Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14].CCN(C(C)C)C(C)C.[C:24]([C:26]1[C:27]([NH:36][C@@H:37]2[CH2:40][C@H:39]([C:41]([NH2:43])=[O:42])[C:38]2([CH3:45])[CH3:44])=[N:28][C:29](S(C)(=O)=O)=[N:30][CH:31]=1)#[N:25]>O>[C:24]([C:26]1[C:27]([NH:36][C@@H:37]2[CH2:40][C@H:39]([C:41]([NH2:43])=[O:42])[C:38]2([CH3:45])[CH3:44])=[N:28][C:29]([NH:1][CH2:2][CH2:3][CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH3:13])[C:5]2=[O:14])=[N:30][CH:31]=1)#[N:25]
Reactant: CC1(C)[C@@H](C(N)=O)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C#N
Reactant: CN1C(=O)C(CCN)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1C(=O)C(CCNc2ncc(C#N)c(N[C@@H]3C[C@H](C(N)=O)C3(C)C)n2)c2ccccc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
3-(2-Aminoethyl)-1-methylindolin-2-one (231 mg, 1.02 mmol) and DIEA (197 mg, 1.53 mmol) were added to the reaction mixture of (1S,3R)-3-(5-cyano-2-(methylsulfonyl)pyrimidin-4-ylamino)-2,2-dimethylcyclobutanecarboxamide (prepared as described above) at 0° C. and stirred at 90° C. for 1 h. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford the crude product, which was purified by standard methods to afford the title compound (17.7 mg, 0.041 mmol, 8% yield over two steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.12-8.01 (m, 1H), 7.42-7.33 (m, 2H), 7.17-6.93 (m, 2H), 4.36-4.09 (m, 1H), 3.62-3.60 (m, 2H), 3.23-3.13 (m, 4H), 2.60-2.25 (m, 5H), 1.39-0.88 (m, 6H). MS (ESI) m/z 433.8 [M+H]+.
Reaction SMILES: BrC1C(C)=CC(C)=CC=1C.[Li]C(C)(C)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CON(C)[C:27]([CH:29]1[CH2:33][CH:32]=[CH:31][CH2:30]1)=[O:28]>C1COCC1.CCCCC>[CH2:32]1[CH2:31][CH:30]=[C:29]([C:27]([C:23]2[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:28])[CH2:33]1
Reactant: CON(C)C(=O)C1CC=CC1
Reactant: COc1ccccn1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ncccc1C(=O)C1=CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Bromo-2,4,6-trimethylbenzene (16.9 g, 85 mmol) was stirred in anhydrous THF (340 mL) at −78° C. under nitrogen and treated with t-BuLi (100 mL of 1.7 M soln. in pentane, 170 mmol) dropwise via an addition funnel over 30 min. A yellow slurry forms and is stirred 1 h. To this was added 2-methoxypyridine (8.45 g, 77.3 mmol) in anhydrous THF (10 mL) over 5 min. The mixture was allowed to warm to 0° C. and stirred for 1 h, then at ambient temperature for 1 h, then recooled to −78° C. and treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (12.4 g, 80 mmol) in anhydrous THF (20 mL) over 5 min. The resulting mixture was stirred 18 h (the bath evaporated and the mixture achieved ambient temperatures). The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) and stirred 20 min. The mixture was extracted with Et2O (3×100 mL). The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4, filtered and concentrated to an oil (26 g). Purification by chromatography on silica gel eluting first with hexane to remove mesitylene followed by 10% then 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude). (TLC 10% Et2O/hexanes Rf 0.36); 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J=4.9, 2.0 Hz, 1H), 8.02 (m, 1H), 6.97 (m, 1H), 5.65 (s, 2H), 4.03 (s, 3H), 4.17, (m, 1H), 2.67 (m, 4H); GCMS m/z 203 (M)+.
Reaction SMILES: O[N:2]=[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])[NH2:4]>CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])(=[NH:2])[NH2:4]
Reactant: COC(=O)c1ccc(C)c(C(N)=NO)c1
Solvent: CO
Product: COC(=O)c1ccc(C)c(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A round-bottom flask, containing a solution of methyl 3-(N′-hydroxycarbamimidoyl)-4-methylbenzoate (compound 1.8, 8 g, 36.50 mmol, 1.00 equiv, 95%) in methanol (150 mL) was purged with nitrogen gas. To the solution was added palladium on carbon (9 g, 10%, 60% water) and the flask was then further purged with nitrogen gas. The atmosphere was then changed to hydrogen and the mixture was stirred overnight at 25° C. under a balloon. After purging the system with nitrogen, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to yield 4 g (54%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)C.[CH2:13]([O:15]CC)C>C1(C)C=CC=CC=1.C(O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:13]=[O:15])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CCOCC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC[Mg]Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(Cl)cc1O
Temperature: 25 °C

Procedure:
Modification of a procedure described by G. Casiraghi et al., (J. Chem. Soc., Perkin Transac. I., 1978, 318), was utilized in the preparation of substituted salicylaldehydes. To a mixture of 26 g of 3-chlorophenol dissolved in 200 mL, of toluene at 10° C. was added dropwise 100 mL, of a 2M solution of ethylmagnesium chloride in diethyl ether. The ether was distilled off and the reaction mixture was cooled to room temperature and 26.0 g of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was added followed by 15.0 g of paraformaldehyde. The reaction mixture was heated at 70° C. for 18 h, cooled to 10° C. and a solution of 20 mL of concentrated HCl in 100 g of ice was added followed by 200 mL of hexane. The organic phase was separated and washed twice with 100 mL of water, once with 100 mL of brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum to afford a viscous oil. This was taken up in 150 mL of ethanol and a solution of 15.0 g of copper (II) acetate dissolved in 150 mL of H2O was added dropwise. The resulting precipitate was filtered, washed with water and then with ether and added to a solution of 200 mL of ether and 20 mL of concentrated H2SO4 in 100 g of ice. The mixture was stirred until ail solids were dissolved, 100 mL of hexane was added, and the organics were washed with 100 mL of H2O, then 100 mL of brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum to afford 15.0 g of a yellow solid, mp 47°-48° C. 1H NMR (CDCl3) δ6.98 (d, 1H), 7.01 (s, 1H), 7.50 (d, 1H), 9.85 (s, 1H), 11.18 (s, 1H). IR (Nujol) 3300-2800, 1670 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]3=[O:21])[CH:11]=2)[N:6]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:4][C:2]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][S:40]([CH3:39])(=[O:42])=[O:41])[O:16][C:15]3=[O:21])[CH:11]=2)[N:6]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])([CH3:1])[CH3:3]
Reactant: CC(C)(C)C1Cc2cc(N3C[C@H](CO)OC3=O)ccc2N1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C1Cc2cc(N3C[C@H](COS(C)(=O)=O)OC3=O)ccc2N1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
The alcohol prepared in Step 5 (11.3 g, 26.6 mmol) is dissolved in CH2Cl2 (125 ml) with triethylamine (11.0 ml, 79 mmol) and cooled to 0°. Methanesulfonylchloride (2.4 ml, 31 mmol) is added and the reaction stirred for 2 hours. Extra CH2Cl2 (100 ml) is added and the solution washed with water (100 ml) and brine (50 ml) then dried (MgSO4). Evaporation gave a gum which is chromatographed over silica gel (500 g) eluting with 25-60% ethyl acetate-hexane. The product is obtained as a white foam (10.95 g, 82%): HRMS (FAB): Calcd for m+Na=525.1672; Found: 525.1671. Anal: Calcd. for C25H30N2O7S: C, 59.74; H, 6.02; N, 5.57. Found: C, 59.44; H, 6.07; N, 5.49.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:21]2[CH2:20][CH2:19][N:18]([CH3:22])[CH2:17][CH2:16][C:15]=2[C:14]([N+:23]([O-:25])=[O:24])=[CH:13][CH:12]=1>CN(C)C=O>[CH3:22][N:18]1[CH2:17][CH2:16][C:15]2[C:14]([N+:23]([O-:25])=[O:24])=[CH:13][CH:12]=[C:11]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:21]=2[CH2:20][CH2:19]1
Reactant: CN1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(Sc3ccccc3)ccc([N+](=O)[O-])c2CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 11.0 g. (0.1 mole) of thiophenol in 200 ml. of dimethylformamide at 0°-10° C., under an atmosphere of nitrogen, is added cautiously, in portions, 4.65 g. (0.11 mole) of a 57% dispersion of sodium hydride in mineral oil. The resulting solution is stirred for 15 minutes at 25° C. and then a solution of 24.1 g. (0.1 mole) of 6-chloro-3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine in 50 ml. of dimethylformamide is added dropwise. The reaction mixture is heated at 100° C. for 2 hours, then it is cooled to 25° C. and poured into ice/water. The resulting solid is filtered, air-dried and recrystallized from ethyl acetate-hexane to give 3-methyl-9-nitro-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([OH:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20]([CH2:22]P(OC)(OC)=O)=[O:21]>O>[CH3:18][O:19][C:20](=[O:21])/[CH:22]=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[C:1]([OH:3])=[O:2]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)/C=C/c1cccc(C(=O)O)c1
Temperature: 2.5 °C
Reaction time: 17 h

Procedure:
3-Carboxybenzaldehyde (25 g, 0.167 mol) and K2CO3 (69 g, 0.499 mol) were added to water (250 mL) and cooled to 0-5° C. Trimethyl phosphonoacetate (32.3 mL, 0.2 mol) was charged dropwise maintaining the reaction temperature below 15° C. The reaction was warmed and stirred at RT for 17 h. The mixture was acidified to pH˜1, filtered and dried in vacuo to afford the product as an off-white solid (37.25 g, >100%—slightly wet). 1H NMR (300 MHz, CD3OD) δ: 8.23 (1H, s), 8.06 (1H, d, J=7.8 Hz), 7.86 (1H, d, J=7.5 Hz), 7.75 (1H, d, J=15.9 Hz), 6.61 (1H, d, J=16.2 Hz), 7.54 (1H, t), 3.81 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([CH3:21])=[C:8]([C:18](O)=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)[N:32]1[CH2:36]CC[CH2:33]1.C(N(CC)C(C)C)(C)C.CNC>CN(C=O)C>[CH3:33][N:32]([CH3:36])[C:18]([C:8]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5]([C:6](=[O:22])[C:7]=1[CH3:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)=[O:19]
Reactant: Cc1c(C(=O)O)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N(C)C)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110 %

Procedure:
In a 50 mL round bottom flask, 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid (0.5 g, 1.60 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 1.11 g, 2.39 mmol) and N,N-diisopropylethylamine (1.11 mL, 6.37 mmol) were added to anhydrous DMF (5.0 mL). The mixture was stirred at room temperature for 30 min. Dimethylamine (2M in THF, 1.6 mL, 3.2 mmol) was added and the reaction mixture was stirred at room temperature for 48 hr. The mixture was concentrated to dryness and the crude was purified by flash chromatography using 3:2 hexane-ethyl acetate to afford 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide (600 mg, >100% yield). MS calcd for C19H17ClN2O2 [(M+H)+] 341, obsd 341.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccncc6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.08 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1)[CH3:2].Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:7]([F:12])[CH:6]=1)[CH3:2]
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCN2CCOCC2)c(F)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
3-Fluoro-4-hydroxybenzoic acid ethyl ester (0.20 g, 1.1 mmol) and N-(2-chloroethyl)morpholine (0.22 g, 1.2 mmol) were dissolved in dry DMF (10 ml). Potassium carbonate (1.88 g, 5 mmol) was added and the turbid reaction mixture was stirred overnight at 40° C. under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue followed by washing with NaHCO3 (½ sat., 3×), water, brine, dried (MgSO4), filtered. The crude oil was purified over silica gel (CH2Cl2/MeOH 39:1): colorless oil 0.16 g (49%);
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1>CCOCC>[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([S:2]([OH:5])(=[O:3])=[O:1])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: O=S(=O)(O)O
Reactant: CN1CCCc2ccccc21
Solvent: CCOCC
Product: CN1CCCc2cc(S(=O)(=O)O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
A solution of H2SO4 (6 g, 60.00 mmol) in ether (40 mL) was added dropwise to a solution of 1-methyl-1,2,3,4-tetrahydroquinoline (9 g, 61.14 mmol) in diethylether (10 mL) at 5° C. The resulting solution was maintained at room temperature for 30 minutes, then under vacuum, with stirring, for an additional 3 hours at 170° C. The resulting mixture was washed with methanol (1×100 mL) and filtered to afford 5 g (34%) of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of 3-(4-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6 mmol) and Pd/C (1.65 g) in MeOH (200 mL) was stirred under 40 psi of H2 at RT for 2 h. After filtration over Celite® and removal of the solvent, 14 g of 3-(4-aminophenyl)propionic acid ethyl ester was obtained. 1H NMR (400 MHz, CDCl3): δ 6.98 (d, J=8.0 Hz, 2H), 6.61 (d, J=8.4 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 2.84 (t, J=8.0 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H). MS (ESI): m/z: 194 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](=[O:21])[NH:6][C:7]([CH3:20])=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].Br[CH2:23]/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[Br:3][C:4]1[C:5](=[O:21])[N:6]([CH2:23]/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])[C:7]([CH3:20])=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: COC(=O)/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/Cn1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of NaH (277 mg, 11 mmol) in anhydrous THF (30 ml), which was cooled to 0° C., was slowly added 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (3.3 g, 10 mmol). The resulting slurry was stirred for 15 min, after which methyl 4-bromocrotonate (1.4 ml, 12 mmol) was added to the reaction. The ice bath was removed and the reaction was heated to reflux for 16 h. The reaction was quenched by the addition of 1N NH4Cl. The layers were separated and the aqueous layer was extracted with CH2Cl2 (5×). The organics were combined, dried, and concentrated in vacuo. The crude yellowish material was then triturated with Et2O to give, after filtration and drying, 1.8 g (43%) of a white solid. 1H-NMR (DMSOd6/300 MHz) δ 7.65 (app q, J=8.7 hz, 1H), 7.36 (app dt, J=12.0, 3.0 hz, 1H); 7.17 (dt, J=8.4, 1.8 Hz, 1H); 6.94 (dt, J=15.9, 4.5 Hz, 1H); 6.57 (s, 1H), 5.52 (d, J=15.9 Hz, 1H), 5.29 (s, 2H), 4.84 (m, 2H), 3.63 (s, 3H), 2.33 (s, 3H). ES-HRMS m/z 428.0301 (M+H calcd for C18H17BrF2NO4=428.0310).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=5)=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([CH:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N+:38]=5[O-:53])=[CH:34][CH:35]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)CCS3(=O)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)CCS3(=O)=O)cc1
Yield: 41.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(2-pyridyl)methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 152) (157 mg) in dichloromethane (10 ml) was added at 0° C. 3-chloroperbenzoic acid (70%, 98 mg), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:9→1:4) to give pale yellow crystals of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 153) (67 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([C:11]1[CH:77]=[CH:76][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:68]C(OC(C)(C)C)=O)[C:24]([O:26][C@H:27]2[C@@H:31]([OH:32])[C@H:30]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[NH2:42])[O:29][C@H:28]2[CH2:43][O:44][P:45]([O:48][C@H:49]2[CH2:53][C@H:52]([N:54]3[CH:59]=[CH:58][C:57]([NH2:60])=[N:56][C:55]3=[O:61])[O:51][C@@H:50]2[CH2:62][O:63][P:64]([OH:67])([OH:66])=[O:65])([OH:47])=[O:46])=[O:25])=[O:18])=[CH:13][CH:12]=1)=[N+:9]=[N-:10]>ClCCl>[NH2:68][C@H:23]([CH2:22][CH2:21][CH2:20][NH:19][C:17]([O:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([N:8]=[N+:9]=[N-:10])=[CH:77][CH:76]=1)=[O:18])[C:24]([O:26][C@H:27]1[C@@H:31]([OH:32])[C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH2:42])[O:29][C@H:28]1[CH2:43][O:44][P:45]([O:48][C@H:49]1[CH2:53][C@H:52]([N:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[N:56][C:55]2=[O:61])[O:51][C@@H:50]1[CH2:62][O:63][P:64]([OH:67])([OH:66])=[O:65])([OH:47])=[O:46])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(COC(=O)NCCC[C@@H](N)C(=O)O[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@H]2COP(=O)(O)O[C@H]2C[C@H](n3ccc(N)nc3=O)O[C@@H]2COP(=O)(O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.4 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy) (hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk59) (22.7 mg, 0.022 mmol) in dichloromethane (0.4 mL), and the mixture was stirred at room temperature for 20 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-((((4-azidobenzyl)oxy)carbonyl)amino)pentanoate (Orn(Acbz)-pdCpA) (Compound tk60) (4.3 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.[NH4+].[Cl-].C(Cl)Cl>C(Cl)Cl.CCO.O.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][S:12][C:13]2[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(O)nc(SCc2ccc([N+](=O)[O-])cc2Cl)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(O)nc(SCc2ccc(N)cc2Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
2-{[(2-chloro-4-nitrophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (282 mg, 1.0 mmol) was dissolved in DCM/EtOH/H2O (20 mL/20 mL/10 mL). Iron (550 mg, 10 mmol) and NH4Cl (540 mg, 10 mmol) were added. The mixture was stirred at room temperature for 3 hours. DCM (200 mL) was added to extract the product. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by CombiFlash (0 to 8% MeOH/DCM) to provide the title compound as a yellow solid (100 mg, 35% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.37 (s, 2H), 5.95 (br, 1H), 6.65 (d, 1H), 6.92 (s, 1H), 7.38 (d, 1H); M+ 282.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH:5]([C:7]1[N:8]=[N:9][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([CH3:13])[N:12]=1)[NH2:6]>C(Cl)Cl.C(OC(C)C)(C)C>[CH3:13][C:11]1[N:12]=[C:7]([NH:5][NH:6][C:3]([NH:2][CH3:1])=[O:4])[N:8]=[N:9][C:10]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN=C=O
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CNC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Yield: 98.7 %

Procedure:
A solution of methyl isocyanate (0.92 g) in methylene chloride (3 ml) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3 g) in methylene chloride (20 ml) at room temperature. The reaction mixture was diluted with diisopropyl ether (30 ml). The resultant precipitates were collected by filtration to give a solid of 5-methyl-3-(4-methylsemicarbazido)-6-phenyl-1,2,4-triazine (3.8 g).