Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH3:15])[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)=O.C([O-])(=O)C.[NH4+:22].CC(O)=O.[OH-].[Na+]>O>[CH3:15][N:5]1[CH:4]=[CH:3][N:22]=[C:6]1[C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1
Reactant: COC(CN(C)C(=O)[C@H]1CC[C@H](O)CC1)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cn1ccnc1[C@H]1CC[C@H](O)CC1
Temperature: 125 °C

Procedure:
A mixture of trans-N-(2,2-Dimethoxyethyl)-4-hydroxy-N-methylcyclohexanecarboxamide (265 mg, 1.08 mmol) and Ammonium acetate (2.2 g, 29 mmol) in AcOH (3.0 mL, 53 mmol) was heated to reflux (oil bath temperature 125° C.) for 16.5 h. To the cooled solution were added 10 N NaOH (≈10 mL) and water (≈10 mL), and the mixture was extracted with DCM (3×20 mL). The combined DCM extracts were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound as light orange solid. Additional material was obtained by saturating the aqueous layer from the previous extractions with NaCl and extracting with more DCM (4×25 mL). The light orange solid was chromatographed on silica gel [Isco Combiflash, 2.5 g loading column/4 g Gold column, eluting with DCM→10% 7N NH3 in MeOH] to give the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.92 (d, J=1.4 Hz, 1H), 6.77 (d, J=1.4 Hz, 1H), 3.73 (tt, J=10.8, 4.2 Hz, 1H), 3.60 (s, 3H), 2.60 (tt, J=12.0, 3.6 Hz, 1H), 2.18-2.08 (m, 2H), 1.99-1.91 (m, 2H), 1.88 (brs, 1H), 1.83-1.71 (m, 2H), 1.46-1.35 (m, 2H). MS (ES+): m/z=181.13 (100) [MH+]. HPLC: tR=0.69 min (very polar—5 min, ZQ3). UV: λmax=216 nm.
Reaction SMILES: [F:1][C:2]([F:34])([CH:8]([OH:33])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=3)[CH:18]=[C:17]([CH3:32])[CH:16]=2)=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1CCN2C(=NCCC2)CC1.[C:46](=[S:48])=[S:47].[CH3:49]I>O.CN(C=O)C>[F:34][C:2]([F:1])([CH:8]([O:33][C:46]([S:48][CH3:49])=[S:47])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][N:23]=3)[CH:18]=[C:17]([CH3:32])[CH:16]=2)=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: S=C=S
Reactant: CI
Reactant: CCOC(=O)C(F)(F)C(O)c1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(F)(F)C(OC(=S)SC)c1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of ethyl 2,2-difluoro-3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate (86.9 mg, 0.180 mmol), anhydrous DMF (1.00 mL), DBU (0.170 mL, 1.13 mmol) and CS2 (0.110 mL, 1.83 mmol) was stirred at room temperature for 1 hour under Ar(g). Methyliodide (0.110 mL, 1.76 mmol) was added to the reaction mixture and t stirred for 45 minutes at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (20% ethyl acetate in hexanes) to afford ethyl 2,2-difluoro-3-{[(methylsulfanyl)carbonothioyl]oxy}-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate. MS APCI C24H22F5N4O3S2 [M+H]+ 573. found 573.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[CH2:21]([S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22]>>[CH2:21]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)(=[O:24])=[O:25])[CH3:22]
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1

Procedure:
The title compound is prepared starting with (4-Bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone and 4-ethanesulfonylphenyl boronic acid perform a procedure analogous to Procedure FF. MS (m/e): 427.2 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:37]([CH2:45][CH3:46])[CH2:38][CH2:39][CH:40]([OH:44])[CH2:41][CH2:42][CH3:43])[CH3:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:44][CH:40]([CH2:39][CH2:38][N:37]([CH2:35][CH3:36])[CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCC(O)CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC(CCN(CC)CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 12 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-(diethylamino)-3-hexanol (45 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (10 mg, yield 10%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:34]2[CH:35]=[N:36][N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:33])[C:17]([N:22]([CH3:32])[CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:34]2[CH:35]=[N:36][N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]([CH3:32])[CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[C:16]([NH:33][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N(C)CCN2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N(C)CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution of acryloyl chloride (0.028 mL, 0.35 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of N4-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-5-methoxy-N1-methyl-N1-[2-(4-methylpiperazin-1-yl)ethyl]benzene-1,2,4-triamine (Intermediate 107, 0.174 g, 0.33 mmol) in CH2Cl2 (2.5 mL) under N2. The mixture was then stirred at r.t. for 1 h and was then diluted with CH2Cl2 (25 mL). This solution was washed with sat. NaHCO3 (25 mL) and the aqueous wash solution was extracted with CH2Cl2 (20 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-8% CH3OH in CH2Cl2 gave the title compound (0.12 g, 63%) as a beige foam; 1H NMR: (CDCl3) 2.31 (3H, s), 2.35-2.6 (10H, m), 2.67 (3H, s), 3.00 (2H, t), 3.88 (3H, s), 5.64-5.82 (1H, m), 6.31-6.50 (2H, m), 6.79 (1H, s), 6.91 (1H, t), 7.29 (1H, t), 7.48 (1H, s), 8.47 (1H, s), 8.54 (2H, t), 8.94 (1H, s), 9.15 (1H, s), 9.38 (1H, s); m/z: ES+ MH+ 576.59.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH2:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:22]=2[CH3:29])=[CH:16][C:15]=1[F:30])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O.O>[C:1]([O:5][C:6](=[O:31])[N:7]([CH2:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:33])[NH2:28])=[CH:23][C:22]=2[CH3:29])=[CH:16][C:15]=1[F:30])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C#N)ccc1-c1cc(F)c(CN(CCC(C)C)C(=O)OC(C)(C)C)c(F)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C(N)=O)ccc1-c1cc(F)c(CN(CCC(C)C)C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
(4′-Cyano-3,5-difluoro-2′-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1d: 30 g) was dissolved in 150 mL dimethyl sulfoxide and combined with potassium carbonate (20 g) and 20 mL of a 30% hydrogen peroxide solution in water. After stirring at room temperature for 12 hours, the reaction mixture was quenched with water and extracted using ethyl acetate (250 mL). The organic layer was washed with water (2 times), brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica eluting with 50% ethyl acetate in heptane to provide 28 g of the title compound (I-1e).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].O[C:9]1[C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:22][CH3:23])[C:14](=[O:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1.Cl[CH2:26]CN(C)C.[CH3:31][OH:32]>ClC1C=CC=CC=1>[CH2:4]([N:5]([CH2:7][CH3:26])[CH2:6][CH2:31][O:32][C:9]1[C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:22][CH3:23])[C:14](=[O:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:3]
Reactant: CN(C)CCCl
Reactant: COc1cccc2c1-c1c(O)cccc1C2=O
Reactant: CO
Agent: Cl
Solvent: Clc1ccccc1
Product: CCN(CC)CCOc1cccc2c1-c1c(OC)cccc1C2=O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
In a manner similar to Example 2B, prepare the free base of 2 -chloroethyl-dimethylamine hydrochloride (0.60 g, 3.5 mmole). As before, separately prepare a solution of 4-hydroxy-5-methoxy-fluoren-9-one (0.54 g, 2.4 mmole) in methanol (4 mL) and chlorobenzene (12 mL), heating to 130° C. while stirring for 30 minutes. Cool reaction to 100° C. before adding the free base of 2-chloroethyl-dimethylamine prepared previously in 15 mL chlorobenzene. Proceed as before in Example 2B to obtain the title compound as an orange-yellow powder (0.79 g, 91%). m.p. 188-191° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[N:8]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12][CH2:11][CH:10]([C:14](OCC)=O)[CH2:9]1.C[Al](C)C.O>C1(C)C=CC=CC=1>[CH2:6]1[N:7]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:9]2)[N:1]2[CH2:5][CH2:4][CH2:3][CH:2]12
Reactant: NCC1CCCN1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(C2=NCC3CCCN23)C1
Temperature: 110 °C
Yield: 43.2 %

Procedure:
To a solution of pyrrolidin-2-ylmethanamine (250 mg, 2.5 mmol) in toluene (8.5 mL) was added 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (635 mg, 2.5 mmol) under nitrogen. The solution was cooled with an ice-water bath and trimethylaluminum (2M in toluene, 2.2 mL, 4.4 mmol) was added. The resulting solution was transferred to a pressure tube and heated to 110° C. for 18 h. The reaction mixture was cooled to room temperature and water was added (10 mL). The mixture was extracted with dichloromethane (40 mL×2). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford tert-butyl 3-(5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-3-yl)piperidine-1-carboxylate as a colorless oil (317 mg, 43.8%). MS (ES+) (M+H) 294.2; LCMS retention time: 1.03 minutes (Method M).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1ccnc(N)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1ccnc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)c1
Yield: 55.3 %

Procedure:
5.0 gm (0.016 mol) of 4-hydroxy-2-methyl-2H-naphtho[ 2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 2.2 gm (0.02 mol) of 2-amino-4-methylpyridine in 220 ml of xylene analogous to Example 10, and yielded 3.5 gm (58% of theory) of 4-hydroxy-2-methyl-N-(4-methyl-2-pyridyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 221° C (decomp.; from ethyl acetate).
Reaction SMILES: C([O:5][C:6](=NNC(N)=O)[CH2:7][C@H:8]([NH:11][C:12](=[O:37])[CH2:13][N:14]([C:22](=[O:36])[C@@H:23]([NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:24]([CH3:26])[CH3:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=[O:10])(C)(C)C.C(O)(C(F)(F)F)=[O:44]>C(Cl)Cl>[C:28]([NH:27][C@@H:23]([CH:24]([CH3:26])[CH3:25])[C:22]([N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][C:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:5])=[O:44])=[O:37])=[O:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C)Cc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1ccccc1
Reaction time: 4 h

Procedure:
To a suspension of compound 705 (600 mg, 1.04 mmol) in CH2Cl2 (10 mL) was added TFA (4.0 mL) and the reaction allowed to stir for 4 hr. The reaction was concentrated in vacuo and the residue co-concentrated with toluene (3×). The residue was dissolved in MeOH (10 mL) and treated with HOAc (2.0 mL) followed by formaldehyde (2.0 mL). After stirring for 3 hr at rt, the reaction was concentrated in vacuo. Prep-HPLC provided 89 mg of compound 706: 1H NMR (500 MHz, CD3OD) 68.34-8.21 (m), 7.80-7.69 (m), 7.51-7.02 (m), 4.99-4.81 (m), 4.73-4.59 (m), 4.57-4.56 (m), 4.35-4.12 (m), 4.07-3.96 (m), 3.93-3.84 (m), 2.64-2.51 (m), 2.49-2.31 (m), 2.29-2.13 (m), 1.02-0.80 (m). ##STR85##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][C:10]([OH:12])=O)=[O:8].[NH2:13][CH:14]1[C:33](=[O:34])[N:16]2[C:17]([C:30]([OH:32])=[O:31])=[C:18]([C:21]([S:23][C:24]3[N:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:22])[CH2:19][S:20][C@H:15]12>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][C:10]([NH:13][CH:14]1[C:33](=[O:34])[N:16]2[C:17]([C:30]([OH:32])=[O:31])=[C:18]([C:21]([S:23][C:24]3[N:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:22])[CH2:19][S:20][C@H:15]12)=[O:12])=[O:8]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(=O)Sc3cccnn3)CS[C@H]12
Reactant: O=C(O)CS(=O)c1ccccn1
Product: O=C(CS(=O)c1ccccn1)NC1C(=O)N2C(C(=O)O)=C(C(=O)Sc3cccnn3)CS[C@H]12

Procedure:
370 mg. of 2-pyridylsulfinylacetic acid and 7-amino-3-(1-oxopyridazine-3-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 341 mg. of 7-(2-pyridylsulfinylacetamido)-3-(1-oxopyridazine-3-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH2:2]2.CC1C=C(OC)C=CC=1C=C[C:13]([O-])=[O:14].C(N(CC)CC)C.C(Cl)(=O)C=CC1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[CH:1]12[CH2:7][CH:4]([CH:3]=[CH:2]1)[CH2:5][CH:6]2[CH2:13][OH:14]
Reactant: COc1ccc(C=CC(=O)[O-])c(C)c1
Reactant: C1=CC2CCC1C2
Agent: O=C(Cl)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC1CC2C=CC1C2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(exo-rich) 5-norbornene-2-methanol (15 g, 0.121 mol) that was synthesized in (2) of Example 1, triethylamine (Aldrich, 61.2 g, 0.605 mol), and 20 ml of THF were put into the two-neck flask having the volume of 250 ml, and then agitated in the ice-water bath at 0° C. Cinnamoyl chloride (22.1 g, 0.133 mol) was dissolved in 60 ml of THF and then slowly added to the above reactant by using the additional flask. After 10 min, the reactant was heated to normal temperature and the agitation was additionally performed for 1 hour. The solution was diluted with ethyl acetate, moved to the separatory funnel, washed by using water and NaHCO3 several times, and subjected to the distillation under reduced pressure to remove the solvent. The purification was performed by using the column chromatography (hexane:ethyl acetate=20:1) to obtain the product (yield: 88%). The molar ratio (mol %) of the exo isomer and the endo isomer of the product was 58:42.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[CH2:10][C:11]#[N:12]>CCCCCCC>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:10][C:11]#[N:12]
Reactant: N#CCCl
Reactant: OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Product: N#CCOCC(F)(F)F
Temperature: 25 °C

Procedure:
At about 50° C., 26.4 g (0.40 mole) of 85% potassium hydroxide are solubilized in 100 g (1.0 mole) of 2,2,2-trifluoroethanol. After cooling at 25° C., 37.8 g (0.50 mole) of chloroacetonitrile are added dropwise to this solution. The temperature rises slowly to 40° C. and a precipitate appears. The reaction mixture is then brought gradually to 60° C.; after the addition of 300 ml of heptane, it is then brought to reflux. The whole of the vapour is condensed by means of a Dean and Stark apparatus. The lower phase of the condensate is separated after settling has taken place and distilled at atmospheric pressure. Yld: 19.6 g (28%), b.p. 125°-140° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:20]=[O:21])C>>[C:1]([O:21][CH:20]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12][C:11]1=[O:16])([CH3:7])([CH3:6])[CH3:2]
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: CN(C)C=O
Product: CC(C)(C)OC=C1C(=O)Nc2ccc(-c3ccccc3)cc21
Yield: 10 %

Procedure:
A solution of 0.62 g (3.0 mmol) of 5-phenyl-1,3-dihydro-indol-2-one (Hewawasam and Meanwell, Tetrahedron Letters 1994, 35, 7303–6) in 10 mL of DMF was treated with 0.90 g (4.5 mmol) of DMF di-tert-butyl acetal for 2 h at rt. DMF was removed under high vaccum, and the residue was subjected to chromatography on silica gel, eluting with hexane:EtOAc (1:1), to yield 0.09 g (10%) of 3-tert-butoxymethylene-5-phenyl-1,3-dihydro-indol-2-one: 1H NMR (DMSO-d6): δ 1.46 (s, 9H), 6.85 (d, J=8.0 Hz, 1H), 7.27 (t, J=7.3 Hz, 1H), 7.34–7.39 (m, 1H), 7.41 (d, J=7.5 Hz, 2H), 7.53 (d, J=7.5 Hz, 2H), 7.72 (s, 1H), 7.83 (s, 1H), 10.28 (s, 1H); APCI+MS m/z 316 (M+23)+. Further elution with EtOAc:MeOH (98:2) gave 0.11 g (14%) of 3-dimethylaminomethylene-5-phenyl-1,3-dihydro-indol-2-one.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:9]1[CH2:10][CH2:11][C@@H:7]([F:6])[CH2:8]1)=[O:4]
Reactant: F[C@@H]1CCNC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCl)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 357.5 %

Procedure:
Chloroacetyl chloride (632 μl, 7.94 mmol) was added dropwise to a solution of (3R)-3-fluoropyrrolidine (1 g, 7.94 mmol) and triethylamine (2.2 mL, 15.9 mmol) in CH2Cl2 (20 mL) at 5° C. The reaction mixture was stirred at room temperature for 1 h. Water and CH2Cl2 were added. The layers were separated and the aqueous was extracted with CH2Cl2. The combined organics were dried (MgSO4), filtered and concentrated in vacuo, to yield 2-chloro-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone (4.7 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH:29]=[N:28][C:27]=4[CH3:31])[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH:29]=[N:28][C:27]=4[CH3:31])[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2scnc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2scnc2C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(4-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (284 mg) in a mixture of tetrahydrofuran (18 ml) and methanol (18 ml) was added 1N sodium hydroxide solution (6 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(4-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (201 mg) as yellow crystals.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:6][CH2:5][CH:3]1[CH2:4][O:1][CH2:2]1)(=[O:17])=[O:16]
Reactant: OCC1COC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1COC1
Temperature: 0 °C

Procedure:
Oxetan-3-ylmethanol (1.85 g, 21.0 mmol) was dissolved in methylene chloride and cooled to 0° C. Triethylamine (5.31 g, 52.2 mmol) was added followed by slow addition of methanesulfonyl chloride (2.89 g, 25.2 mmol). The mixture was allowed to warm to ambient temperature for 2 h and quenched with sat. sodium bicarbonate (14 mL). The aqueous solution was extracted with methylene chloride 3×. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give crude oxetan-3-ylmethyl methanesulfonate (quant.).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.C([O:15][C:16]([C:18]1[C:27]2[C:26]3[N:28]=[CH:29][N:30]=[CH:31][C:25]=3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=O)C.O>C(Cl)Cl.[NH4+].[Cl-]>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16]([C:18]1[C:27]2[C:26]3[N:28]=[CH:29][N:30]=[CH:31][C:25]=3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=[O:15]
Reactant: CCOC(=O)c1c[nH]c2c1-c1ncncc1CCC2
Reactant: Nc1ccccc1F
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1F)c1c[nH]c2c1-c1ncncc1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 2-fluoroaniline (108 mg, 0.972 mmol) in CH2Cl2 (2.0 mL) at 0° C. under N2 is slowly added AlMe3 (0.49 mL, 2.0 M in toluene). The resulting solution is stirred at room temperature for 1 h. Next, 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester (50 mg, 0.194 mmol) is added in one portion. The resulting mixture is then stirred at reflux for 2 h. After cooling, the reaction mixture is carefully diluted with saturated aq NH4Cl (˜5 mL) and some H2O. The mixture is stirred vigorously for 15 min. and then extracted three times with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 40:1 CHCl3—MeOH followed by 30:1 CHCl3—MeOH and finally 20:1 CHCl3—MeOH afforded 45 mg (72%) of 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid (2-fluoro-phenyl)-amide as a light yellow solid. Electrospray mass spectrum: m/z 321 [M−1].