Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH:26]4[CH2:27][CH2:28][CH2:29][O:25]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCC1CCCO1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydrofuran-2-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.67 (m, 1H) 1.75-1.89 (m, 2H) 1.89-2.01 (m, 1H) 2.44 (s, 3H) 3.35-3.42 (m, 2H) 3.65 (q, J=7.49 Hz, 1H) 3.80 (q, J=6.82 Hz, 1H) 4.00 (t, J=6.32 Hz, 1H) 7.67 (d, J=7.83 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.18 (br. s., 1H) 8.43 (d, J=6.57 Hz, 2H) 8.82 (t, J=5.31 Hz, 1H) 8.93 (s, 1H) 13.20 (br. s., 1H). MS m/z [M+H]+ 404.2
Reaction SMILES: CO.[OH-].[Na+].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[C:15](=[O:41])[O:16][C:17]([OH:40])([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:18]=3[CH2:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)=[CH:13][C:8]=2[O:7][CH2:6]1>O>[O:5]1[C:9]2[CH:10]=[CH:11][C:12](/[C:14](=[C:18](/[CH2:19][C:20]3[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=3)\[C:17]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)=[O:40])/[C:15]([OH:41])=[O:16])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)/C(Cc2cc(OC)c(OC)c(OC)c2)=C(/C(=O)O)c2ccc3c(c2)OCO3)cc1
Yield: 9 %

Procedure:
To 150 mL methanol to which 3.95 mL 1.00N NaOH had been added was added 3-benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxyphenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 2.00 g (3.95 mmol). The suspension was stirred to give solution and was placed in a 400 mL Pyrex™ beaker and diluted with 150 mL water. The beaker was covered with a quartz evaporating dish (100 mm o.d.×15 mm h., QRD 100; Quartz Scientific, Inc., Fairport Harbor, Ohio). The covered solution was irradiated for 30 hours in an Atlas Sunchex™ simulated sunlight exposure instrument (Xenon arc lamp, set to 0.35 W/m2 at 340 nm, filtered to exclude wavelengths less than 280 nm; Atlas Electric Devices Co., Chicago, Ill.). The mixture was filtered to remove insoluble solids, and the filtrate was evaporated in vacuo to remove methanol. The residual aqueous solution was extracted repeatedly with ethyl ether, while the pH of the aqueous phase was adjusted incrementally between 7.5 and 8 by addition of 3N HCl. The aqueous phase was then acidified to pH 1 with HCl and extracted with ethyl ether. The ether phase was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Addition of petroleum ether gave a crystalline solid which was filtered and dried under vacuum at 40° C., giving a solid melting at 192-193° C., 180 mg. The product was identified by 1H NMR, MS, [M-H]+ =505.3 Da. and microanalysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](F)=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1F
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)cnc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-chloro-2-fluoro-3-nitropyridine (5 g, 28 mmol) in THF (40 mL) was added morpholine (4 mL, 42 mmol). The reaction was stirred at 0° C. for ten min, at rt for 1 h, and refluxed for four h. The reaction was then cooled to rt, taken up in EtOAc, and washed with satd aq. sodium bicarbonate and brine. The organic layer was dried (magnesium sulfate) and concentrated, affording 4-(5-chloro-3-nitropyridin-2-yl)morpholine as a yellow oil. Mass Spectrum (ESI) m/e=244.0 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:11][C:12]1[C:20]2[C:19]([NH2:21])=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]([CH2:22][C:23]2[S:27][C:26]([CH3:28])=[N:25][CH:24]=2)[N:13]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]3[C:45]([C:48](OCC)=[O:49])=[CH:46][N:47]=[C:41]3[CH:40]=2)[CH2:32][CH2:31]1>C1COCC1.O>[I:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[NH:21][C:48]([C:45]2[N:42]3[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[CH:40][C:41]3=[N:47][CH:46]=2)=[O:49])[N:14]([CH2:22][C:23]2[S:27][C:26]([CH3:28])=[N:25][CH:24]=2)[N:13]=1
Reactant: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(Cn2nc(I)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Temperature: 25 °C
Yield: 16.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.24 mL) was added dropwise at ambient temperature and under a nitrogen atmosphere to a solution of 3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-amine (40 mg, 0.108 mmol) in anhydrous THF (3 mL). The resulting brown mixture was added via syringe to a cooled (ice-water bath) solution of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation D; 35.9 mg, 0.108 mmol) in anhydrous THF (3 mL). The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with water, and extracted multiple times with dichloromethane. The dichloromethane extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, 7 N ammonia/MeOH:MeOH:DCM in a 3:7:90 ratio as eluent) to afford the product (11.6 mg) as a tan solid. MS (ES+APCI) m/z=657 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH2:19][CH2:18][C:17]([F:22])([F:21])[F:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(I)cc2)CCNCC1
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CC1(c2ccc(I)cc2)CCN(CCC(F)(F)F)CC1
Temperature: 60 °C
Yield: 97.9 %

Procedure:
To a solution of the crude 4-(4-iodo-phenyl)-piperidine-4-carbonitrile (0.60 g, ˜1.9 mmol) in CH3CN (6 mL) was added (3,3,3-trifluoro)-propyl bromide (1.02 mL, 9.6 mmol, 5 eq.) and K2CO3 (1.33 g, 9.6 mmol, 5 eq.) and the resulting mixture was stirred and heated to 60° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc (20 mL) and washed with H2O (25 mL) and saturated brine (2×25 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude 4-(4-iodo-phenyl)-1-(3,3,3-trifluoro-propyl)-piperidine-4-carbonitrile as a red solid (0.761 g, 1.86 mmol, 98%). 1H NMR (300 MHz, CDCl3): δ 7.83 (dd, 2H), 7.33 (dd, 2H), 3.09 (d, 2H), 2.82 (dd, 2H), 2.66 (td, 2H), 2.45 (m, 2H), 2.18 (m, 4H); MS (ESI): 409.1/410.2 (M +1).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:11][CH2:12][O:13][C:14]([CH:16](P(OCC)(OCC)=O)[CH3:17])=[O:15].C[O-].[Na+]>CN(C=O)C.CO>[OH:10][CH2:9][C:7]1[N:8]=[C:3](/[CH:2]=[C:16](\[CH3:17])/[C:14]([O:13][CH2:12][CH3:11])=[O:15])[CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(CO)n1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
6-hydroxymethylpyridine-2-carbaldehyde (2.95 g) and triethyl 2-phosphonopropionate (5.12 g) were dissolved in 20 mL of dry DMF, and to the solution was added a solution of 1.30 g of sodium methoxide in 10 mL of methanol dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was thrown into ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=1:1) to give 2.42 g of ethyl (E)-3-(6-hydroxymethylpyridin-2-yl)-2-methylacrylate as a colorless oil.
Reaction SMILES: Cl.[CH3:2][C:3]([NH:6][NH2:7])([CH3:5])[CH3:4].CO[CH:10](OC)[CH2:11][CH:12](OC)OC.Cl>C(O)C.CO>[CH3:2][C:3]([N:6]1[CH:12]=[CH:11][CH:10]=[N:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)(C)NN
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)(C)n1cccn1
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of (1,1-dimethylethyl)hydrazine hydrochloride (1.02 g, 8.19 mmol) (Aldrich), 1,1,3,3-tetrakis(methyloxy)propane (1.344 g, 8.19 mmol) (Aldrich) and hydrochloric acid (0.672 ml, 8.19 mmol) in ethanol (10 ml) was heated under reflux. A solution formed. After 16 h the reaction had gone to completion and so was concentrated in vacuo to yield the crude product. This was dissolved in methanol and passed through an aminopropyl cartridge (20 g), eluting with methanol. The combined filtrates were concentrated in vacuo to yield the title compound as a cream gum (210 mg)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@H:4]2[CH2:3]1.CC(C)([O-])C.[K+].Br[C:27]1[CH:32]=[N:31][C:30]([CH:33]2[CH2:35][CH2:34]2)=[CH:29][N:28]=1.CO>O1CCCC1>[CH:33]1([C:30]2[N:31]=[CH:32][C:27]([O:1][C@@H:2]3[CH2:19][N:5]4[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@H:4]4[CH2:3]3)=[N:28][CH:29]=2)[CH2:35][CH2:34]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](O)C[C@@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Reaction time: 0.08 h
Yield: 52 %

Procedure:
tert-Butyl (8S,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (55 mg, 0.203 mmol, Part F) was dissolved in tetrahydrofuran (1.2 mL). Potassium tert-butoxide (0.400 mL, 0.400 mmol, 1.0 M in tetrahydrofuran, 2.0 equivalents) was added at room temperature, and the resulting solution was stirred for five minutes. Then 2-bromo-5-cyclopropylpyrazine (81 mg, 0.407 mmol, 2.0 equivalents) was added as a solution in tetrahydrofuran (0.5 mL). The reaction was allowed to stir at room temperature for 16 hours, at which point it was quenched with 3 drops of saturated sodium bicarbonate. The mixture was concentrated in vacuo, and the residue was loaded onto a 12 g silica column eluted with 100:0 to 95:5 dichloromethane:methanol over 20 minutes to give the titled compound (41 mg, 52% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.02 (d, J=1.0 Hz, 1H), 7.93 (d, J=1.4 Hz, 1H), 5.44 (t, J=4.0 Hz, 1H), 4.45-4.17 (br s, 2H), 4.07-3.98 (m, 2H), 3.67 (dd, J=13.8, 4.1 Hz, 1H), 3.00 (br s, 1H), 2.73-2.66 (m, 3H), 2.49 (dd, J=12.0, 7.6 Hz, 1H), 2.01-1.82 (m, 2H), 1.48 (s, 9H), 1.02-0.89 (m, 4H); MS (ESI+) m/z 333.0 (M-tBu+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)c2cc1OC
Yield: 84 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (100 mg) was dissolved in toluene (10 ml) with heat, 2,4-difluorophenyl isocyanate (120 μl) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and then washed with toluene to obtain 128 mg of the title compound (yield: 84%).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([P:15](OCC)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:14]>C(O)C>[CH2:11]([O:10][C:1]([CH:2]([P:15]([O:16][CH2:17][CH3:18])([CH2:13][CH3:14])=[O:19])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CCOP(=O)(CC)OCC
Reactant: CCOC(=O)/C=C/C(=O)OCC
Solvent: CCO
Product: CCOC(=O)CC(C(=O)OCC)P(=O)(CC)OCC
Yield: 90.9 %

Procedure:
172 g of diethyl fumarate are slowly added at 65°-70° C. under nitrogen to a mixture of 140 g of diethyl ethanephosphonate in 46 g of ethanol. After a further 3 hours the solvent (excess ethanol and diethyl ether) is removed by vacuum distillation; the crude product is obtained in a yield of 285 g with a 95.7% purity, which corresponds to a theoretical yield of 90.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[N-:14]=[N+]=[N-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:13])[NH:14][C:11]=2[CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)NC(=O)CCC2
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Combined 7-Methoxy-1-tetralone (5.0 g, 0.028 mol) with Polyphosphoric acid (80 g, 0.7 mol) in 2-neck 500 ml Flask fit with overhead mechanical stirrer and septa under nitrogen flow. Sodium azide (2.2 g, 0.034 mol) added portionwise over 5 min and the reaction was heated to 55° C. Continue stirring overnight. The mixture was poured into water and a white precipitate ensued. The mixture was filtered and washed with water then hexane and dried over 60 h. 8-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one obtained as a white solid (3.34 g, 62%). MP: 103-104° C.; 1H-NMR (CDCl3, 400 MHz) δ 7.45 (broad s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.72-6.69 (m, 1H), 6.54 (d, J=2.1 Hz, 1H), 3.81 (s, 3H), 2.76 (t, J=7.2 Hz, 2H), 2.38 (t, J=7.3 Hz, 2H), 2.25-2.18 (m, 2H); LC/MS: 192.07 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[Cl:31])[CH2:27][C:26]1([C:35](=[O:36])[NH:34][C:33](=[O:37])[N:32]1[CH3:38])[CH2:25]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:31][C:30]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26]3([C:35](=[O:36])[NH:34][C:33](=[O:37])[N:32]3[CH3:38])[CH2:27]2)=[CH:23][C:22]=1[NH:21][C:8](=[O:10])[CH2:7][N:6]1[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:2]1=[O:1]
Reactant: CN1C(=O)NC(=O)C12Cc1cc(N)c(Cl)cc1C2
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)NC(=O)C12Cc1cc(Cl)c(NC(=O)Cn3c(=O)n(-c4ccccn4)c4ccccc43)cc1C2

Procedure:
A mixture of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (57 mg, 0.211 mmol, described in Intermediate 4), 5′-amino-6′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, enantiomer B (51 mg, 0.192 mmol, described in Intermediate 48), PyBOP (120 mg, 0.230 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.192 mmol) was stirred in DMF (1 mL) at 50° C. for 18 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=517 (M+1). HRMS: m/z=517.1383; calculated m/z=517.1386 for C26H22ClN6O4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:41]([O:40][C:38]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:17]([CH2:16][O:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])[CH2:18]1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccc(OCC2CNc3ccccc3C2)c(NC(=O)OC(C)(C)C)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OCC2Cc3ccccc3N(C(=O)OCc3ccccc3)C2)c(NC(=O)OC(C)(C)C)c1
Reaction time: 24 h

Procedure:
To a stirred solution of [5-Methyl-2-(1,2,3,4-tetrahydro-quinolin-3-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester. To a stirred solution of 2-N-Boc-amino-4-methylphenol (129 mg, 0.35 mmol) in CH2Cl2 (1.5 mL) at 0° C. under nitrogen was added DIEA (61 μL, 0.35 mmol) followed by benzyl chloroformate (50 μL, 0.35 mmol) and DMAP (4 mg, 0.035 mmol). After 24 hours, the reaction was diluted to 30 mL with CH2Cl2 and washed (2×30 mL) with 2N HCl and (2×30 mL) with saturated NaHCO3. The organics were dried (MgSO4), filtered and concentrated to a brown oil, which appeared to be a mixture of product and starting material.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][NH:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:13][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](CO[Si](C)(C)C(C)(C)C)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(c2ccncc2[N+](=O)[O-])C1

Procedure:
Method 1 was followed using cis (+/−)-tert-butyl 5-((tert-butyl-dimethylsilyloxy)methyl)piperidin-3-ylcarbamate and 4-chloro-3-nitropyridine yielding cis (+/−)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-1-(3-nitropyridin-4-yl)-piperidin-3-ylcarbamate. LCMS (m/z): 467.0 (MH+); LC Rt=4.02 min.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8](=O)[CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O=P(Cl)(Cl)[Cl:20].CCN(CC)CC>C(Cl)(Cl)Cl>[Cl:20][C:8]([C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[Cl:1])=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C#N)C(=O)c1scc(C)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=C(Cl)c1scc(C)c1Cl
Temperature: 5 °C
Yield: 66.9 %

Procedure:
To a solution of ethyl 3-(3-chloro-4-methyl-2-thienyl)-2-cyano-3-oxopropanoate (15.40 g, 56.67 mmol, 1 eq.) in 200 ml of CHCl3 was added POCl3 (86.9 g, 566 mmol, 10 eq.). Et3N (14.33 g, 141.6 mmol, 2.5 eq.) was added dropwise with stirring at 5° C., and the mixture was refluxed for 4 h. The mixture was evaporated. After evaporation, the mixture was diluted with DCM (CH2Cl2) and with ice water and was extracted with DCM (CH2Cl2) and washed with brine. The organic layers were combined and dried over MgSO4 before concentration under reduced pressure. The residue was subjected to column chromatography on silica gel to give ethyl 3-chloro-3-(3-chloro-4-methyl-2-thienyl)-2-cyanoacrylate (11 g, 66% yield) as a mixture of 2 isomers
Reaction SMILES: [OH:1][C:2]1C2C(=CC=CC=2)N=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>>[F:25][C:24]1[CH:23]=[C:22]2[C:20](=[CH:19][C:18]=1[F:17])[N:21]=[CH:4][C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:2]2[OH:1]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Reactant: Nc1ccc(F)c(F)c1
Product: CCOC(=O)c1cnc2cc(F)c(F)cc2c1O

Procedure:
The title compound was prepared following the procedure described Step 1 for the synthesis of 2a using 3,4-difluoroaniline instead of aniline. 1H NMR (DMSO-d6) δ (ppm): 1.15 (3H, t, J=7.08 Hz), 4.1 (2H, q, J=7.08 Hz), 7.61 (1H, dd, J=8.30, 2.93 Hz), 7.68 (1H, dd, J=4.63, 9.03 Hz), 7.80 (1H, dd, J=9.27, 2.93 Hz), 8.56 (1H, s). m/z 254.3 (MH+).
Reaction SMILES: ClC1C=CC(S(O[CH2:12][C@@H:13]2[O:19][C@@H:18]3[N:15]([C:16](=[O:20])[CH2:17]3)[CH2:14]2)(=O)=O)=CC=1.[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>C(OCC)(=O)C>[N:21]([CH2:12][C@H:13]1[O:19][C@@H:18]2[N:15]([C:16](=[O:20])[CH2:17]2)[CH2:14]1)=[N+:22]=[N-:23]
Reactant: O=C1C[C@@H]2O[C@@H](COS(=O)(=O)c3ccc(Cl)cc3)CN12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CN2C(=O)C[C@@H]2O1
Temperature: 65 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of (3R,5S)-3-(4-chlorobenzenesulfonyl)oxymethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one (400 mg, 1.26 mmol), sodium azide (212 mg, 3.8 mmol) and DMF (5 ml) was stirred at 65° C. for 2 hrs. The resulting mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as eluent and 210 mg of (3S,5S)-3-azidomethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].O[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[O:14][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of 3-nitro-5-(trifluoromethyl)phenol (0.583 g, 2.82 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.850 g, 4.22 mmol), PPh3 (1.11 g, 4.22 mmol), DIAD (0.67 mL, 4.22 rnmol), and benzene (8.7 mL) was allowed to stir at rt until reaction was judged to be complete. The reaction mixture was concentrated. The resulting off-white solid was purified by column chromatography to give tert-butyl 4-(3-nitro-5-(trifluoromethyl) -phenoxy)piperidine-1-carboxylate (0.750 g, 66%). 1H NMR (400 MHz, CD3OD) δ: 8.05-7.97 (m, 2H), 7.64 (s, 1H), 4.84-4.78 (m, 1H), 3.75-3.69 (m, 2H), 3.42-3.35 (m, 2H), 2.03-1.96 (m, 2H), 1.77-1.69 (m, 2H), and 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH3:17])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:14]=[CH:15][C:16]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1OCc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(C)c(OCc2ccccc2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
Under a nitrogen atmosphere, to a solution of 3-(benzyloxy)-4-methylbenzaldehyde (2.50 g) in toluene (50 mL) was added ethyl (triphenylphosphoranylidene)acetate (4.20 g), and the mixture was stirred at 70° C. for 15 hr. The reaction mixture was concentrated, diethyl ether (100 mL) was added, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.50 g) as a colorless oil. This compound was used for the next step without further purification.