Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.O=P(Cl)(Cl)Cl.[C:18](=O)(O)[O-:19].[Na+]>CN(C=O)C>[F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][C:8]([CH:18]=[O:19])=[C:7]([OH:11])[CH:6]=1
Reactant: CN(CCF)c1cccc(O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(CCF)c1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
169 mg (1 mmol) 3-[(2-Fluoro-ethyl)-methyl-amino]-phenol are dissolved in 4 mL DMF and cooled below 10° C. 0.101 mL (1.1 eq.) POCl3 are added dropwise over the course of one minute, the reaction mixture is stirred 10 minutes at room temperature, then heated to 90° C. for 30 minutes. The reaction mixture is allowed to cool to 30° C. and cautiously treated with a slow addition of 8 mL saturated aqueous sodium bicarbonate solution. The desired product is extracted with ethyl acetate and saline, the organic phase dried over sodium sulfate and evaporated to yield 130 mg (66%) crude product as a slightly brownish oil. This compound is used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[C:18]([OH:23])([C:17]([F:25])([F:24])[F:16])[C:12]1[C:13](=[O:14])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[NH:10][C:11]=1[CH3:15]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: Cc1cc(=O)n(-c2ccc(C#N)cc2)[nH]1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C#N)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(4-cyanophenyl)-3-methyl-5-pyrazolone (100 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (174 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH2:32][N:33](C(C)C)C(C)C.C(N)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([NH:33][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1)[CH3:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (75.0 mg, 0.184 mmol) was suspended in DMF (1.0 mL) and DIPEA (0.15 mL) was added followed by ethylamine (30 mg, 0.665 mmol) and HATU (85.0 mg, 0.224 mmol). The reaction mixture was stirred at ambient temperature for 2 h and another portion of HATU (60.0 mg, 0.158 mmol) was added. The reaction mixture was stirred overnight and purified using HPCL (10-75% acetonitrile in water, NH4HCO3 buffered). The fractions were concentrated in vacuo and the resulting residue was crystallized with MeOH-water (1:10, 5 mL) to afford the title compound as a light green solid (24.0 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.09 (t, J=7.20 Hz, 3 H) 1.85-2.01 (m, 3 H) 2.18 (dt, J=5.37, 2.75 Hz, 1 H) 2.43-2.48 (m, 4 H) 3.18-3.28 (m, 6 H) 3.35 (s, 2 H) 3.37-3.45 (m, 1 H) 3.54-3.67 (m, 1 H) 3.94-4.05 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.99 (d, J=2.02 Hz, 1 H) 7.62 (d, J=2.02 Hz, 1 H) 7.71 (d, J=9.09 Hz, 2 H) 8.17 (t, J=5.56 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C24H30N6O2, 435; found, 435.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]#[CH:20].ClC1C=CC2NC(=O)C3C=CC=CC=3NC=2C=1>>[CH2:20]([N:8]1[C:7](=[O:16])[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2)[C:19]#[CH:18]
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: C#CCBr
Agent: O=C1Nc2ccc(Cl)cc2Nc2ccccc21
Product: C#CCN1C(=O)c2ccccc2Oc2ccccc21

Procedure:
Using Procedure H-3 (Table 5) with dibenzo[b,f][1,4]oxazepin-11(10H)-one and 3-bromoprop-1-yne the title compound 85 was obtained (1.58 g, 89%) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 7.76 (ddd, J=7.5, 1.7, 0.4 Hz, 1H), 7.65 (dd, J=8.0, 1.7 Hz, 1H), 7.61 (ddd, J=8.2, 7.2, 1.8 Hz, 1H), 7.41 (dd, J=7.8, 1.6 Hz, 1H), 7.37 (ddd, J=8.2, 1.0, 0.4 Hz, 1H), 7.34-7.24 (m, 3H), 4.83 (d, J=2.3 Hz, 2H), 3.31 (t, J=2.3 Hz, 1H). MS (m/z): 250.0 (M+H)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH:2]=[CH2:3].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(C)C.CCCCCC>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:6]=1/[CH:7]=[N:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Br)ccc1C=O
Reactant: Nc1ccccc1
Solvent: CC(C)O
Solvent: CCCCCC
Product: C=CCOc1cc(Br)ccc1/C=N/c1ccccc1
Temperature: 50 °C
Yield: 86.1 %

Procedure:
2-(Allyloxy)-4-bromobenzaldehyde (5.05 g, 20.9 mmol) was dissolved with warming in isopropanol (18 mL). Freshly distilled aniline (1.99 g, 21.3 mmol) was added with isopropanol (4 mL) and the reaction was heated to 50° C. A yellow precipitate formed within 30 min and isopropanol (5 mL) was added to aid stirring. The reaction was stirred at 50° C. for 16 h, by which time proton NMR showed no aldehyde present. The reaction was cooled with stirring. The mixture was diluted with hexane (20 mL), the solid was filtered and washed with the mother liquor, washed with hexane and air dried to afford N-{(1E)-[2-(allyloxy)-4-bromophenyl]methylene}aniline (5.69 g, 86% yield) as a light yellow powder; 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.27-7.17 (m, 4H), 7.099 (d, J=1.8 Hz, 1H), 6.06 (ddt, J=17.2, 10.5, 5.3 Hz, 1H), 5.43 (AB q, J=17.3, 3.0 Hz, 1H), 5.33 (AB q, J=10.5, 2.8 Hz, 1H), 4.62 (ddd, J=5.2, 1.5, 1.5 Hz, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([OH:33])=O)[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cc([C@H]3CCCN3c3cc(F)cc(F)c3)c3oc(N4CCOCC4)cc(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylic acid (see Example 1.03b for preparation, 97 mg, 0.21 mmol), DIPEA (0.185 mL, 1.06 mmol) and 1-methylpiperazine (0.047 mL, 0.43 mmol) were mixed at room temperature in DCM (3 mL). N-propylphosphonic acid anhydride, cyclic trimer (50 wt % solution in EtAc) (0.633 mL, 1.08 mmol) was then added and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was purified by preparative HPLC to afford 8-[(2R)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)]-6-(4-methylpiperazine-1-carbonyl)-2-morpholino-4H-chromen-4-one (67 mg, 59%) as a white foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]C=2)[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:2]1.O1C2(CCC(C3C4C(=CC=CC=4)N[N:28]=3)CC2)OCC1>>[NH:1]1[C:9]2=[N:28][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: c1ccc2c(C3CCC4(CC3)OCCO4)n[nH]c2c1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: O=C1CCC(c2c[nH]c3ncccc23)CC1
Yield: 95 %

Procedure:
This compound was prepared in the manner described above for intermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-azaindole (2.48 g) to afford 1.96 g (95%) of the title compound as a white solid: mp 162-164° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].[S-:9][C:10]#[N:11].[Na+]>>[C:2]([N:11]=[C:10]=[S:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:1])[CH3:3]
Reactant: N#C[S-]
Reactant: C=C(C)CC(C)(C)C
Agent: [Na+]
Product: CC(C)(C)CC(C)(C)N=C=S

Procedure:
The t-octylisothiocyanate was prepared from the reaction of diisobutylene and sodium thiocyanate as follows:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH3:11])[C:3]([C:5]1[O:6][CH:7]=[CH:8][N:9]=1)=[O:4].Cl.[CH3:13][C:14]([CH3:33])([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:15][C@H:16]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[C:17](O)=[O:18]>>[O:6]1[CH:7]=[CH:8][N:9]=[C:5]1[C:3]([C@@H:2]([NH:1][C:17](=[O:18])[C@@H:16]([CH2:20][C:21]([N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:15][C:14]([CH3:13])([CH3:33])[CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:10][CH3:11])=[O:4]
Reactant: CC[C@H](N)C(=O)c1ncco1
Reactant: CC(C)CC(C)(C)C[C@H](CC(=O)N1CCOCC1)C(=O)O
Agent: Cl
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC(C)(C)CC(C)C)C(=O)c1ncco1

Procedure:
It is similarly prepared according to the general procedure for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one; hydrochloride as the amino component and (R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid as the acidic component but without further oxidation step.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]#[N:12].[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[N:13][OH:14])[C:11]#[N:12]
Reactant: N#CCc1nc2ccccc2[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(=NO)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To an ice-cooled stirred solution of 10 g of 2-benzimidazolylacetonitrile (63.6 mmol, 1 eq) in 50 ml of glacial acetic acid is added dropwise a solution of 4.83 g of sodium nitrite (70 mmol, 1.1 eq) dissolved in a minimum amount of water (10 mL). When the addition is completed, the reaction mixture is allowed to stir at room temperature for 1 h. The precipitate formed in the course of the reaction is filtered and washed with 2×20 ml of cold water and 2×30 ml of diethylether to provide 11.8 g of the product as light yellow solid.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([S:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][N:5]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30])(=[O:3])[NH2:2].CO[CH:44](OC)[N:45](C)C>>[N+:39]([C:36]1[CH:37]=[CH:38][C:33]([CH2:32][O:31][C:29]([N:5]2[CH2:6][C@@H:7]([S:9][C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][C@H:4]2[C:1]2[O:3][N:45]=[CH:44][N:2]=2)=[O:30])=[CH:34][CH:35]=1)([O-:41])=[O:40]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1c1ncno1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To (2S,4R)-2-Carbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-(tritylthio)pyrrolidine (2 g) was added N,N-dimethylformamide dimethyl acetal (1 ml) and the mixture was stirred at 70° C. for 1 hour, and evaporated in vacuo. The oily residue was dissolved in acetic acid (20 ml) and to this solution were added sodium acetate (0.43 g) and hydroxylamine hydrochloride (0.37 g) at room temperature. After stirring at 70° C. for 1 hour, the mixture was poured into water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine successively, and dried over magnesium sulfate. After the solvent was evaporated, the residue was subjected to a column chromatography on silica gel and eluted with a mixture of acetone and dichloromethane (1:20, V/V) to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(1,2,4-oxadiazol-5-yl)-4-(tritylthio)pyrrolidine (1.16 g).
Reaction SMILES: O1C=CCCC1.[N+:7]([C:10]1[S:24][C:13]2[S:14][C:15]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:16][C:17](=[O:18])[C:12]=2[CH:11]=1)([O-:9])=[O:8].[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[CH2:26].O.O.O.C([O-])(=O)C.[Na+]>CO.O>[N+:7]([C:10]1[S:24][C:13]2[S:14][C:15]3([CH2:19][CH2:20][N:21]([CH2:26][CH2:25][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:22][CH2:23]3)[CH2:16][C:17](=[O:18])[C:12]=2[CH:11]=1)([O-:9])=[O:8]
Reactant: C=Cc1ccccn1
Reactant: O=C1CC2(CCNCC2)Sc2sc([N+](=O)[O-])cc21
Agent: C1=COCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CC2(CCN(CCc3ccccn3)CC2)Sc2sc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A solution containing 660 mg (2.05 mmol) of 2'-Nitro-spiro(piperidine-4,6'-(6H)thieno[2,3-b]thiopyran)-4'(5'H)-one dihydropyran, 430 mg (4.1 mmol) of 2-vinylpyridine and 557 mg (4.1 mmol) of sodium acetate trihydrate in 10 ml of 1:1 methanol/water was heated at reflux for 4 hours. The reaction was cooled to room temperature and a solid separated. The solid was collected and dissolved in methanol and treated with excess ethanolic HCl. The dihydro chloride separated and was collected and dried over night in vacuo to give 482 mg of the product.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: CC(C)(C)C(=O)Cl
Product: CCOC(=NC(=O)C(C)(C)C)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and pivaloyl chloride, there is obtained ethyl N-pivaloyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 350 (2), 321 (5), 293 (100), 265 (18), 194 (29), 167 (92);
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])(=[O:6])[CH3:5].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16]>CO>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[O:6])=[CH:19][CH:18]=1)#[N:16]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: N#Cc1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C=CC(=O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.8 %

Procedure:
Part A. Sodium methoxide (25% in MeOH, 1.5 mL, 6.8 mmol) was added dropwise to a solution of 3-acetylbenzonitrile (0.987 gm, 6.8 mmol) and 4-cyanobenzaldehyde (0.891 gm, 6.8 mmol) in dry methanol. Within 5 minutes, a precipitate began to form. The mixture was stirred at room temperature for 4 hrs and diluted with methanol. The solids were filtered off, washed with cold methanol and dried to give 3-[3-(4-cyanophenyl)-1-oxo-2-propenyl]benzonitrile as a white solid 1.7 gm (97%). MS: (M+H)+ 259; 1H NMR (CDCl3): 7.55 (d, 1H), 7.65 (t, 1H), 7.75 (s, 4H), 7.85 (m, 2H), 8.25 (d, 1H), 8.30 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.[NH4+].[Cl-]>CC(O)C>[N:8]1([C:5]2[N:6]=[N:7][C:2]([NH:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: Clc1ccc(N2CCOCC2)nn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Product: COC(=O)c1ccc(CNc2ccc(N3CCOCC3)nn2)cc1
Temperature: 150 °C
Yield: 8.2 %

Procedure:
To a solution of 64 (2.0 g, 10.0 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (2.2 g, 11.0 mmol) in i-PrOH (200 mL) was added NH4Cl (2.14 g, 40.0 mmol). The reaction mixture was heated at 150° C. for 72 h and concentrated. The residue was dissolved in water and the aqueous phase was extracted with. \the aqueous phase was separated, treated with 1N NaOH (pH 8) and extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98 to 5/95) to afford the title compound 65 (270 mg, 0.82 mmol, 8% yield). 1H NMR: (400 MHz, CDCl3) δ (ppm): 7.97 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 6.90 (d, J=9.2 Hz, 1H), 6.69 (d, J=9.2 Hz, 1H), 5.16-5.06 (bs, 1H), 4.67 (s, 2H), 3.90 (s, 3H), 3.82 (t, J=4.8 Hz, 4H), 3.41 (t, J=4.8 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2nccc(N3CCC(O)C3)c2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nccc(N3CCC(OS(C)(=O)=O)C3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
1-(6-Methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-ol (7.67 g, 31.3 mmole), triethylamine (8.73 mL, 63 mmole) and catalytic amount of 4-dimethylaminopyridine dissolved in DCM (100 mL) and cooled to 0° C. The solution was degassed with argon. Methanesulfonyl chloride (2.9 mL, 37.6 mmole) was added dropwise over 30 minutes. The reaction was stirred under argon for 30 minutes at 0° C. and then stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified on column chromatography (silica, 1-5% MeOH in chloroform). The solvent was removed in vacuo to afford the title compound as a white solid (7.0 g, 69%): LC-MS (ES) m/z 324 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:16]=[CH:17]\[CH2:18]Cl)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:38].[Na+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:16]=[CH:17]/[CH2:18][I:38])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of diphenylmethyl 7-t-butoxycarbonylamino-3- [(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate (IIIa) (541 mg, 1 mmol) and sodium iodide (450 mg, 3 mmol) in acetone (5.4 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml), washed with aqueous sodium thiosulfate and water successively, dried with MgSO4 and concentrated to yield 632 mg of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@@H:10]([OH:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)/C=C/c1ccc(Br)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](O)/C=C/c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 5.55 g (24.7 mmol) of the ketone from Step A dissolved in 100 mL of toluene was added 3.7 mL (3.7 mmol, 1M in toluene) of (R)-2-methyl-CBS-oxazaborolidine catalyst and the resultant mixture was stirred at ambient temperature for 15 min. The mixture was cooled to −78° C. and 4.0 mL (37.1 mmol) of catecholborane in 30 mL of toluene was added dropwise over 30 min. After the addition, the slurry was stirred at −78° C. for 60 min while slowly turning homogeneous. The solution was then stirred at −78° C. an additional 4 h (reaction time varies from 4-24 h) until TLC revealed complete disappearance of starting material. Next, the reaction mixture was diluted with 100 mL of water and the resultant mixture was extracted with three 100-mL portions of diethyl ether. The organic phases were then combined and washed with two 100-mL portions of 1 N NaOH aqueous solution, two 100 mL portions of 5% hydrochloric acid solution, 100-mL portions of saturated aqueous brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the crude waxy solid. The crude material was then purified by flash chromatography on a Biotage® system (silica gel, 0 to 20% ethyl acetate/hexanes gradient) to give the alcohol as a colorless crystalline solid. This compound was recrystallized in hexanes to yield the alcohol as colorless crystals (96% ee by Mosher ester analysis). LC/MS 209.0 (M-H2O+3), 211.0 (M-H2O+3).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:9]=[CH:8]2.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C(#N)C>[F:20][C:19]([F:22])([F:21])[C:15]1[CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]3[C:12](=[C:3]([CH2:2][NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1cccc(-c2ccc3cccc(CCl)c3n2)c1
Reactant: NC1CCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(-c2ccc3cccc(CNC4CCCC4)c3n2)c1
Yield: 91.8 %

Procedure:
A solution of 8-(chloromethyl)-2-(3-(trifluoromethyl)phenyl)quinoline (70 mg, 0.22 mmol), cyclopentylamine (0.1 ml, 1.09 mmol) and DIPEA (0.18 ml, 1.09 mmol) in acetonitrile (2 ml) was stirred at 100° C. under microwave for 10 min. The mixture was concentrated. Purified by Prep-TLC to give a white solid (74.8 mg, 91% yield). MS (ESI) calcd for C22H21F3N2 (m/z): 370.17. found: 371 [M+1].