5-fluoroaniline hydrochloride (2.9 g, 85% yield) was used in the next reaction without further purification. Retention time (min)=2.077, method [4], MS (ESI) 192.0 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8]([CH2:11][C:12]1[CH2:13][CH2:14][N:15]([C:18](=[S:20])[OH:19])[CH2:16][CH:17]=1)(=[O:10])=[O:9].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[N:29]2[CH2:32][C:31](=[O:33])[CH2:30]2)=[CH:24][CH:23]=1>O1CCCC1.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[N:29]2[CH2:30][C:31]([CH2:7][S:8]([CH2:11][C:12]3[CH2:17][CH2:16][N:15]([C:18](=[S:20])[OH:19])[CH2:14][CH:13]=3)(=[O:9])=[O:10])([OH:33])[CH2:32]2)=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)CC1=CCN(C(O)=S)CC1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(CC1=CCN(C(O)=S)CC1)CC1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
The phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methylsulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid is prepared in the following manner: 0.52 g of potassium tert-butoxide is added to a mixture of 0.72 g of the phenolic ester of 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-1-carbothioic acid and 0.708 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 15 cm3 of dry tetrahydrofuran cooled under an inert atmosphere to −78° C. The reaction mixture is stirred at −78° C. for 4 hours and then 0.354 g of 1-[bis(4-chlorophenyl)-methyl]azetidin-3-one are added. After two hours at −78° C., the temperature is allowed to return to 20° C. The reaction mixture is diluted in 100 cm3 of water and then the tetrahydrofuran is evaporated off under 2.7 kPa at 40° C. The aqueous phase is extracted with twice 100 cm3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, concentrated under 2.7 kPa at 40° C. The residue obtained is chromatographed on silica (200 g of silica, Amicon, 20-45 μm, porosity 60Angstroem, column 5 cm in diameter), eluting with a cyclohexane:ethyl acetate (6:4 by volume) mixture. The fractions with an Rf={fraction (11/64)} (cyclohexane:ethyl acetate 6:4, silica plate, Merck reference 1.05719, Merck KGaA, 64721 Darmstatd, Germany) are combined and concentrated under 2.7 kPa at 40° C. to give 240 mg of the phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methylsulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.CO[CH:12](OC)[CH2:13][NH2:14]>>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][O:9][CH:12]([CH2:13][NH2:14])[C:4]=2[CH:3]=1
Reactant: OCCc1ccc(Br)s1
Reactant: COC(CN)OC
Product: NCC1OCCc2sc(Br)cc21

Procedure:
The title compound was synthesized from 2-(5-bromothiophen-2-yl)ethanol and aminoacetaldehyde dimethylacetal according to General Procedure A.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccc(Cl)c3)cc2)c2ccc3ccccc3c2N1
Yield: 52.2 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.063 mmol) obtained in Example 1, (3), and 3-chlorobenzoyl chloride (17 mg, 0.095 mmol), the title compound (15 mg, yield 52%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O1CCCC1.O>[CH3:27][O:28][CH2:29][C:30]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])=[O:31]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCC(OC(=O)COC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (150 mg, 0.365 mmol), methoxyacetic acid (0.0453 mL, 0.59 mmol), triethylamine (0.25 mL, 1.79 mmol) and 4-dimethylaminopyridine (48.0 mg, 0.39 mmol) in tetrahydrofuran (5.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (170 mg, 0.887 mmol) at room temperature. The mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/diisopropyl ether to give the title compound (98.4 mg, 0.204 mmol, 56%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[C:20]([CH3:21])=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=1[CH3:22])=[O:8].[O:25]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:25]1[C:29]2([CH2:34][CH2:33][N:32]([C:2]3[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=3)[C:7]([NH:9][C:10]3[C:20]([CH3:21])=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=3[CH3:22])=[O:8])[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2C)c(C)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC4(CC3)OCCO4)ccc2C)c(C)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a solution of ethyl 4-[(5-bromo-2-methyl-benzoyl)amino]-3,5-dimethyl-benzoate (0.5 g, 1.28 mmol), 1,4-dioxa-8-azaspiro(4.5)decane (0.22 g, 1.54 mmol) and Cs2CO3 (1.25 g, 3.84 mmol) in THF (10 ml) is added Pd(OAc)2 (0.04 g, 0.19 mmol) followed by racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (119.7 mg, 0.19 mmol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 90° C. After 16 hours, the reaction is cooled to ambient temperature and diluted with ammonium chloride and extracted twice with EtOAc. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 0-100% ethyl acetate in hexane to afford the title compound as a brown solid (0.21 g, 36.2%). Mass spectrum (m/z): 453.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][O:20][CH2:21]3)[CH:3]=1.Cl.[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][O:28][CH2:27]2.C(=O)([O-])[O-].[K+].[K+].CCN(C(C)C)C(C)C>O1CCOCC1.ClCCl>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][O:20][CH2:21]4)[CH:3]=[C:2]([N:33]3[CH:26]4[CH2:32][CH2:31][CH:30]3[CH2:29][O:28][CH2:27]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CC2COCC1N2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3C4CCC3COC4)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)cc(N3C4CCC3COC4)n2)cc1
Temperature: 220 °C
Yield: 45.9 %

Procedure:
In a 2-5 mL microwave vial was placed 8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (36, 214 mg, 0.617 mmol) in dioxane (4 ml) to give a yellow suspension. 3-Oxa-8-azabicyclo[3.2.1]octane hydrochloride (33, 277 mg, 1.851 mmol), potassium carbonate (341 mg, 2.469 mmol) and DIPEA (0.647 ml, 3.70 mmol) were added. The reaction was heated under microwave irradiation at 220° C. for 1 h. The reaction mixture was diluted with dichloromethane and washed with sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (10-40%) to give the title compound (120 mg) as a yellow solid. In addition, mixed fractions were concentrated, applied to a silica gel column and eluted with methanol in dichloromethane (2-5%) to give an additional 19 mg of title compound for a combined yield of 139 mg (0.33 mmol, 53%). HRMS: [M+H]+ mass error=0.6 mDa or 1.45 ppm.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:14]=[CH:13][C:9]2[NH:10][N:11]=[N:12][C:8]=2[CH:7]=1>S(=O)(=O)(O)O>[N+:1]([C:7]1[C:8]2[N:12]=[N:11][NH:10][C:9]=2[CH:13]=[CH:14][C:6]=1[CH3:5])([O-:4])=[O:2]
Reactant: Cc1ccc2[nH]nnc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc2[nH]nnc2c1[N+](=O)[O-]
Yield: 94 %

Procedure:
Nitric acid (40 ml, excess) was added drop wise over 20 minutes to a stirred solution of 5-methyl-1H-benzotriazole (2.66 g, 20 mmol) in conc. sulphuric acid (40 ml) at 0° C. Stirring was continued at room temperature for 90 minutes by which time TLC (A) indicated complete reaction. The solution was poured onto ice to precipitate a flocculent white solid. The solid was collected by filtration and washed with water to afford [23] in 94% yield. Rf (A) 0.60 δH(400 MHz; DMSO-d6) 2.79 (3H, s, CH3) 7.52 (1H, d, J8.4, BT) 8.36 (1H, br s, BT) 16.26 (1H, s, NH); m/z (EI−HR) 178.04937 [(M) calc. for C7H6N4O2 178.04908].
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([Br:46])[CH:42]=3)[N:37]=2)(=O)=O)=CC=1>C(#N)C>[Br:46][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([CH2:35][CH2:34][N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[CH3:11])[CH:45]=[CH:44]2
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3cc(Br)ccc3n2)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Temperature: 60 °C
Yield: 92.2 %

Procedure:
(2R)-2-Methylpyrrolidine L-tartrate (7.00 g, 0.0298 mole, milled), potassium carbonate (9.04 g, 0.0655 mole, milled), and acetonitrile (190 mL) were combined and heated at 60° C. with agitation for 48 hours. The mixture was allowed to cool to 30° C., and treated with the product from Example 42C (8.00 g, 0.0197 mole). The reaction mixture was heated at −60° C. for 36 hours and then distilled down to ˜¼ volume, and isopropyl acetate (200 mL) was added. The mixture was washed with 5% NaHCO3 aq. solution (200 mL×2), and 25% brine (200 mL). The upper organic was dried over anhydrous sodium sulphate, filtered, and the filtrate was concentrated to dryness. The crude product was purified with a short-path silica gel column eluted with heptane:ethyl acetate:TEA (60:40:1) to give 5.8 g (92% yield) of product as an oil, which solidified on standing; mp 49-50° C. (uncorrected); MS (ESI): 319, 311 (M+H)+; 1H-NMR (CDCl3) δ 7.95 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2.2 Hz), 7.89 (1H, d, J=8.9 Hz), 7.72 (1H, dd, J=8.9, 2.2 Hz), 7.35 (1H, d, J=8.5 Hz), 3.23 (2H, m), 3.18 (2H, m), 2.55 (1H, m), 2.38 (1H, m), 2.25 (1H, q, J=8.9 Hz), 1.93 (1H, m), 1.80 (1H, m), 1.71 (1H, m), 1.42 (1H, m), 1.11 (3H, d, J=6.0 Hz); 13C-NMR (CDCl3) δ 161.3, 146.1, 134.7, 132.3, 130.3, 129.2, 127.6, 122.2, 119.2, 59.9, 54.0, 53.6, 38.6, 33.0, 22.0, 19.4.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[OH:7][C@H:8]([CH3:31])[C@H:9]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1)=[O:16])[C:10](OC)=[O:11].Cl>CO>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:15]([NH:14][C@H:9]([C:10]([NH:2][OH:3])=[O:11])[C@H:8]([OH:7])[CH3:31])=[O:16])=[CH:18][CH:19]=1)(=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(C(=O)c2ccccc2)cc1)[C@@H](C)O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)[C@H](NC(=O)c1ccc(C(=O)c2ccccc2)cc1)C(=O)NO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
To a solution of hydroxylamine hydrochloride (121 mg, 1.74 mmol) in anhydrous MeOH (2.0 mL) at 0° C. under N2 atmosphere was added sodium methoxide (25 wt % in MeOH, 680 mg, 3.14 mmol). A precipitate was immediately observed and the cloudy white solution was stirred for 10 minutes at 0° C. A solution of methyl(2S,3R)-3-hydroxy-2-{[4-(phenylcarbonyl)phenyl]carbonylamino}butanoate (1) (534 mg, 1.56 mmol) in MeOH (3.0 mL) was added and the reaction stirred 3 h at 0° C., then warmed gradually to ambient temperature overnight (18 h total). Aqueous 0.5 M HCl (20 mL) was added and the solution extracted with 5:1 chloroform/isopropyl alcohol (4×40 mL). The organic layers were combined, dried over Na2SO4 and concentrated to give an orange foam. Purification by silica gel chromatography (increasing eluant polarity from 30:1 CH2Cl2/MeOH to 15:1 CH2Cl2/MeOH) afforded 228 mg (43%) of 4-benzoyl-N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][NH2:22])=[N:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([CH:30]([CH:37]2[CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=1.C(N(CC)C(C)C)(C)C.O>C(#N)C>[CH:37]1([CH:30]([C:26]2[CH:25]=[C:24]([NH:22][CH2:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])[N:14]=3)[N:29]=[CH:28][N:27]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:39][CH2:38]1
Reactant: COc1ccc(F)c(-c2ccc(CN)nc2OCC(C)C)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CC(c1cc(NCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 54.1 %

Procedure:
To a solution of 1-(5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methanamine (56 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (137 mg) in acetonitrile (3.0 mL) was added N,N-diisopropylethylamine (96 μL), and the mixture was stirred at 70° C. for 15 hr. Water was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (52 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.O=[C:15]([CH3:23])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21]>C1C=CC=CC=1>[C:20]([NH:19][CH2:18][CH2:17][CH2:16][C:15]1([CH3:23])[C:3]2=[C:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12][O:13]1)(=[O:22])[CH3:21]
Reactant: Cc1cn(CCO)c2ccccc12
Reactant: CC(=O)CCCNC(C)=O
Solvent: c1ccccc1
Product: CC(=O)NCCCC1(C)OCCn2c1c(C)c1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-methylindole-1-ethanol (4.2 g.) and N-(4-oxopentyl)acetamide (3.7 g), described by L. P. Kuhn et al., J. Am. Chem. Soc., 89, 3858 (1967), in 300 ml of dry benzene is stirred and heated at reflux. Water is collected in a DeanStark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. Again stirring at room temperature overnight the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated to yield 1-[3-(acetamido)propyl]1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole γmaxCHCl3 1650 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][CH2:19]Cl>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:17][O:18][CH3:19]
Reactant: COCCl
Reactant: COc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1cc(OC)ccc1Br
Temperature: 23 °C
Yield: 91.1 %

Procedure:
Protected haloorganoboronic acid 14 was synthesized by a multi-step process. To a stirred mixture of 2-bromo-5-methoxyphenol (Albert, 2002) (2.19 g, 10.8 mmol) and K2CO3 (4.46 g, 32.3 mmol) in acetone (55 mL) was added chloromethyl methyl ether (1.63 mL, 21.5 mmol). The mixture was refluxed for 3 h and then allowed to cool to 23° C. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was then purified by flash chromatography (SiO2, hexanes:EtOAc 95:5) to provide 2-bromo-5-methoxy-1-methoxymethoxybenzene as a colorless liquid (2.43 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([CH:11]([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[CH:9]=[CH2:10]>>[CH2:8]([C:11]1[C:12](=[O:13])[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:17]=1[OH:18])[CH:9]=[CH2:10]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccn1
Product: C=CCc1c(O)nc2ccccn2c1=O
Temperature: 160 °C
Yield: 27.1 %

Procedure:
2-aminopyridine (996 mg, 10.58 mmol) and diethyl allylmalonate (2098 μl, 10.58 mmol) were combined and heated to 160° C. neat for 9 hours. The brown solution solidified upon cooling to room temperature. The solid was filtered and washed with Et2O to yield the title compound as a tan solid (580 mg, 27%) LCMS (ES+) m/z 203.02 (M+H)+.