Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>C(OCC)(=O)C.O>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To 24.9 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic acid anhydride in 100.4 g of ethyl acetate were added 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride and 7.6 g (0.055 mole) of potassium carbonate dissolved in 9.3 g of water. The reaction was carried out for 3 hours with stirring at 15°-20 C. Thereafter, 100.4 g of acetic acid and 75.3 g of water was added to the concentrate and the mixture was stirred for one hour at 15°-20.C. Precipitated crystals were filtered, washed and dried to obtain crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:33][C:34]1[S:35][C:36]([S:40](Cl)(=[O:42])=[O:41])=[C:37]([CH3:39])[N:38]=1>ClCCl>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([S:40]([C:36]5[S:35][C:34]([CH3:33])=[N:38][C:37]=5[CH3:39])(=[O:42])=[O:41])[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-((2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine hydrochloride (Intermediate 15, 0.050 g, 0.153 mmol), dichloromethane (1.5 mL), and triethyl amine (0.043 mL, 0.306 mmol) was added 2,4-dimethyl-thiazole -5-sulfonyl chloride (0.049 g, 0.229 mmol) and the reaction stirred at room temperature for 2 hours. The solution was concentrated and purified by flash column chromatography on silica gel eluting with 0-100% ethyl acetate in hexanes to afford the desired product.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[C:36]([O:40][C:41]([NH:43][CH2:44][C@@H:45]([C:47]([OH:49])=[O:48])[NH2:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClC(Cl)C>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:46][C@H:45]([C:47]([OH:49])=[O:48])[CH2:44][NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:42])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)NC[C@H](N)C(=O)O
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Solvent: CC(Cl)Cl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 85 °C

Procedure:
2.45 g (5.0 mmol) of the compound from example 1A was dissolved in 40 ml dichloroethane. 1.03 g, (5.0 mmol) 3-[(tert-Butoxycarbonyl)amino]-L-alanine was added. The reaction mixture was heated to 85° C. for 2 h. The solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 150 ml silica gel. Solvents used were dicloromethane/methanol 20/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.23 g (2.2 mmol, 44% of theory) of the desired product.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[O:18]1CCOCC1>>[CH3:17][C:12]1[C:11]([C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:18])[N:10]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Cc1ncccc1-c1ccnc(S(C)(=O)=O)n1
Reactant: C1COCCO1
Product: Cc1ncccc1-c1cc[nH]c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methanesulfonyl-4-(2-methyl-pyridin-3-yl)-pyrimidine (446 mg, 1.79 mmol) was dissolved in dioxane (13 ml) and then 2N NaOHaq (8.9 ml, 17.9 mmol) was added. After stirring at room temperature for 1 hour, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was re-dissolved in DCM-MeOH—NH4OH (95-5-0.5) and evaporated. The crude was purified by flash chromatography with DCM-MeOH (9-1) to give 343 mg of the title compound. (quantitative yield).
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])(O)=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[CH2:4][C:3]1[N:19]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:18][C:2]=1[CH3:10]
Reactant: NC(=O)c1ccccc1
Reactant: COC(=O)CC(=O)C(C)Br
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 95 °C
Yield: 34.9 %

Procedure:
To a solution of 140 g (0.67 mol) of methyl 4-bromo-3-oxo-pentanoate in 300 mL of anhydrous toluene was added 210 g (1.73 mol) of benzamide, 132 g (0.93 mol) of sodium hydrogen phosphate, and ˜20 mL of EtOH. The suspension was stirred with heating to 95° C. for 24 h, then cooled to 0° C., filtered, and the solids washed with cyclohexane (2×100 mL) followed by 20% EtOAc in hexanes (200 mL). The combined filtrates were washed with 2×100 mL 10% KOH solution and brine (100 mL). The organics were dried (MgSO4), concentrated to a thin oil, and purified by chromatography on 1 kg of silica gel (230-400 mesh). Gradient elution of the column with 10% to 50% EtOAc in Hexanes gave 54 grams (35% yield) of the title compound as a pale yellow oil; 1H NMR (CDCl3, 400 MHz) δ8.0-7.98 (m, 2H), 7.43-7.40 (m, 3H), 3.73 (s, 3H), 3.59 (s, 2H), 2.37 (s, 3H); low resolution MS (ES+)m/e 232.4 (MH+); TLC Rf=0.64 (4/1 hexanes/EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH2:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].Cl.[O-:25][C:26]#[N:27].[K+]>C(O)C.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH:20][C:26]([NH2:27])=[O:25])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3N
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3NC(N)=O
Yield: 57.1 %

Procedure:
To a solution of 4-amino-1,8-diethyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetic acid methyl ester 12 (prepared in Example 1) (1.10 g, 3.48 mmol) in ethanol (20 mL), stirred at room temperature under nitrogen, was added aqueous 1N HCl (6.96 mL) followed by potassium cyanate (0.565 g, 6.96 mmol) dissolved in a little water. After 2 hours the ethanol was removed in vacuo and the residue was extracted with ethyl acetate. Drying (MgSO4) and flash chromatography (1% MeOH in EtOAc eluent) afforded the product (0.714 g, 75%) as a mixture of diastereomers which were separated by reverse phase chromatography (C18 silica gel; 30% acetonitrile in water). The less polar Isomer A (190 mg) had m.p. 179.5°-180.5° C. (methylene chloride-petroleum ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][N:4]=1)[CH:9]=[O:10]
Reactant: COc1cc(CO)ccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C=O)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a solution of (2-methoxypyridin-4-yl)methanol (6.74 g) and triethylamine (67.5 mL) in DMSO (200 mL) was added sulfur trioxide pyridine complex (30.8 g), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (4.33 g) as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:15]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[C:16]2[C:21](=[CH:22][C:23]=1[Cl:24])[N:20]=[C:19]([O:25][CH3:26])[C:18]([O:27][CH3:28])=[N:17]2.O[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:13][C:14]1[C:15]([N:29]([CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[S:30]([CH3:33])(=[O:32])=[O:31])=[C:16]2[C:21](=[CH:22][C:23]=1[Cl:24])[N:20]=[C:19]([O:25][CH3:26])[C:18]([O:27][CH3:28])=[N:17]2
Reactant: OCc1cccnc1
Reactant: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(Cl)c(N(Cc3cccnc3)S(C)(=O)=O)c2nc1OC
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Diethyl azodicarboxylate (90 μl, 0.57 mmol) was added to a stirred solution of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (200 mg, 0.57 mmol - see Preparation 3), 3-(hydroxymethyl)pyridine (55 gl, 5 0.57 mmol), and triphenylphosphine (149 mg, 0.57 mmol) in dry tetrahydrofuran (12 ml) under nitrogen at 23° C. After 8 hours, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (gradient elution with ether/methanol) to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(3-pyridylmethyl)methanesulphonamide (145 mg, 57%) as a white solid, m.p. 217° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:34]I>[Ag-]=O.C(OCC)C>[F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])([O:15][CH3:34])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: O=[Ag-]
Solvent: CCOCC
Product: COC1(CNC(=O)OC(C)(C)C)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl {[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-yl]methyl}carbamate (8.0 mg, 0.014 mmol) and silver (I) oxide (12 mg, 0.05 mmol) were taken into methyl iodide (0.5 mL) and the mixture was brought to reflux for 4 hours. The suspension was then cooled to room temperature and diluted with an excess of ethyl ether then filtered. The filtrate was concentrated and purified by silica gel flash chromatography using hexanes:ethyl acetate (1:1) as eluent to give 1,1-dimethylethyl {[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(methyloxy)azetidine-3-yl]methyl}carbamate (2 mg). The material was taken into TFA (0.5 mL) and allowed to stand for 5 minutes then concentrated in vacuo. The residue was azetroped twice from methanol (2 mL) and the residue dried in vacuo to afford 6-{[3-(aminomethyl)-3-(methyloxy)azetidin-1-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline trifluoroacetate salt (2.3 mg, 27% yield) as an amorphous solid. MS (EI) for C18H17F3IN3O: 492 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][O:34][NH:35][CH3:36].CCN(CC)CC>C(Cl)Cl.O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:35]([O:34][CH3:33])[CH3:36])=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a stirred solution of 6-hydroxynicotinic acid (5.0 g, 1.0 eq), EDCI (8.3 g, 1.2 eq) and HOBt (5.8 g, 1.2 eq) in 150 mL CH2Cl2 were added N-methoxymethanamine hydrochloride (4.2 g, 1.2 eq) and Et3N (14.5 g, 4.0 eq) at rt, the mixture was stirred at rt overnight, water was added, and the mixture was extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (3.5 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.82 (brs, 1H), 7.87 (d, J=2.8 Hz, 1H), 7.72 (dd, J=9.6 Hz, 2.8 Hz, 1H), 6.32 (d, J=9.6 Hz, 1H), 3.59 (s, 3H), 3.20 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])/[C:3](/[C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:4]/OS(C1C=CC(C)=CC=1)(=O)=O.[NH3:29]>C(OCC)C>[F:27][C:2]([F:1])([F:28])[C:3]1([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:4][NH:29]1
Reactant: N
Reactant: CCOC(=O)c1cccc(/C(=N\OS(=O)(=O)c2ccc(C)cc2)C(F)(F)F)c1
Solvent: CCOCC
Product: CCOC(=O)c1cccc(C2(C(F)(F)F)NN2)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of ethyl 3-(2,2,2-trifluoroacetyl)benzoate (500 mg, 2.15 mmol) in ethanol was added pyridine (5 mL) and hydroxylamine hydrochloride (500 mg, 7.2 mmol) and the resulting mixture stirred at 57° C. for 3 hours. The reaction mixture was cooled and passed through an ion exchange column eluting with methanol (30 mL). The methanol solution was evaporated in vacuo to give (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate as an oil in 71% yield, 401 mg which was used in the next step without further purification. To a stirred solution of (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate (401 mg, 1.54 mmol) in dichloromethane (10 mL) was added DMAP (17 mg, 0.14 mmol) and the mixture cooled to 0° C. 4-methylbenzene-1-sulfonyl chloride (331 mg, 1.74 mmol) was added portion-wise as a solution in dichloromethane (5 mL). The reaction mixture was then left to stand at room temperature for 18 hours. The mixture was diluted with water (10 mL) and the organic layer separated, dried over magnesium sulfate and evaporated in vacuo to afford (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate as an oil in 78% yield, 500 mg. This material was used in the next step without further purification. A mixture of (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate (500 mg, 1.2 mmol) in diethylether (5 mL) in a 3-necked flask equipped with an internal thermometer and condenser was cooled to −78° C. Ammonia gas was introduced for 5 min and then stirring continued for 45 min. The reaction mixture was warmed to −33° C. and stirred for 2 hours after which it was allowed to warm to room temperature overnight with stirring.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6]C)[CH3:5].[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=O)=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)=[CH:13][CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10]2)[N:16]=1)=[O:18])=[O:24])[CH3:5]
Reactant: CNC(C)COC
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: COCC(C)NC(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 32 %

Procedure:
According to the general method described in step 3 of example 53, reaction of (2-methoxy-1-methyl-ethyl)-methyl-amine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (32%) as amorphous yellow solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CCN(C(C)C)C(C)C.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:4][CH2:3][CH2:1][OH:2])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(CNCCO)cc1

Procedure:
A solution of ethanolamine (10.05 mL, 166.6 mmol), DIPEA (5.08 mL, 29.2 mmol) and 4-nitrobenzyl bromide (6.00 g, 27.8 mmol) in DCM (50 mL) was stirred at room temperature for 4 hours. The volatiles were removed in vacuo and the resulting residue partitioned between water and EtOAc. The aqueous phase was separated and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound A68 as a light yellow solid (3.34 g, 61%); 1H NMR (300 MHz, d6-DMSO) δ 8.18 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 4.49 (t, J=5.4 Hz, 1H), 3.84 (s, 2H), 3.47 (q, J=5.6 Hz, 2H), 2.56 (t, J=5.8 Hz, 2H), 2.28 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[O:8][CH2:7][C:6]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]#[N:10])[CH2:5]1.[NH2:22][OH:23].[C:24]([C:31]([O:33][CH2:34][CH3:35])=[O:32])#[C:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[NH2:10][C:9](=[N:22][O:23][C:25](=[CH:24][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:6]1([NH:11][C:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:21])[CH2:5][CH:4]([CH2:3][CH2:2][Cl:1])[O:8][CH2:7]1
Reactant: NO
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: N#CC1(NC(=O)OCc2ccccc2)COC(CCCl)C1
Solvent: C1CCOC1
Product: CCOC(=O)C=C(ON=C(N)C1(NC(=O)OCc2ccccc2)COC(CCCl)C1)C(=O)OCC
Reaction time: 24 h
Yield: 82 %

Procedure:
A solution of benzyl 5-(2-chloroethyl)-3-cyanotetrahydrofuran-3-ylcarbamate (0.86 g, 2.79 mmol) and 50% aq. hydroxylamine (0.853 mL, 13.93 mmol) in THF (25 mL) was stirred at room temperature for 18 h. The mixture was concentrated and the residue was redissolved in EtOH (20 mL) and treated with diethyl acetylenedicarboxylate (0.490 mL, 3.06 mmol) at room temperature. After 24 h, the reaction mixture was concentrated and the resulting pale yellow residue was taken up in Et2O (75 mL), washed with 1% aq. NH4OH (20 mL), water (20 mL) followed by brine (20 mL), then dried (Na2SO4), filtered, concentrated and purified by flash column chromatography on silica gel column using 1:3, 2:3 and 1:1 ethyl acetate/hexane to afford diethyl 2-(amino(3-(benzyloxycarbonylamino)-5-(2-chloroethyl)tetrahydrofuran-3-yl)methyleneaminooxy)but-2-enedioate (1.1707 g, 2.287 mmol, 82% yield) as a pale yellow paste. 1H NMR (500 MHz, CDCl3) δ: 7.30-7.39 (5 H, m), 5.75-5.88 (2 H, m), 5.26-5.62 (2 H, m), 5.05-5.12 (2 H, m), 4.21-4.37 (3 H, m), 4.12-4.20 (3 H, m), 4.02-4.10 (1 H, m), 3.57-3.67 (2 H, m), 2.60-2.85 (1 H, m), 1.87-2.20 (3 H, m), 1.29-1.38 (3 H, m), 1.22-1.28 (3 H, m). LCMS (M+H) calcd for C23H31ClN3O8: 512.18; found: 512.25.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Reactant: OC[C@H]1CC(c2ccc(Br)cn2)=NO1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@@H](CO)C3)nc2)c(F)c1
Temperature: 75 °C
Yield: 55.5 %

Procedure:
[(5R)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (intermediate 12, 0.139 g, 0.54 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 7, 0.2 g, 0.514 mmol), potassium carbonate (0.355 g, 2.57 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.059 g, 0.05 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane (2×10 ml), the solids were further purified by column chromatography, eluted with 5% DMF in dichloromethane to give the title compound as a white solid (0.125 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:36][CH:37]=1)#[N:7]
Reactant: CCOC(=O)COc1ccc(CCNC)cc1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: CCOC(=O)COc1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1f with 2k produced 3al. MS found M+H=497. The oxalate salt of 3al was recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1>>[O:9]1[CH2:10][CH:11]=[C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCOCC1
Reactant: C#Cc1ccccn1
Product: C(#Cc1ccccn1)C1=CCOCC1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), tetrahydro-4H-pyran-4-one (6.0 mmol, 600 mg); yields 2-(3,6-dihydro-2H-pyran-4-ylethynyl)pyridine as a transparent oil (200 mg, 18% overall yield). 1H NMR (CDCl3, 300 MHz) δ 8.57 (m, 1H), 7.63 (m, 1H), 7.44 (m, 1H), 7.21 (m, 1H), 6.29 (m, 1H), 4.25 (m, 2H), 3.81 (m, 2H), 2.36 (m, 2H). MS (EI ionization) 185 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.O.C([O-])([O-])=O.[K+].[K+].Cl[C:39]([O:41][C:42]([CH3:44])=[CH2:43])=[O:40]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:23][C:39](=[O:40])[O:41][C:42]([CH3:44])=[CH2:43])([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)OC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (48 mg, 0.11 mmol) was stirred in THF (0.5 mL) and H2O (0.05 mL) at room temperature. K2CO3 (100 mg, 0.72 mmol, 6.6 eq) was added followed by the addition of isopropenyl chloroformate (0.030 mL, 0.275 mmol, 2.5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate concentrated to dryness to give crude (R)-prop-1-en-2-yl 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamate as colorless film (60 mg, yield: quantative). LCMS: 4.18 min 409.27 (M-COOisopropenyl-NH3+H) (4 min gradient, MeOH/H2O 0.1% TFA).