Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[P:6]([O-:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(C1CCCN1)(=O)=O.N1CCC[C@H]1C(O)=O.C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N)CC(O)=O)=O)CCCNC(N)=N)=O)C(C)C)=O)CC2C=CC(O)=CC=2)=O)C(C)C)=O)CC2NC=NC=2)=O)CCC1)=O)C(O)=O>>[NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[P:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:21])[O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Reactant: C1=NCCC1
Agent: CC(C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(=O)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)O)C(C)C
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P(=O)C1CCCN1
Product: O=P(Oc1ccccc1)(Oc1ccccc1)C1CCCN1
Temperature: 85 °C
Yield: 49 %

Procedure:
This compound was synthesized from 1-pyrroline trimer (Nomura, Y., Ogawa, K., Takeuchi, Y., Tomoda, S., One Step Synthesis and Structural Confirmation with 1-Pyrroline Trimer, Chem. Lett. 1977, 693-696) and diphenyl phosphite using the procedure previously described for the synthesis of the diethyl ester (Petrillo, E. W., Spitzmiller, E. R., Synthesis of 2-Phosphopyrrolidine and Its Substitution for Proline in an Inhibitor of Angiotensin-Converting Enzyme, Tet. Lett. 1979, 51, 4929). A mixture of 1-pyrroline trimer (17 mmol, 3.5 g) and diphenyl phosphite (50 mmol, 11.7 g) was heated at 85° C. for 1.5 h under argon to give crude diphenyl pyrrolidine-2-phosphonate which was dissolved in 100 ml of dry diethyl ether, filtered and saturated with dry gaseous HCl. The precipitated hydrochloride 1 was collected by filtration, washed with ether and recrystallized from acetone, to give the pure product as a white solid in 49% yield: mp 146°-148° C.; 1H-NMR (D2O) δ(ppm): 2.0-2.5 (m, 4H), 3.40 (m, 2H), 4.25 (m, 1H), 6.90-7.30 (m, 10H); MS (FAB) m/e 304 (M-Cl)30. Anal. (C16H19NO3PCl): C, H, N, Cl.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH:9]2[O:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Na+].[OH:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]([OH:23])[C:20]([O-:22])=[O:21])=[CH:17][CH:16]=1.[OH-].[K+].Cl>CO.O>[OH:11][CH:9]([CH2:8][O:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:10][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]([OH:23])[C:20]([OH:22])=[O:21])=[CH:17][CH:16]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)C(O)c1ccc(OCC(O)COc2ccccc2)cc1
Yield: 52.8 %

Procedure:
7.5 g (50 mmol) of 2,3-epoxypropyl phenyl ether (phenyl glycidyl ether) are added to a suspension of 10.4 g (50 mmol) of 4-hydroxymandelic acid sodium salt monohydrate, and 300 mg (5.0 mmol) of potassium hydroxide in 25 ml of methanol, and the mixture is refluxed for 8 hours. The homogeneous reaction mixture is then diluted with 300 ml of water, acidified with 25 ml of concentrated hydrochloric acid and extracted three times with dichloromethane. The organic phases are washed with water, combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator to give 8.4 g (53%) of 4-(2-hydroxy-3-phenoxypropoxy)mandelic acid as a yellowish resin (compound (204), Table 2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J11) (160 mg. 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol) according to the general procedure M. Obtained as a yellow solid (159 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)=[O:10])=[CH:5][CH:4]=1)=O.[C:23]1([NH2:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:29][CH2:1][C:3]2[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][CH:15]=[CH:14]4)=[O:10])=[CH:5][CH:4]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(CNC(=O)c2ccc3ncccc3c2)cc1
Reactant: Nc1ccccc1
Product: O=C(NCc1ccc(CNc2ccccc2)cc1)c1ccc2ncccc2c1

Procedure:
The title compound (13.8 mg) was obtained according to an analogous method to Example E-26 using quinoline-6-carboxylic acid 4-formyl-benzylamide described in Preparation Example E+-6 (50 mg, 0.172 mmol) instead of formalin, and phenylamine (31 μl, 10.34 mmol) instead of quinoline-6-carboxylic acid 4-benzyl amino-benzylamide. Trifluoroacetic acid salt of the title compound was obtained by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:21].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)nc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
A mixture of 4-bromomethyl-2-(4-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (2.22 g, 6.18 mmol), tert-butoxycarbonylamino-acetic acid ethyl ester (1.32 g, 6.48 mmol) and sodium hydride (60% in mineral oil, 296 mg, 7.4 mmol) in anhydrous dimethylformamide (30 mL) was stirred at 0° C. for one hour and room temperature for four hours before it was quenched with brine. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (964 mg): 1H NMR (CDCl3, 200 MHz): δ=7.87 (d, 2H), 7.39 (d, 2H), 4.99 (m, 2H), 4.21 (m, 6H), 1.45 (s, 9H), 1.26 (t, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>N1C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:5]1)=[O:22]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCN1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCN1CCN(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from step (i) above (3 g) was dissolved in pyridine (12 ml), 3,4-dichlorobenzoyl chloride (2.05 g) was added and the mixture stirred at room temperature for 18 hours. A solid was collected by filtration and purified by chromatography (dichloromethane:methanol: 0.880 NH4OH, 90:9:1) to give the sub-titled product as an oil (3.59 g).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]1[C:23](=[O:24])[N:7]2[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]3[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=3)[CH2:10][S:11][C@H:6]12.C[Si](C)(C)NC(=O)C.[NH2:33][C:34]1[S:38][N:37]=[C:36](/[C:39](=[N:47]/[O:48][CH2:49][C:50]([OH:52])=[O:51])/[C:40](OS(C)(=O)=O)=[O:41])[N:35]=1.C(OCC)C>O1CCCC1>[NH2:33][C:34]1[S:38][N:37]=[C:36]([C:39](=[N:47][O:48][CH2:49][C:50]([OH:52])=[O:51])[C:40]([NH:4][C@@H:5]2[C:23](=[O:24])[N:7]3[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]4[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=4)[CH2:10][S:11][C@H:6]23)=[O:41])[N:35]=1
Reactant: CS(=O)(=O)OC(=O)/C(=N\OCC(=O)O)c1nsc(N)n1
Reactant: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c3nsc(N)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of 7β-amino-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (6.96 g) and N-(trimethylsilyl)acetamide (21.8 g) in tetrahydrofuran (150 ml) was added methanesulfonyl (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetate (4.86 g) at ambient temperature. After being stirred for 30 minutes at the same temperature, the mixture was poured into diethyl ether (2 l), and the resultant precipitate was collected by filtration. The precipitate was dissolved in water, and the solution was adjusted to pH 2.0 with aqueous sodium bicarbonate solution. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin, Diaion HP-20. The desired product was eluted with 5% isopropyl alcohol solution and lyophilized to give 7β[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer)(5.20 g).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.CSC.B.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](=[O:35])[CH3:34])=[N:31][CH:32]=1>C1COCC1>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C@@H:33]([OH:35])[CH3:34])=[N:31][CH:32]=1
Reactant: CC(=O)c1ccc(Br)cn1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@H](O)c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The (R)-(+)-2-Methyl-CBS-oxazaborolidine (2.08 g, 7.5 mmol) was dissolved in THF (10 mL), cooled to 0° C. and borane-dimethyl sulfide complex (2 M solution in THF, 7.50 mL, 15.0 mmol, 2.0 equiv.) was added dropwise. The resulting solution was stirred for 1 hour, then cooled to −40° C. and a solution of 1-(5-bromopyridin-2-yl)ethanone in THF (8.0 mL) was added dropwise over 5 min. A white precipitate formed toward the end of the addition. The slurry was stirred for 1 hour, warmed to −10° C., and stirred for another 60 min at this temperature. Analysis of the solution (HPLC) showed >95% conversion to the desired product. The reaction was poured into ethyl acetate (100 mL), washed with saturated ammonium chloride, water, and brine (50 ml each), dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The residual oil was purified by flash chromatography over silica gel (90 g), eluting with 40% ethyl acetate in hexanes to give the title compound (1.34 g) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: O=C(O)c1cc(F)cc(Cl)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-chloro-5-fluorobenzoic acid (CAS RN 25026-64-6) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Yellow solid (17%). MS (ESI): m/z=355.10 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][CH:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:26]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][CH:14]([C:15]2[N:19]([CH3:26])[N:18]=[N:17][N:16]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1ccc(CC(=O)NC(c2ccccc2)c2nnn[nH]2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CC(=O)NC(c2ccccc2)c2nnnn2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
To a solution 2-(4-isopropylphenyl)-N-[phenyl(1H-tetrazol-5-yl)methyl]acetamide (34.0 mg, 0.101 mmol) in 0.5 ml of anhydrous DMF was added K2CO3 (14.0 mg, 0.101 mmol) and MeI (0.006 ml, 0.101 mmol). The resulting solution was stirred at RT for 3 hour. Filtered and the residue was purified by preparative HPLC (5-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 8.0 mg (23%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.342 (m, 3H); 7.226 (m, 2H), 7.172 (ABq, J=8.2 Hz, 4H), 6.894 (br d, J=7.6 Hz, 1H), 6.424 (d, J=7.9 Hz, 1H), 3.910 (s, 3H), 3.587 (s, 2H), 2.888 (sept, J=7.0 Hz, 1H), 1.234 (d, J=7.0 Hz, 6H). ES-MS [M+1]+: 350.2.
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7]([CH2:9][CH2:10][CH:11]([NH:15][C:16]([NH2:18])=[NH:17])[C:12]([OH:14])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].[BrH:19].Br.[NH2:21][CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=3)[CH:32]=2)=[O:29])=[CH:25][CH:24]=1.CC(N(C)C)=O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[BrH:19].[ClH:1].[C:2]([O:6][C:7]([CH2:9][CH2:10][CH:11]([NH:15][C:16]([NH2:18])=[NH:17])[C:12]([NH:21][CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=3)[CH:32]=2)=[O:29])=[CH:25][CH:24]=1)=[O:14])=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Reactant: CC(C)(C)OC(=O)CCC(NC(=N)N)C(=O)O
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)CCC(NC(=N)N)C(=O)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
To 4.6 g of 4-t-butoxycarbonyl-2-guanidinobutyric acid hydrochloride, 5.3 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrobromide and 220 mg of DMAP were added 110 ml of DMA and 36 ml of pyridine and the resulting mixture was stirred while cooling with ice. After 10 minutes, 4 g of DCC was added and the mixture was stirred for 3 hours while cooling with ice and then for 16 hours at room temperature. The precipitated were filtered off, the filtrate was added in small portions into 3 l of ether and stirred at room temperature for 3 hours. After removing the supernatant by decantation, the residue was dissolved in 60 ml of DMF, then 3 g of active carbon was added thereto, and the mixture was stirred for 30 minutes while cooling with ice. The insolubles were filtered off, and the filtrate was added dropwise into 3 l of ether and stirred for 5 hours while cooling with ice. The crystals thus precipitated were collected by filtration to obtain 6.7 g of the intended product.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25](O)=[O:26])(=[O:3])[NH2:2].O1CC(N)C1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([CH2:25][OH:26])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Agent: NC1COC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1CO
Yield: 6.2 %

Procedure:
2-carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with 3-oxetanamine similar to as described in Example 2 g to afford 3 mg of 9-fluoro-3-(hydroxymethyl)-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 429 (M)+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:25][N:24]4[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[C-:26]#[N:27].[Na+]>CN(C)C=O>[C:26]([C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:25][N:24]4[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1)#[N:27]
Reactant: Brc1ccc2c(c1)C(=C1CCC3CCCCN3C1)c1ccccc1S2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)C(=C1CCC3CCCCN3C1)c1ccccc1S2

Procedure:
A stirred mixture of 3.96 g. (0.01 mole) of 3-(2-bromothioxanthen-9-ylidene)quinolizidine, 2.70 g. (0.015 mole) of cuprous cyanide, 50 mg. of cupric sulfate, 50 mg. of sodium cyanide in 40 ml. of dimethylformamide is heated at reflux temperature for eighteen hours. The cooled reaction mixture is then poured into 200 ml. of 1 M sodium cyanide. The resulting mixture is extracted with ether. After being washed with an aqueous solution of sodium cyanide and water, the ether solution is dried over magnesium sulfate. The dried solution is concentrated. The residual liquid is chromatographed on an alumina column using ether as the eluate. Evaporation of the appropriate fractional eluant gives 3-(2-cyanothioxanthen-9-ylidene)quinolizidine. A solution of the product in ethanol is treated with a molar equivalent of fumaric acid. The resulting crystals are recrystallized from ethanol to give 3-(2-cyanothioxanthen-9-ylidene)quinolizidine fumarate.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:7][C:8]([C:10]1[C@:11]2([CH2:27][CH2:26][C@H:25]3[C@@H:16]([CH2:17][CH2:18][C:19]4[CH:20]=[C:21]([OH:28])[CH:22]=[CH:23][C:24]=43)[C@@H:13]2[CH2:14][CH:15]=1)[CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6].Cl[S:30]([NH2:33])(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>CN(C=O)C>[S:30](=[O:32])(=[O:31])([O:28][C:21]1[CH:22]=[CH:23][C:24]2[C@@H:25]3[C@H:16]([C@H:13]4[C@@:11]([CH2:27][CH2:26]3)([CH3:12])[C:10]([C:8](=[O:9])[NH:7][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:15][CH2:14]4)[CH2:17][CH2:18][C:19]=2[CH:20]=1)[NH2:33]
Reactant: NS(=O)(=O)Cl
Reactant: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Reaction time: 0.42 h
Yield: 95.2 %

Procedure:
Sodium hydride (20 mg) was added to a solution comprising 73 mg of compound 10a in 2 ml of anhydrous DMF at 0° C. The solution was stirred for 25 minutes and 126 mg of chlorosulfonamide was added in one portion. The solution was then stirred at room temperature for 2 hours. Ice and saturated sodium bicarbonate solution was added to the reaction mixture. The precipitate formed was filtered and washed with water. The residue was purified by chromatography on silica gel (CHCl3:methanol, 50:1), yielding compound 11a (85 mg, 96%). FAB-MS m/z 433 (M+H)+; 1H NMR (270 MHz, DMSO-d6) δ 0.88 (t, 3H, J=7.5 Hz, CH2CH3), 0.91 (s, 3H, CH3), 3.08 (dt, 2H, J=5.6, 6.6 Hz, NHCH2), 6.34 (s, 1H, 16-CH), 6.97 (s, 1H, ArH), 7.01 (dd, 1H, J=2.6, 8.6 Hz, ArH), 7.33 (d, 1H, J=8.6 Hz, ArH), 7.71 (t, 1H, J=5.6 Hz, NHCH2), 7.88 (s, 2H, NH2).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].[Na]>CO.C(OCC)(=O)C.ClCCl>[CH3:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][OH:9])=[CH:4][CH:5]=1)=[O:16]
Reactant: COC(=O)CCC(=O)Cl
Reactant: OCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCC(=O)c1ccc(CCO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To a dry 250 mL flask under a nitrogen atmosphere was added phenethyl alcohol (2.50 g, 0.02 mol), anhydrous dichloromethane (150 mL), and methyl-4-chloro-4-oxobutyrate (6.02 g, 0.04 mol). The contents of the flask were cooled to 0° C. with an ice bath. To the solution was added aluminum chloride (25 g, 0.2 mol) in portions being careful to avoid a violent exotherm. The resulting yellowish mixture was stirred for 3 hours. At this point the reaction was quenched with ice water. The mixture was diluted with dichloromethane and transferred to a separatory funnel. The organic layer was washed with a saturated solution of sodium bicarbonate, brine and then dried over magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure provided a crude yellow oil. The oil was suspended in anhydrous methanol (100 mL) and sodium metal was added to the mixture until a pH of 9 was obtained. The mixture was stirred for 3 hours. The volume was reduced and then diluted with ethyl acetate. The solution was transferred to a separatory funnel and washed with aqueous 0.05 N hydrochloric acid, brine and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give a crude yellow oil with a mass of 5.88 g. Column chromatography [silica gel; eluent hexanes-ethyl acetate (3:2)] provided the desired product (2.69 g, 57%). 1H(CDCl3) δ(ppm): 2.65 (t, 2H); 2.81 (t, 2H); 3.19 (t, 2H); 3.6 (s, 3H); 3.75 (t, 2H); 7.22 (d, 2H); 7.81 (d, 2H). 13C(CDCl3) δ(ppm): 27.76, 33.03, 38.66, 51.52, 62.68, 127.97, 128.99, 134.47, 144.78, 173.21, 197.64.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([N:12]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)C(=O)OC(C)(C)C)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[ClH:27].C(OCC)(=O)C>COCCOC>[ClH:27].[CH2:1]([C:3]1[C:11]([NH:12][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccccc2c1N(CC1CCOCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCc1nn2ccccc2c1NCC1CCOCC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of tert-butyl N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylcarbamate (17.5 g, 50 mmol) dissolved in 1,2-dimethoxyethane (175 mL) was added a 4N hydrochloric acid-ethyl acetate solution (175 mL), and the reaction mixture was stirred for 3 hours at 45° C. The solvent was then evaporated under reduced pressure, 1,2-dimethoxyethane (175 mL) and hexane (175 mL) were added to the residue, the mixture was cooled on ice and the precipitate was collected by filtration to afford 11.8 g of the title compound (87% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:30])[C:5]([C:25]([O:27]CC)=[O:26])=[C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:7]2[CH:16]1[CH2:18][CH2:17]1.[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:30])[C:5]([C:25]([OH:27])=[O:26])=[C:6]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[N:7]2[CH:16]1[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1c(-c2ccccc2)n(C2CC2)c2c(OC)c(F)c(F)c(N)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)c(-c3ccccc3)n(C3CC3)c12
Yield: 62953556 %

Procedure:
A solution of ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-2-phenylquinoline-3-carboxylate (980 mg, 2.36 nmol) and 1M aq. NaOH (5 mL) in EtOH (15 mL) was stirred at 50° C. for 24 h. After the reaction mixture was concentrated in vacuo, the residue was dissolved in water and 2M HCl was added to pH<3. The crude product was extracted with EtOAc, washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 5:1→1:1) to yield 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-2-phenylquinoline-3-carboxylic acid (574 mg, 63%) as a yellow amorphous solid.