Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15](O)=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][C@H:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][OH:27]>>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([NH:24][C@H:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][OH:27])=[O:16])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Product: O=C(N[C@@H](CO)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and commercial (2R)-2-amino-2-phenylethanol, the title compound was obtained in 98% purity by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Na]>>[CH2:16]([O:15][C:13](=[O:14])/[C:12](/[OH:18])=[CH:10]/[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:11])[CH3:17]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for example 11 a], 1-(3,4-dichloro-phenyl)-ethanone was reacted with diethyl oxalate in the presence of metallic sodium to give (Z)-4-(3,4-dichloro-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester as off-white solid.
Reaction SMILES: [OH:1][C:2]1([CH2:20][CH2:21]O)[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49]>ClCCl>[Br:49][CH2:21][CH2:20][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(N2CCC(O)(CCO)CC2)cc1C(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(N2CCC(O)(CCBr)CC2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a solution of compound 27a (687 mg, 2.09 mmol) in anhydrous dichloromethane (10 mL) at 0° C. under argon were added potassium carbonate (1.16 g, 8.39 mmol), triphenylphosphine (1.1 g, 4.19 mmol) and carbon tetrabromide (1.39 g, 4.19 mmol). The solution was allowed to return to room temperature and stirred for 1 hr. The resulting solution was diluted with dichloromethane (50 mL) and filtered on a cotton plug. Purification of the resulting crude product by flash chromatography using ethyl acetate/hexane (2:8) gave the desired compound 28a (470 mg, 57%). 1H NMR (400 MHz, MeOD) δ: 1.72 (m, 4H), 2.11 (m, 2H), 3.37 (m, 2H), 3.54 (m, 2H), 3.77 (m, 2H), 7.18 (dd, 1H, J1=6.26 Hz, J2=2.62 Hz), 7.27 (d, 1H, J=2.07 Hz), 7.69 (d, 1H, J=8.83 Hz).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=1[CH3:20])=[O:7]>C(O)C>[Cl:3][C:4]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=1[CH3:20])=[O:7]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2Cl)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 89.1 %

Procedure:
A solution of 2.38 mL (1.1eq) of 1N NaOH was added dropwise to a refluxing solution of 76.89 g (0.217 mole) of ethyl 5-(2,4-dichlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate (3) in 750 mL absolute ethanol. The mixture was heated under reflux for 20 minutes. The reaction was poured into 3N HCl/ice and extracted three times with diethyl ether. The organics were washed with water (twice), brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a tan oil which was crystallized from acetonitrile to give 63.05 g of product: mp 140-143° C.; mass spectrum (Cl—CH4) m/z=326 (M+1); NMR 300 MHz (Me2SO-d6) d 7.8 (s, 1 H); 7.6 (m, 1 H); 7.4 (m, 1 H); 6.0 (s, 1 H); 3.8 (s, 3 H); 3.75 (s, 2 H); 1.45 (s, 3 H). Anal Calcd for C15H13Cl2NO3: C, 55.24; H, 4.02; N, 4.29. Found: C, 55.47; H, 3.84; N, 4.29.
Reaction SMILES: [Na+].[C:2]([S-:10])(=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.II>>[C:2]([S:10][S:10][C:2](=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=C([S-])c1ccccc1
Agent: II
Agent: [Na+]
Product: S=C(SSC(=S)c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by oxidizing an aqueous solution of dithiobenzoic acid sodium salt with a mild oxidizing agent, e.g. an aqueous solution of iodine.
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8]([CH3:25])=[C:9]([CH3:24])[C:10]([OH:23])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[C:30]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[S:1]1[C:5]([CH2:6][C:7]2[C:8]([CH3:25])=[C:9]([CH3:24])[C:10]([O:23][CH3:30])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: Cc1c(Cc2cc3ccccc3s2)cc(C2OC(CO)CC(O)C2O)c(O)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C2OC(CO)CC(O)C2O)cc(Cc2cc3ccccc3s2)c(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A 20 ml vial was charged with 22 (38.2 mg, 0.09 mmol) and Cs2CO3 (45 mg, 0.14 mmol) and to which was added 1 ml of dry acetone, followed by methyl iodide (12 μL, 0.18 mmol). The resulting mixture was stirred at room temperature for 16 h and the solid was filtered of, washed with acetone. The solvent was evaporated and the crude residue was purified by flash column chromatography on silica gel (4 g column, EtOAc/heptane: 0>>>100%) to afford 28.4 mg (71.8%) of 23 as a white solid. 1H NMR (CD3OD) δ 7.71 (d, J=7.58 Hz, 1H), 7.60 (d, J=7.58 Hz, 1H), 7.14-7.28 (3H), 6.87 (s, 1H), 4.52 (d, J=9.60 Hz, 1H), 4.22 (s, 2H), 3.76 (s, 3H), 3.65-3.75 (m, 2H), 3.49-3.59 (m, 3H), 2.23 (s, 3H), 2.20 (s, 3H), 2.02 (m, 1H), 1.50 (q, J=11.62 Hz, 1H). MS (ES) 451.1 (M+Na+).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH2:19][OH:20])[CH2:16]3)=[CH:12][C:10]=2[N:11]=1.[BrH:22].CN(C=O)C>CCOC(C)=O>[Br:22][C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH2:19][OH:20])[CH2:16]3)=[CH:12][C:10]=2[N:11]=1
Reactant: Br
Reactant: Nc1nc2cc3c(cc2[n+]([O-])n1)CC(CO)C3
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [O-][n+]1nc(Br)nc2cc3c(cc21)CC(CO)C3
Temperature: 20 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
NaNO2 (23 mg, 0.33 mmol) was added to a stirred mixture of amine 124 (77 mg, 0.33 mmol), HBr (48%, 2 mL) and DMF (2 mL) at 20° C. and the mixture stirred at 20° C. for 1 h. CuBr (57 mg, 0.40 mmol) was added and the reaction mixture stirred at 20° C. for 90 min. The mixture was diluted with EtOAc (50 mL) and washed with water (3×20 mL). The organic solution was dried and the solvent evaporated to give an orange oil, that was purified by chromatography, eluting with a gradient (0-30%) of EtOAc/pet. ether, to give bromide 125 (40 mg, 41%) as an oil: 1H NMR δ 8.19 (s, 1H, H-9), 7.74 (s, 1H, H-5), 3.72 (d, J=6.5 Hz, 2H, CH2O), 3.22-3.33 (m, 2H, CH2), 2.96-3.08 (m, 2H, CH2), 2.80-2.89 (m, 1H, CH), OH not observed; HRMS calcd for C11H1079BrN3O2 (M+) m/z 294.9956, found 294.9949; calcd for C11H1081BrN3O2 (M+) m/z 296.9936, found 296.9943.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=1)([O-:3])=[O:2].CN(C1C=CC=CN=1)C.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH:39]2[CH2:38][CH2:37][N:36]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:41][CH2:40]2)=[O:9])=[C:6]([NH:13][C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])[CH:5]=1)([O-:3])=[O:2]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1NC(=O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
0.39 g (0.0014 mol) of 4-nitro-2-trifluoroacetamido-benzoic acid was dissolved in 7 ml of dimethylformamide, treated with 0.0855 g (0.0007 mol) of dimethylaminopyridine and cooled to 0°. 0.268 g (0.0014 mol) of 1-benzyl-4-hydroxy-piperidine and 0.295 g (0.00154 mol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the mixture was stirred at 0° for 2 hrs. Thereafter, the mixture was warmed to room temperature. The mixture was stirred at room temperature for 48 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate and washed with semi-saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 0.28 g (44%) of 1-benzyl-piperidin-4-yl 4-nitro-2-trifluoroacetamido-benzoate was obtained as a yellow oil. MS: me/e=452 (C21H21F3N3O5 +).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1(=[N:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.[C:14](Cl)(=[N:21][OH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(Cl)Cl>[C:15]1([C:14]2[N:12]([NH2:13])[C:7]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[O:22][N:21]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NN=C1CCCC1
Reactant: ON=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: NN1C(c2ccccc2)=NOC12CCCC2
Temperature: 25 °C
Yield: 50341.3 %

Procedure:
A round bottom flask was charged with a solution of 20 g of K2CO3 in 50 mL of water and cooled in an ice bath. Cyclopentylidene-hydrazine (7.9 g, 80 mmol) in 25 mL of CH2Cl2 was added, followed by a drop-wise addition of benzohydroximoyl chloride (5 g, 0.032 mmol) in 25 mL of CH2Cl2 over a period of 15 minutes. The mixture was stirred for several days, and allowed to warm to room temperature. Water (50 mL) and CH2Cl2 (50 mL) were added and the phases were separated. The organic layer was washed twice with 50 mL of water, dried over MgSO4, and filtered. The solvent was removed in vacuo, leaving 9 g of a waxy solid. Crystallization from ethyl acetate/hexane provided 3.5 g (50%) of 3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-ylamine after drying. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.72 ((m, 2H), 7.46 (m, 3H), 3.54 (s, 2H), 2.1 (m, 2H), 2.0 (m, 2H), 1.85 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][S:18][C:19]3[CH:24]=[C:23]([Br:25])[C:22]([NH2:26])=[C:21]([Br:27])[CH:20]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:34]O>>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][S:18]([C:19]3[CH:24]=[C:23]([Br:25])[C:22]([NH2:26])=[C:21]([Br:27])[CH:20]=3)=[O:34])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCSc1cc(Br)c(N)c(Br)c1)CC2
Reactant: OO
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCS(=O)c1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[2-(4-amino-3,5-dibromophenylthio)-ethyl]-methylamine and 30% hydrogen peroxide (in glacial acetic acid) analogously to Example 4.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:20]1([C:25]2[N:30]=[CH:29][C:28]([CH2:31][CH:32]=O)=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1>>[N:20]1([C:25]2[N:30]=[CH:29][C:28]([CH2:31][CH2:32][N:5]3[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]5[C:13](=[CH:18][CH:19]=4)[C:14](=[O:17])[O:15][CH2:16]5)[CH2:3][CH2:4]3)=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1
Reactant: O=CCc1ccc(-n2cnnn2)nc1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: Cl
Product: O=C1OCc2cc(CCN3CCN(CCc4ccc(-n5cnnn5)nc4)CC3)ccc21

Procedure:
5-[2-[4-[2-[6-(Tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetaldehyde. LC-MS (IE, m/z): 392.0 [(M+1)+−28]. (0.91 μM)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>C(C(C)=O)C>[CH2:12]([NH:16][C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1)=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN=C=O
Reactant: O=c1oc2ccc(O)cc2s1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCCCNC(=O)Oc1ccc2oc(=O)sc2c1

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (14.3 grams) was mixed with n-butyl isocyanate (8.85 grams) in 175 milliliters of methyl ethyl ketone in the presence of 1.3 milliliters of triethylamine. The reaction mixture was then heated at reflux temperature for 2.5 hours. The solvent was then removed from the reaction mixture by evaporation in vacuo. The off-white solid residue was recrystallized from toluene and the purified product, 5-(n-butylcarbamoyloxy)-1,3-benzoxathiol-2-one was obtained, as a white, fluffy, crystalline solid with a melting point of 99°-100° C. Elemental analysis calculated for C12H13NO4S (percent): carbon--53.92; hydrogen--4.90; nitrogen--5.24. Found: carbon--54.1; hydrogen--4.89; nitrogen--5.27.
Reaction SMILES: [CH3:1][C:2]1([CH:12]([C:18]#[N:19])C(OCC)=O)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[Li+].[Cl-].O>CS(C)=O>[C:18]([CH2:12][C:2]1([CH3:1])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)#[N:19]
Reactant: CCOC(=O)C(C#N)C1(C)CC(C)(C)CC(C)(C)C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(C)(C)CC(C)(CC#N)C1
Temperature: 155 °C
Yield: 92.3 %

Procedure:
The mixture of ethyl (1,3,3,5,5-pentamethylcyclohexyl)cyanoacetate (17) (1 g, 3,7 mmol), LiCl (0.05 g) and water (0.15 ml) in DMSO (2.5 ml) was heated at 150-160° C. for 4 h. Solution was poured into water (70 ml) and extracted with ether (4*20 ml). Ether was washed with saline (2*50 ml), dried over Na2SO4, filtered and evaporated. Crude product was purified on silica gel column, eluting with a petroleum ether--ethyl acetate mixture (20:1) to give 0.66 g (94%) of 18 as an oil. 1H NMR (CDCl3, TMS) δ: 0.98 (9H, s, 3,5-CH3eq and 1-CH3); 1.02 (6H, s, 3,5-CH3ax); 1.21 (3H, s, ring protons); 1.31 (3H, s, ring protons) and 2.31 ppm (2H, s, CH2CN). IR (neat) νCN =2242 cm1.
Reaction SMILES: CO.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=O)[CH3:13])[N:7]=1)(=O)[CH3:4].[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)=O>[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[N:18]=[C:3]([C:6]1[N:7]=[C:8]([C:12](=[N:18][C:17]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]=2[CH3:15])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4]
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CO
Solvent: O=CO
Product: CC(=Nc1ccc(C)cc1C)c1cccc(C(C)=Nc2ccc(C)cc2C)n1
Reaction time: 1 h
Yield: 43.3 %

Procedure:
100 ml of methanol, 1.63 g of 2,6-diacetylpyridine (molecular weight 163.18; 10 mmols), and 4.84 g of 2,4-dimethylaniline (molecular weight 121.18; 40 mmols) were put into a 300 ml flask, and thoroughly stirred to prepare a homogeneous mixture. 0.6 ml of formic acid was added to this, and further the mixture was stirred for 12 hours to make the compounds reacted completely. The reaction mixture was left at −78° C. for 1 hour, and the resulting pale yellow crystal was taken out through filtration, washed with methanol, and dried under reduced pressure. Its 1H-NMR spectrum was assigned as the intended product, 2,6-diacetylpyridine-bis(2,4-dimethylphenylimine) (molecular weight 369.52; 1.60 g, 4.33 mmols, yield 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][N:10]=2)[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: BrCc1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (99) and benzyl bromide according to General Procedure B. Yield 136 mg (18%), MP 216° C.; 1H-NMR (DMSO-d6): δ 3.72 (m, 4H), 3.95 (m, 4H), 5.53 (s, 2H), 6.66 (dd, J=2.0, 3.6 Hz, 1H), 7.08 (d, J=3.6 Hz, 1H), 7.21-7.28 (m, 5H), 7.89 (d, J=2.0 Hz, 1H), 8.18 (dd, J=2.8, 9.2 Hz, 1H), 8.77 (d, J=2.8 Hz, 1H); EIMS: 458 (M+1). Anal. (C25H20FN5O3) C, H, N.
Reaction SMILES: [Si:1]([O:8][C:9]([C:11]([F:27])([F:26])[C@H:12]([C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])[OH:13])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[F:34][C:35]([F:48])([F:47])[S:36]([O:39]S(C(F)(F)F)(=O)=O)(=[O:38])=[O:37]>ClCCl>[Si:1]([O:8][C:9]([C:11]([F:26])([F:27])[C@:12]([O:39][S:36]([C:35]([F:48])([F:47])[F:34])(=[O:38])=[O:37])([C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])[OH:13])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@@H](O)[C@H](O)C(O)C(=O)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@](O)(OS(=O)(=O)C(F)(F)F)[C@H](O)C(O)C(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 85.9 %

Procedure:
To a solution of 2.3 gm (5.9 mMol) 1-t-butyldimethylsilyloxy-5-benzoyl-2-deoxy-2,2-difluoroxylose in dichloromethane (100 mL) were added 7.2 mL (88.5 mMol) pyridine and the reaction mixture was cooled to -20° C. To this was then added a solution of 1.5 mL (8.9 mMol) trifluoromethanesulfonic anhydride in dichloromethane (20 mL) dropwise at such a rate as to maintain the temperature between -5° and -20° C. The reaction mixture was stirred for 40 minutes at -15° C. The reaction mixture was then allowed to warm to room temperature and was washed with saturated aqueous sodium bicarbonate. The remaining organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 2.8 gm (90%) of the desired compound as a yellow oil. FD-MS: m/e=463(M-57, loss of t-butyl).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].CS(O[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][C:31]=1[CH:40]1[CH2:42][CH2:41]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=[CH:32][C:31]=3[CH:40]3[CH2:41][CH2:42]3)[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCc1c(C2CC2)cnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (400 mg, 1.26 mmol) in DMF (3.16 ml) was added (3-cyclopropylquinolin-4-yl)methyl methanesulfonate (421 mg, 1.52 mmol) and cesium carbonate (1.24 g, 3.79 mmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (498 mg, 79%) as an off-white solid. MS m/z 498 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:60]([N:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1)([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:70]2[CH2:69][CH2:68][N:67]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:72][CH2:71]2)=[O:28])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(O)cc3c2[C@]2(C)CC[C@H]4C(C)(C)CCC[C@]4(C)[C@H]2CS3(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxyl ic acid (65) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methyl morpholine (0.1 mL, 1.5 mmol) and 1-Boc-piperazine (0.27 g, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1) to give tert-butyl 4-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]carbonyl}piperazine-1-carboxylate (99) (0.13 g, 46%) as a white solid.