Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH:7]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)=O.O.C1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:7]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1CCC(C=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=CC1CCC(C(=O)OC)CC1
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a mixture of 25.2 g (70.5 mmol) of methyltriphenylphosphonium bromide with 125 ml of tetrahydrofuran (THF) was added 7.9 g (70.5 mmol) of potassium-tert-butoxide (t-BuOK) while being kept at a temperature lower than −20° C. and stirred at the same temperature for 1 hour. Then, 50 ml of solution of 10.0 g (58.8 mmol) of methyl 4-formylcyclohexanecarboxylate in THF was added dropwise to the reaction solution while being kept at a temperature lower than −20° C. and stirred at the same temperature for 2 hours. After finishing of the reaction, 50 ml of water was added to the reaction mixture and then the product was extracted with 200 ml of toluene. The organic layer thus obtained was washed with water thrice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (eluent: toluene) to obtain 6.8 g of a crude methyl 4-vinylcyclohexanecarboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[CH3:14][O:15][P:16]([O:19]C)[O:17][CH3:18]>>[CH3:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:2][P:16](=[O:19])([O:17][CH3:18])[O:15][CH3:14]
Reactant: COP(OC)OC
Reactant: Cc1ccc2ccccc2c1CCl
Product: COP(=O)(Cc1c(C)ccc2ccccc12)OC
Yield: 59.1 %

Procedure:
A solution of 1-chloromethyl-2-methylnaphthalene (9.50 g, 0.050M) in trimethylphosphite (15 mL, 15.8 g, 0.13 M) is heated at reflux temperature for 48 hours. Excess trimethylphosphite is removed under reduced pressure, giving a yellow oil which is chromatographed over silica gel (40-63 μ, 400 g, 50 mL fractions) using ethyl acetate for elution of the column. Fractions 18-21 are pooled and after concentration gave a white solid (7.78 g). Recrystallization from ether-pentane gave title compound (6.94 g) as colorless crystals, mp 54°-57° C.
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[C:21]=2[CH2:20][CH2:19]1>>[CH2:2]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]4[N:25]=[C:26]5[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]5)=[C:22]([C:34]([F:36])([F:35])[F:37])[CH:23]=4)[CH2:15][CH2:16]3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=CCCCOc1cc(C(F)(F)F)c2c(n1)NC(=O)CC2
Reactant: c1cc2c(c(N3CCNCC3)c1)CCC2
Agent: Cl
Product: O=C1CCc2c(C(F)(F)F)cc(OCCCCN3CCN(c4cccc5c4CCC5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 1-indan-4-yl-piperazine hydrochloride was coupled by reductive amination to 4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 489.4 (Exact Mass: 488.24).
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]([C:23]([NH2:25])=O)=[C:10]([CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[N:1]1([C:7]2[S:8][C:9]([C:23]#[N:25])=[C:10]([CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1sc(N2CCOCC2)nc1Cc1ccc2ccccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1sc(N2CCOCC2)nc1Cc1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 2-(morpholin-4-yl)-4-(2-naphthylmethyl)-1,3-thiazole-5-carboxamide (229 mg, 0.648 mmol) (for amide coupling, see example 61-step 1) and phosphoryl chloride (4.00 mL, 42.9 mmol) was stirred at 80° C. for 30 min. The reaction slowly turned homogeneous. The resulting solution was concentrated under reduced pressure and carefully quenched with 1N NaOH solution at 0° C. The resulting mixture was distributed between 1N NaOH solution and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layer was dried and concentrated to provide 2-(morpholin-4-yl)-4-(2-naphthylmethyl)-1,3-thiazole-5-carbonitrile as a yellow solid (213 mg, 98.0% yield). LCMS: (AA) ES+ 336; 1H NMR (400 MHz, DMSO) δ 7.90-7.83 (dd, J=9.0, 1.9 Hz, 3H), 7.80-7.72 (s, 1H), 7.53-7.46 (m, 2H), 7.46-7.38 (m, 1H), 4.18-4.09 (s, 2H), 3.70-3.60 (t, J=4.9 Hz, 4H), 3.51-3.41 (t, J=4.9 Hz, 4H).
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11](O)[CH2:12][N+:13]([O-:15])=[O:14])=[CH:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[N+:13]([O-:15])=[O:14])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=[N+]([O-])CC(O)c1ccn2c(I)cnc2c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])/C=C/c1ccn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a solution of 1-(3-Iodo-imidazo[1,2-a]pyridin-7-yl)-2-nitro-ethanol (116 mg, 0.35 mmol) in CH2Cl2 (2 ml) at 0° C. was added triethylamine (121 μl, 0.87 mmol) and methanesulfonyl chloride (38 μl, 0.49 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The mixture was partitioned between CH2Cl2 and H2O, the organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography (0-50% MeOH in Et2O) to afford the product (57 mg). MS: [M+H]+=316.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:28]([Cu])#[N:29]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(F)cc3)cc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(F)cc3)cc2c1O

Procedure:
Synthesized from 1-bromo-6-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to Example 3a.; MS-(−)-ion: M−1=379.2.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:6][C@H:5]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH3:8])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([C@@H:3]1[CH2:6][C@H:5]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH3:8])[CH2:4]1)#[N:2]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](C#N)C1
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](C#N)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-cyano-cyclobutyl)-ethyl]-amide (34 mg, 0.06 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL, 13.0 mmol). The bright yellow-orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylene diamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then concentrated directly purified via silica gel chromatography with 50% to 100% EtOAc/hexanes to 5% MeOH/EtOAc to afford 15 mg (58%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-cyanocyclobutyl)-ethyl]-amide as a white solid. MS: (M+H)+=418; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.86 (br. s., 1H), 9.08 (s, 1H), 8.44 (s, 1H), 8.40 (dd, J=9.1, 5.3 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.70 (dd, J=9.8, 1.9 Hz, 1H), 7.25 (td, J=9.0, 2.1 Hz, 1H), 4.17-4.28 (m, 1H), 4.14 (s, 3H), 3.20 (t, J=8.7 Hz, 1H), 2.30-2.46 (m, 3H), 2.04-2.20 (m, 2H), 1.18 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:16]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:15]=[C:14]([Cl:24])[CH:13]=3)[O:8][C:7](=[O:25])[C:6]=2[CH:5]=[C:4]([C:26]#[N:27])[CH:3]=1.[CH3:28][NH2:29]>O1CCCC1>[Cl:24][C:14]1[CH:13]=[C:12]([C:9]([NH:10][C:11]2[C:6]([C:7]([NH:29][CH3:28])=[O:25])=[CH:5][C:4]([C:26]#[N:27])=[CH:3][C:2]=2[Cl:1])=[O:8])[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=1
Reactant: CN
Reactant: N#Cc1cc(Cl)c2nc(-c3cc(Cl)nn3-c3ncccc3Cl)oc(=O)c2c1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(Cl)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 8-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-4H-3,1-benzoxazin-4-one (i.e. the cyanobenzoxazinone product of Step C) (187 mg, 0.446 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 49 mg of the title compound, a compound of the present invention, as a white solid that melted at 197-200° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11]23[CH2:22][CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:10]2=[CH:9]1)[C:14]1[CH:23]=[CH:24][CH:25]=[CH:26][C:13]3=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C([BH3-])#N.[Na+].Cl>C(O)(=O)C>[CH2:1]([N:8]1[CH2:12][C:11]23[CH2:22][CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH:10]2[CH2:9]1)[C:14]1[CH:23]=[CH:24][CH:25]=[CH:26][C:13]3=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=C2c3ccccc3C3CC2(CN1Cc1ccccc1)c1ccccc13
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CN2CC3c4ccccc4C4CC3(C2)c2ccccc24)cc1

Procedure:
A mixture of 37.7 g of finely powdered 2-benzyl-2,3-dihydro-8H-3a, 8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c] pyrrole (5e), 300 ml of methanol, and 40 ml of acetic acid is cooled with ice, and 14.8 g of sodium cyanoborohydride is added slowly with stirring. The mixture is stirred at room temperature for 3 hours, cooled, and treated with 50 ml of conc. hydrochloric acid. After stirring at room temperature for 0.5 hour the mixture is made basic and extracted several times with methylene chloride. Removal of the solvent from the dried extracts gives 37.5 g of 2-benzyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]-cyclohepta[1,2-c]pyrrole, identical by nmr spectroscopy with the product obtained in Example 4. The hydrochloride melts with decomposition at 195°-200° after crystallization from ethanol.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH2:9]1)C1C=CC=CC=1.[ClH:24]>C(O)C.[C].[Pd]>[ClH:24].[NH:8]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH2:9]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C1CCNC1
Reaction time: 12 h

Procedure:
12.70 g of N-(1-benzylpyrrolidin-3-yl)phthalimide was dissolved in 100 ml of ethanol and then subjected to hydrogenating decomposition with addition of 1.0 g of 10% palladium-carbon and 5.2 ml of concentrated hydrochloric acid at 60° C. under 1 atm. After 12 hours, the catalyst was filtered out and the solvent was distilled off to obtain 11.03 g of N-(3-pyrrolidyl)phthalimide hydrochloride.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:13]=2[O:17][CH2:18][CH2:19][CH3:20])[N:8]1[C:27](=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[C:27]([N:8]1[C:9]2[C:14](=[C:13]([O:17][CH2:18][CH2:19][CH3:20])[C:12]([CH:21]3[CH2:26][CH2:25][N:24]([C:2]([O:4][CH3:5])=[O:3])[CH2:23][CH2:22]3)=[CH:11][CH:10]=2)[CH2:15][CH2:16][C@@H:7]1[CH3:6])(=[O:29])[CH3:28]
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1c(C2CCN(C(=O)OC)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Methyl chloroformate (5 μL, 0.06 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (20 mg, 0.05 mmol) and triethylamine (0.04 mL, 0.27 mmol) in dichloromethane (0.5 mL), and the reaction stirred at room temperature overnight. The reaction was quenched via the addition of water (5 mL). The organic layer was collected and further washed with water (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 10-20% methanol in ethyl acetate) to afford methyl (S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate (19 mg, 89%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94-1.07 (m, 6H), 1.17-1.26 (m, 1H), 1.43-1.57 (m, 2H), 1.60-1.79 (m, 4H), 2.01 (s, 3H), 2.16-2.31 (m, 2H), 2.68-2.91 (m, 3H), 2.95-3.03 (m, 1H), 3.58 (s, 3H), 3.61-3.73 (m, 2H), 4.04-4.15 (m, 2H), 4.56 (br d, J=6.45 Hz, 1H), 7.05 (br s, 2H). MS (ESI, pos. ion) m/z 389 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[Li]CCCC.[CH:15](=[O:19])[CH:16]([CH3:18])[CH3:17]>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][CH:15]([OH:19])[CH:16]([CH3:18])[CH3:17])[CH3:2]
Reactant: CC(C)C=O
Reactant: C#CC(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(O)C(C)C)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-Diethoxy-propyne (1.82 g, 14.2 mmol) in THF (40 ml) was cooled to −78 C under N2. A solution of n-BuLi (2.0M in cyclohexane, 9.2 mL, 18.46 mmol) was added. After 30 min, Isobutyraldehyde (1.33 g, 18.46 mmol) in THF (10 ml) was added. After 3 h, the reaction was quenched by dilution with 1N HCl, warmed to room temperature and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give product, 3.18 g (100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:13]2[N:26]([C:29](=[O:55])[CH:30]([NH:38][C:39](=[O:54])[CH:40]([N:42]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH3:43])[CH3:41])[CH:31]([O:33]C(C)(C)C)[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:13]2[N:26]([C:29](=[O:55])[CH:30]([NH:38][C:39](=[O:54])[CH:40]([N:42]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH3:43])[CH3:41])[CH:31]([OH:33])[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OC(C)(C)C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution containing crude 45 (330 mg, 0.44 mmol) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 300 mg of 46 as a pale brown-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz) mixture of rotamers: δ8.38 (s, 0.5H), 8.34 (s, 0.5H), 8.12 (dd, J=5.1, 8.7 Hz, 0.5H), 8.03 (dd, J=5.4, 8.4 Hz, 0.5H), 7.35-7.26 (m, 5H), 7.05-6.87 (m, 2H), 6.77 (s, 0.5H), 6.62 (s, 0.5H), 5.29-5.12 (m, 3H), 4.76-4.52 (m, 1.5H), 4.34-4.30 (m, 1H), 4.22-4.19 (m, 0.5H), 3.89 (app t, J=5.4 Hz, 1H), 3.57-3.42 (m, 2H), 2.82 (s, 3H), 2.45-2.39 (m, 0.5H), 2.27-2.21 (m, 0.5H), 1.90 (br s, 1H), 1.38 (d, J=7.5 Hz, 3H), 1.16 (d, J=6.3 Hz, 3H) ppm. Mass spectrum, m/z [700.3] (M+H)+.
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH3:8])[CH3:7])(=[O:4])=[O:3].C([Li])CCC.[P:14](Cl)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[CH2:17]([O:16][P:14]([CH2:1][S:2]([O:5][CH:6]([CH3:8])[CH3:7])(=[O:4])=[O:3])([O:19][CH2:20][CH3:21])=[O:15])[CH3:18]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CC(C)OS(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)OC(C)C)OCC
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a rapidly stirred solution of 8.28 g (60 mmol) of isopropyl methanesulfonate in 150 mL of THF at -73° C. (internal temp.) was added 25 mL (60 mmol) of 2.4M n-butyllithium dropwise over 20 min. The internal temperature was not allowed to rise above -69° C. throughout the course of the addition. After an additional 15 min., 5.17 g (30 mmol) of freshly distilled diethyl chlorophosphate was added at a rate to keep the solution temperature below -69° C. The reaction mixture was stirred for 0.3 h at -73° C. and for 0.5 h at -40° C. when it was quenched with 125 mL of saturated NH4Cl solution. The reaction mass was warmed to room temperature and the THF removed under pressure. The remainder was partitioned between methylene chloride and water (3×75 mL). The extracts were dried (Na2SO4), concentrated, and purified by flash chromatography (350 g silica gel) eluting with 1:1 methylene chloride/ether to provide 5.20 g (67%) of title compound as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1([C:13]([O:15][CH3:16])=[O:14])[C:11](=[O:12])[CH:10]=[CH:9][S:8]1>C(O)(=O)C>[OH:12][C:11]1[CH:10]=[C:9]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[S:8][C:7]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: c1cn[nH]c1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Solvent: CC(=O)O
Product: COC(=O)c1sc(-n2cccn2)cc1O
Reaction time: 48 h

Procedure:
Pyrazole (18 mmol) was added to a solution of 2-chloro-2-methoxycarbonylthiophene-3(2H)-one in acetic acid (10 ml). The mixture was allowed to stand at room temperature for 2 days and the precipitate filtered, m.p. 162°-164° C. (acetic acid).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]=[C:11]2[C:13]([CH3:17])([CH3:16])[CH2:14][CH2:15][C:10]2=[CH:9][C:8]=1[C:18]#[N:19]>>[Cl:3][C:7]1[N:12]=[C:11]2[C:13]([CH3:17])([CH3:16])[CH2:14][CH2:15][C:10]2=[CH:9][C:8]=1[C:18]#[N:19]
Reactant: CC1(C)CCc2cc(C#N)c(O)nc21
Reactant: O=P(Cl)(Cl)Cl
Product: CC1(C)CCc2cc(C#N)c(Cl)nc21
Temperature: 27.5 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
Phosphorous oxychloride (1.9 mL, 24 mmol) was added to 2-hydroxy-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile (0.8 g, 4.3 mmol), obtained in step-1, at 0° C. over a period of about 10 min. The mixture was warmed to a temperature of about 20-35° C. and was heated further to about 80° C. The mixture was stirred at about 80° C. for about 18 h. The reaction mixture was cooled to a temperature of about 20-35° C. and then was poured into crushed ice. The solid which separated out was filtered off and dried under reduced pressure to get 2-chloro-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile (0.7 g).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][N:11]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[C:37]([NH:38]C(=O)OCC3C=CC=CC=3)=[CH:36][C:35]3[C:30](=[CH:31][C:32]([N:49]4[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]4)=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:10]1)=O)(C)(C)C.Br>CC(O)=O>[NH2:38][C:37]1[C:28]([C:26]([NH:25][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:19]=2[N:11]2[CH2:12][C@H:13]([C:15]([F:17])([F:18])[F:16])[CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:27])=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[C:32]([N:49]1[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]1)[CH:31]=2
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)Nc4cnccc4N4C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCN(c2ccc3cc(N)c(C(=O)Nc4cnccc4N4C[C@@H](N)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl [2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(4-methylpiperazin-1-yl)quinolin-3-yl]carbamate (0.006 g, 0.008 mmol) and 2 mL of 4.0 M HBr in AcOH was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was then treated with 4.5 mL of MeOH and 0.5 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H32F3N8O [M+H]+: m/z=529.3. found: 529.3.
Reaction SMILES: Cl.[CH:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])=[CH2:3]>>[N:4]1([CH:2]=[CH:3][CH:2]([N:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[O:9])[CH3:3])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: C=CN1CCCC1=O
Agent: Cl
Product: CC(C=CN1CCCC1=O)N1CCCC1=O

Procedure:
A stream of HCl gas was passed through a capillary into 25 g of N-vinylpyrrolidone, which had been purified by crystallization, under nitrogen for 10 sec. The mixture was stored at 0° C. under a nitrogen atmosphere overnight, during which slow crystallization started. 10 ml of ether were added to complete the crystallization. 1,3-Bis-(1-pyrrolidonyl)butene crystallized in clusters of needles. The product was recrystallized from ether/acetone (1/5).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:46](=[O:47])[N:6]2[C:7]([C:33]([O:35]CC3C=CC([N+]([O-])=O)=CC=3)=[O:34])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].I[CH2:49][C:50]([NH2:52])=[O:51]>>[C:50]([CH2:49][N+:23]1[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=[C:21]([C:19]([C:16]2[N:17]=[CH:18][N:13]3[CH:12]=[C:11]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:46](=[O:47])[N:6]5[C:7]=4[C:33]([O-:35])=[O:34])[S:15][C:14]=23)=[O:20])[CH:22]=1)(=[O:51])[NH2:52]
Reactant: NC(=O)CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(-c6ccccc6)c5)c4s3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5cc(-c6ccccc6)c[n+](CC(N)=O)c5)c4s3)[C@H](C)[C@H]12
Yield: 19.6 %

Procedure:
An N-quaternarized compound (91 mg) was prepared in substantially the same manner as in Example 24, except that 97 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-phenylpyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate and 185 mg of 2-iodoacetamide were used as the starting compounds. The title compound (16.7 mg) was prepared in substantially the same manner as in step c) of Example 1, except that this compound was used as the starting compound.