Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:34]=[CH:33][C:19]([CH2:20][N:21]4[CH:25]=[C:24]([CH:26]=O)[C:23]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)=[N:22]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OP([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(OCC)=O)C.O>CN(C)C=O>[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:21]4[CH:25]=[C:24](/[CH:26]=[CH:43]/[C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:23]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)=[N:22]4)=[CH:33][CH:34]=3)[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Sodium hydride (60%, oily, 150 mg) was added to a solution of 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1.54 g) and ethyl diethylphosphonoacetate (0.82 g) in N,N-dimethylformamide (15 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl(E)-3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propenoate (1.65 g, yield: 93%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 104˜105° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH2:32]C)([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N1CCCC(C(O)=O)CC1.C(=O)([O-])[O-].CO.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O)(=O)C>>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH2:32][CH:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: O=C(O)C1CCCNCC1
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCCC(C(=O)O)CC4)ccc3c2)CC1
Yield: 24 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using Perhydro-azepine-4-carboxylic acid (0.138 g, 0.967 mmol) HCl, 250 mg solid supported carbonate resin (1.34 mmol/g), Methanol (1.6 mL, 4.0E1 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.250 g, 0.805 mmol) and Acetic acid (0.16 mL, 2.8 mmol) to give 86 mg the title compound as a white solid (24%). ESI-LCMS 438 (M+H). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.96 (s, 1H), 7.81-7.91 (m, 2H), 7.51-7.65 (m, 1H), 7.43 (d, J=1.8 Hz, 1H), 7.14-7.26 (m, 1H), 4.45 (br. s., 3H), 3.00-3.57 (m, 4H), 2.63-2.75 (m, 1H), 1.58-2.33 (m, 10H), 1.00-1.51 (m, 6H), 0.89 (s, 9H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.O.[NH3:12]>>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:12])=[O:9])[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCOCC1
Reactant: N
Solvent: O
Product: NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 43.5 h
Yield: 74.6 %

Procedure:
To methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) was added concentrated ammonia water (50 mL), and the reaction mixture was stirred at room temperature for 43.5 hours. Thereafter, the reaction mixture was cooled in an ice water bath, and the precipitate was filtrated. Then, the precipitate was dried at 40° C. under reduced pressure, to obtain 33.4 g of a title compound (yield: 74.6%).
Reaction SMILES: [ClH:1].[CH3:2][NH:3][S:4](/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=1)(=[O:6])=[O:5]>CN(C=O)C.O.CO.[Pd]=O>[ClH:1].[CH3:2][NH:3][S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)(=[O:5])=[O:6]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 24 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulphonamide hydrochloride (500 g) and 10% palladium oxide on charcoal (50% wet paste, 700 g added as three charges) in DMF (3 L), water (3 L) and methanol (1.5 L) was hydrogenated at atmospheric pressure over 24 hr. The suspension was filtered and the filter cake washed with water (500 mL). The filtrate was concentrated to approximately 2 L by distillation in vacuo. Ethyl acetate (5 L) was added over 10 mins and the mixture cooled to 5°. The product was filtered off, washed with ethyl acetate (1 L) and dried in vacuo at 45° overnight (453 g, 90.1% of theory). Recrystallisation from hot water (1.36 L) afforded white crystals (324.0 g, 71.2% of theory).
Reaction SMILES: [C:1]1([CH3:42])[C:2]([S:7]([O:10][CH2:11][C@H:12]([CH2:21][O:22][C:23](=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:13][CH:14](OCC)[O:15]CC)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(OCC)(=O)C>[C:23]([O:22][CH2:21][C@@H:12]([CH2:11][O:10][S:7]([C:2]1[C:1]([CH3:42])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH:14]=[O:15])(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](COS(=O)(=O)c1ccccc1C)CC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CC=O)COS(=O)(=O)c1ccccc1C
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
The product of Example 31, step b) (29.38 g, assayed at 23.12 g, 0.037 moles) was dissolved in THF (90 mL) and charged into a 250 mL round bottomed flask equipped with a magnetic stir bar and a temperature probe. Charged water (38 mL) and cooled to 10° C. Trifluoroacetic acid (55 mL) was poured in and the mixture was stirred for 25 minutes. The reaction mixture was poured into a 2 L separatory funnel containing 20% (w/w) K2CO3 solution (690 g), ice (600 g), and ethyl acetate (500 mL). The upper organic layer was separated. The aqueous layer was extracted a second time with ethyl acetate (500 mL). The combined organic extracts were washed with 23% (w/w) NaCl solution. The organic layer was separated, dried with Na2SO4 and filtered. The solution was concentrated to 21.5 g of an oil, dissolved in heptane (150 mL), and stirred slowly (crystals formed after 10 minutes). The slurry was stirred 15 hrs. at ambient temperature, filtered and washed with ambient heptane (20 mL). The desired product was obtained as white crystals which were dried to a constant weight of 12.3 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:9]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH2:30])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:9]2[C:15]([NH:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[C:26]([F:27])([F:28])[F:29])=[O:17])=[CH:6][CH:7]=1
Reactant: NC(c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=C1CC[C@@H](C(=O)O)[C@H](c2ccc(Br)cc2)C1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: O=C1CC[C@@H](C(=O)NC(c2ccc(Cl)cc2)C(F)(F)F)[C@H](c2ccc(Br)cc2)C1

Procedure:
A solution of (1R,2R)-2-(4-bromophenyl)-4-oxo-cyclohexane-carboxylic acid (100 mg, 0.300 mmol), 1-(4-chlorophenyl)-2,2,2-trifluoro-ethanamine (the faster eluting enantiomer on AD-H chiral column using MeOH/SF CO2; 62.8 mg, 0.300 mmol) and HOBT (45.9 mg, 0.300 mmol) in CH2Cl2 (5 mL) was reacted with EDC (115 mg, 0.600 mmol) and DMAP (36.6 mg, 0.300 mmol). The reaction was aged at rt until it was complete. The mixture was concentrated and purified on a silica gel column by eluting with 0-50% EtOAc/hexanes to afford the title compound. HPLC/MS: 488.1/490.0 (M+1); Rt=1.19 min (LC-2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(C(C)C)C(C)C.[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C/c1cc(Br)ccc1N
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Temperature: 80 °C
Yield: 72.5 %

Procedure:
To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 2.29 mol, 1.0 equiv) in 1,4-dioxane (4.0 L) was added DIPEA (1.26 L, 8.88 mol, 3.9 equiv, GLR) and degassed with nitrogen for 20 mins. XantPhos (92.9 g, 106 mmol, 0.05 equiv, GLR), and tris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 equiv, Hindustan Platinum) was added to the reaction mixture. The mixture was purged with nitrogen and heated to 80° C. for 30 mins. The reaction was cooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equiv, Alfa Aesar) was added and the reaction was heated at 80° C. for an additional 4 h. The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was filtered through celite and the celite bed was washed with ethyl acetate (2×1.0 L). The filtrate was concentrated under reduced pressure to obtain the crude material which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%), as yellow solid. TLC solvent system: 30% ethyl acetate in hexanes. Product's Rf: 0.4. MS (ESI, positive ion) m/z; 314.1 (M+1). NMR (400 MHz, DMSO) δ 7.79 (d, J=16.1 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.25-7.17 (m, 5H) 7.10 (dd, J=8.4, 2.1 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.32 (d, J=15.2 Hz, 1H), 5.75 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.01 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41]>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccc1F
Agent: O=C(N=C=S)c1ccccc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 93%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])#[N:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:26]#[N:27])(=[O:36])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C#N)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-cyanobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:9]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>CCOC(C)=O>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[NH:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncccc1-c1ccncn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(N)cc1Nc1ncccc1-c1ccncn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The title compound was prepared according to the procedure described in J. Am. Chem. Soc. 1993, 115, 905-916. To [4-methyl-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester (550 mg, 1.46 mmol) was added CH2Cl2 (15 mL) and TFA (3.0 mL). The mixture was stirred for 3 h at 0° C., diluted with EtOAc and extracted with 50% aqueous Na2CO3. The organic layer was dried over Na2SO4, filtered and concentrated to yield 4-methyl-N3-(3-pyrimidin-4-yl-pyridin-2-yl)-benzene-1,3-diamine. MS m/z=278 [M+1]+. Calc'd for C16H15FN5: 277.33.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[C@H:14]([OH:26])[C@@H:13]1[OH:27])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].C(OC([NH:38][C@H:39]([C:55](O)=[O:56])[CH2:40][CH2:41][CH2:42][CH2:43][NH:44]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[ClH:1].[ClH:1].[NH2:38][C@H:39]([C:55]([NH:2][C@H:3]([C:8]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[C@H:14]([OH:26])[C@@H:13]1[OH:27])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5])=[O:56])[CH2:40][CH2:41][CH2:42][CH2:43][NH2:44]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 Gram (2.42 mmol) of 5'-O-isoleucyl-5-fluorouridine hydrochloride was dissolved in dimethylformamide (20 ml), and 1.00 g (2.85 mmol) of Nα,Nε -di-benzyloxycarbonyllysine and 0.67 g (3.69 mmol) of diethylphosphoryl cyanide were then added. To this solution was added under ice-cooling 1.54 g (15.2 mmol) of triethylamine, and the mixture was stirred overnight at room temperature. After addition of ice water the reaction liquid was extracted with chloroform (200 ml). The organic layer was dried (over Na2SO4) and concentrated under reduced pressure, and the residue was subjected to separation/purification by way of silica gel column chromatography (first time: 2.5×11 cm, chloroform containing 4% methanol; second time: 5×14 cm, a linear gradient of ethyl acetate-n-hexane (1:1) containing 0→6% methanol) whereby 0.46 g (26%) of 5'-O-{N-(Nα,Nε -di-benzyloxycarbonyllysyl)isoleucyl}-5-fluorouridine was obtained as a colorless powdery solid.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.I[CH:21]([CH3:23])[CH3:22]>O.CC(O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH2:7][N:8]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccnc1)C(=O)O
Reactant: CC(C)I
Solvent: O
Solvent: CC(C)O
Product: CC(C)N1C=C(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)C=CC1
Temperature: 0 °C
Reaction time: 96 h
Yield: 78.3 %

Procedure:
Boc-D-Pal (4.0 g, 17.7 mmol) and Ag2O (8.0 g, 34.4 mmol) in 22 ml water was stirred at room temperature for 4 hours. The reaction vessel was cooled to 0° C., and 2-iodopropane (20.4 g, 120 mmol) in 40 ml 2-propanol was added. After addition was complete, the mixture was allowed to warm to room temperature and stirred for 4 days. Additional Ag2O (2 g) and 2-iodopropane (2 g) were added after 24 hours and again after 48 hours. The mixture was filtered, and the precipitate was washed with ethanol (2×15 ml). The filtrate was evaporated to yield 4.3 g of a yellow oil. Crystallization from ethanol/ethyl acetate gave light yellow crystals (3.0 g); Yield: 63%; m.p. 182-185° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][C@@H:32]([F:33])[C@@H:28]([CH2:27][NH:26][CH:23]3[CH2:24][CH2:25]3)[CH2:29]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:17][CH2:18]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(N2C[C@H](CNC3CC3)[C@H](F)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 9 h
Yield: 68.6 %

Procedure:
5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (250 mg), (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), triethylamine (0.17 mL) and dimethylsulfoxide (4 mL) were mixed together. The mixture was stirred at 100° C. for 9 hours and was subsequently concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=40:1). The eluted yellow solid was recrystallized from ethanol to give 5-amino-1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid as yellow crystals (248 mg).
Reaction SMILES: [C:1]12([O:8][C:7]3[CH:9]=[CH:10][C:11]([C:13]4([C:16]([O:18]C)=[O:17])[CH2:15][CH2:14]4)=[CH:12][C:6]=3[O:5]1)[CH2:4][CH2:3][CH2:2]2.[Li+].[OH-].Cl>C1COCC1.O>[C:1]12([O:8][C:7]3[CH:9]=[CH:10][C:11]([C:13]4([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]4)=[CH:12][C:6]=3[O:5]1)[CH2:2][CH2:3][CH2:4]2
Reactant: COC(=O)C1(c2ccc3c(c2)OC2(CCC2)O3)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2ccc3c(c2)OC2(CCC2)O3)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a mixture of methyl 1-(spiro[benzo[d][1,3]dioxole-2,1′-cyclobutane]-5-yl)cyclopropanecarboxylate (0.60 g, 2.3 mmol) in THF/H2O (4:1, 10 mL) was added LiOH (0.30 g, 6.9 mmol). The mixture was stirred at 60° C. for 24 h. HCl (0.5 N) was added slowly to the mixture at 0° C. until pH 2-3. The mixture was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine, dried over anhydrous MgSO4, and washed with petroleum ether to give 1-(spiro[benzo[d][1,3]-dioxole-2,1′-cyclobutane]-5-yl)cyclopropane carboxylic acid (330 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 6.78-6.65 (m, 3 H), 2.65-2.58 (m, 4 H), 1.86-1.78 (m, 2 H), 1.63-1.60 (m, 2 H), 1.26-1.19 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CN(C)C=O>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][O:14][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: OCCOc1ccc(Oc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)OCCOc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of 2.5 g of 2-[p-(p-fluorophenoxy)phenoxy]-ethanol in 25 ml of dimethylformamide is added dropwise during 20 minutes while stirring to a suspension of 0.5 g of sodium hydride (55% in oil) in 5 ml of dimethylformamide. The mixture is then allowed to stir at 40° C. for 4 hours, then treated dropwise with 1.18 g of dimethylcarbamoyl chloride and allowed to react at 40° C. for 16 hours. The cooled mixture is poured into 75 ml of ice/water and extracted three times with 50 ml of ethyl acetate each time. The extracts are washed three times with 50 ml of water each time, dried and evaporated. The residue is purified by chromatography on silica gel with n-hexane/ethyl acetate (85:15) to yield pure [2-[p-(p-fluorophenoxy)phenoxy]-ethyl]N,N-dimethylcarbamate; nD20 =1.5444.
Reaction SMILES: CN(C)C=O.NC(N)=S.[Cl-].[NH4+].[C:12]1([CH2:18][C:19]([NH:21][CH:22]2[C:47](=[O:48])[N:24]3[C:25]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[C:26]([CH2:29]Cl)[CH2:27][S:28][C@H:23]23)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.[Zn]>[C:12]1([CH2:18][C:19]([NH:21][CH:22]2[C:47](=[O:48])[N:24]3[CH:25]([C:31]([O:33][CH:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:32])[C:26](=[CH2:29])[CH2:27][S:28][C@H:23]23)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: NC(N)=S
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -15 °C
Yield: 88.1 %

Procedure:
To N,N-dimethylformamide (20 ml) were added thiourea (0.76 g), zinc powder (0.5 g) and a solution of ammonium chloride (0.67 g) in water (3 ml). To the mixture was added benzhydryl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate (2.67 g) under cooling to -15° C. with stirring, and the mixture was stirred for an hour at -15° to -10° C., and then filtered. To the filtrate were added ethyl acetate (100 ml) and water (100 ml), and the organic layer was separated therefrom. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was pulverized with diisopropyl ether to give benzhydryl 7-phenylacetamido-3-methylenecepham-4-carboxylate (2.2 g).