Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:30][C:31]1[N:32]=[C:33]([Sn](CCCC)(CCCC)CCCC)[S:34][CH:35]=1.[Li+].[Cl-]>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:33]4[S:34][CH:35]=[C:31]([CH3:30])[N:32]=4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(-c3nc(C)cs3)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
To a suspension of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (40 mg, 0.0808 mmol, example 58) in dioxane (1.5 ml) was added a solution of 4-methyl-2-(tributylstannyl)-thiazole (38 mg, 0.0970 mmol) in dioxane (0.5 ml) and argon was bubbled through the resulting mixture for 10 minutes. Then LiCl (10 mg, 0.242 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.00404 mmol) were added and the mixture was stirred at reflux for 3.5 h. The reaction mixture was allowed to cool to room temperature, diluted with DCM and filtered through a pad of silica gel. The filtrate was evaporated and the remaining light brown solid was purified by silica column chromatography (DCM/EtOAc 4:1) to obtain a white solid (15 mg) which was triturated with ether to obtain the title compound (9 mg, 22%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:26](OCC)=[O:27]>CN(C=O)C>[CH:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CCOC=O
Solvent: CN(C)C=O
Product: O=CNc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
200 mg (0.6 mmol) of (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and 5 ml of ethyl formate are stirred in 2.5 ml of DMF for 60 hours at 90° C. After removal of the solvent in vacuo ethyl acetate is added and the mixture is again concentrated by evaporation. The residue is stirred with ether, suction filtered and dried.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[CH:28]\[CH2:29][OH:30])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:30][CH2:29]/[CH:28]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]\1[CH2:19][C:20](=[O:51])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1/C(=C/CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1/C(=C/CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 60 %

Procedure:
The title compound II-bh was prepared in 60% yield from 3,3:17,17-bis(ethylendioxy)-6-(E)-(2-hydroxyethylidene)androstane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 70/30). 1H-NMR (300 MHz, acetone-d6, ppm from TMS: δ 5.14 (m, 1H), 4.17 (m, 2H), 3.53 (t, 1H), 2.84 (dd, 1H), 2.65-1.01 (m, 20H), 0.97 (s, 3H), 0.85 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[Br:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([Cl:9])=[C:6]([CH2:8][CH:20]([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(Br)c(C#N)nc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1nc(Cl)c(CC(O)c2ccccc2)cc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 3-bromo-6-chloro-5-methylpicolinonitrile (from the previous step) in THF (0.2 M) was cooled to −78° C. LDA (2N solution, 2 eq) was added dropwise. The reaction was kept stirring at −78° C. for 1 hour, followed by addition of benzaldehyde (1 eq). The reaction was kept stirring at −78° C. for another 30 minutes before allowing it to slowly warm to room temperature. The reaction was quenched with sat. NH4Cl and extracted with EtOAc. Combined organic washes were concentrated. Flash chromatography (silica gel, 20-50% EtOAc in hexanes) afforded the product 3-bromo-6-chloro-5-(2-hydroxy-2-phenylethyl)picolinonitrile as a yellow solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[NH2:12][C:13]([CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=2)[CH2:21]1)([CH3:19])[C:14](OCC)=[O:15]>C(OCC)(=O)C>[NH2:12][C:13]([CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=2)[CH2:21]1)([CH3:19])[CH2:14][OH:15]
Reactant: CCOC(=O)C(C)(N)C1CCc2cc(OC)ccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(C(C)(N)CO)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a 2 L flask cooled by ice water was added 60 g LiAlH4, and 1 L of THF. When the mixture was cooled to below 10° C., a mixture of 118.8 grams of ethyl 2-amino-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate and 350 mL THF was added dropwise. No starting material remained by HPLC. The temperature was kept below 30° C. while 100 mL ethyl acetate was added. To the concentrated mixture was added 400 mL ethyl acetate, followed by 25 mL ice water. The mixture was filtered, and the filter cake with 300 mL ethyl acetate. The combined organic layers washed with brine 100 mL×2, dried with Na2SO4, decolorized with carbon and concentrated. To the oil, was added ether, the mixture stirred for overnight, filtered and dried to afford 50 g of 2-amino-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol.
Reaction SMILES: CNC(NC)=O.[P:7]([O:22]C1C=CC=CC=1)([O:15]C1C=CC=CC=1)[O:8]C1C=CC=CC=1.CCCC=S.[CH3:34][N:35]1[C:39](=[O:40])[N:38]([CH3:41])[CH:37]([CH2:42][CH2:43][S:44][CH3:45])P1(=O)OC1C=CC=CC=1.C1(O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:41][N:38]([CH:37]([P:7](=[O:8])([OH:15])[OH:22])[CH2:42][CH2:43][S:44][CH3:45])[C:39]([NH:35][CH3:34])=[O:40]
Reactant: CSCCC1N(C)C(=O)N(C)P1(=O)Oc1ccccc1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Agent: CCCC=S
Agent: CNC(=O)NC
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C(CCSC)P(=O)(O)O

Procedure:
When a mixture of 0.5 mole each of 1,3-dimethylurea, triphenyl phosphite, and 3-methylthiopropionaldehyde in 100g of toluene is warmed to 75°, a reaction is initiated and the temperature increases rapidly to 120°. After further warming at 105° for 1 hr, the resulting yellow product has a 31P nmr signal at -28.2 ppm for the cyclic ester, 1,4-dimethyl-3-(2-methylthioethyl)-2-phenoxy-1,4,2-diazaphospholidin-5-one-2-oxide. The above product is then employed in a toluene solution from which byproduct phenol is removed by stripping to 110° /1 mm, after which one-third of the residue is dissolved in 75ml of acetonitrile and 10g of water, and this solution is refluxed for 3 hr. The reaction mixture is allowed to evaporate to dryness, and the residue is extracted with ether and then with hot acetonitrile and recrystallized twice from acetic acid to give a white solid: mp 164.5°-167°; 31P nmr (DMSO-d6) -21.4 ppm; 1H nmr 9.6 (broad, 2, OH), 4.5 (m, 1, PCH), 2.8 (s, NCH3), 2.6 (s, NCH3), 2.0 (s, SCH3), 1.9-2.6 (m, CH2CH2S).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: CCc1cc2c(NCc3ccccc3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[C:12](C(O)=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].C(=O)=O.C1(C)C=CC=CC=1>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(C=C(C(=O)O)c2ccccc2)c1
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(C=Cc2ccccc2)c1
Temperature: 220 °C
Yield: 90.1 %

Procedure:
1 g of copper powder was added to 13 g (0.044 mol) of 3-(2-carboxy-2-phenyl-vinyl)-benzoic acid ethyl ester, dissolved in 100 ml of quinoline, and the mixture was heated to 220° C., whilst stirring, until no further evolution of carbon dioxide could be observed (about 1 hour). The mixture was then cooled immediately to room temperature. After adding 300 ml of toluene to the reaction mixture, it was extracted by shaking twice with 100 ml of concentrated hydrochloric acid each time and then washed with 500 ml of water. The organic phase was separated off and dried over magnesium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was distilled in vacuo. 10 g (90.2% of theory) of 3-(2-phenyl-vinyl)-benzoic acid ethyl ester were obtained as a yellow oil with the boiling point 165°-170° C./2 mm Hg (isomer mixture with a cis proportion of about 90%). ##STR61##
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][NH2:36]>>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:36]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=465.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.O=S(Cl)[Cl:16].CN(C=O)C>C(Cl)Cl>[Cl:16][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1CCl
Reaction time: 16 h
Yield: 92.1 %

Procedure:
To a solution of (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (14.5 g, 71 mmol) in 100 mL CH2Cl2 at room temperature under argon was added SOCl2 (16.8 g, 142 mmol), followed by about 1.5 mL DMF, which was added to re-dissolve the rapidly formed, precipitating hydrochloride salt of the starting material. The resulting reaction mixture was stirred for 16 h. HPLC/MS analysis indicated that the reaction was complete. Solvent was evaporated under vacuum. The resulting residue was dissolved in 200 mL Et2O, and the resulting solution was washed with 10% aqueous sodium carbonate solution (100 mL), then saturated aqueous NaCl (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 13.7 g of the title compound as a tan oil, which was greater than 98% pure. HPLC/MS: retention time=2.9 min, [M+H]30 =210.
Reaction SMILES: [OH:1][C@@:2]1([CH3:20])[CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[C@H:3]1[CH:17]([CH3:19])[CH3:18]>O>[CH:17]([C@H:3]1[C@@:2]([CH3:20])([OH:1])[CH2:6][CH2:5][NH:4]1)([CH3:19])[CH3:18]
Reactant: CC(C)[C@@H]1N(C(=O)OCc2ccccc2)CC[C@]1(C)O
Solvent: O
Product: CC(C)[C@@H]1NCC[C@]1(C)O

Procedure:
By an operation in the same manner as in Reference Example 4 and using benzyl (2S,3S)-3-hydroxy-2-isopropyl-3-methylpyrrolidine-1-carboxylate (1.78 g) and 50% water containing −10% Pd/C (0.09 g), the title compound was obtained as a colorless solid (yield: 1.07 g, yield: 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(OC)c(C)c1
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(OC)cc1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
2-Methyl-1,4-bis(methyloxy)benzene (6.12 g, 40 mmol) was dissolved in acetic acid (20 mL) and heated at 40° C. A solution of nitric acid (4.32 g) in acetic acid (10 mL) was added to above solution drop wise over 5 minutes. The reaction mixture was stirred at 40° C. for 30 min (yellow precipitates formed), then room temperature for 30 min and then diluted with water (300 mL). The precipitate was collected by filtration, washed with water, and dried in the air for 16 h to afford the title compound (7.56 g, 96%) as a yellow solid. MS (ES) m/e 198 [M+H]+.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[F:16][C:17]1[C:18](I)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:16][C:17]1[C:18]([C:14]#[C:13][C@@H:12]2[CH2:11][C@H:10]([OH:15])[CH2:9][NH:8]2)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: C#C[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H]3C[C@H](O)CN3)c21
Reaction time: 2 h

Procedure:
Using Method C above, (3S,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (132 mg, 0.62 mmol) (Example 103A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated, and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 4 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.2 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (Z)-1,3-Dihydro-5-fluoro-4-[(2S,4S)-(4-hydroxy-pyrrolidin-2-yl)-ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 45 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1.O>[C:16]1([S:22]([NH:1][C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Yield: 41.5 %

Procedure:
Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.113 g) was added to a solution of benzenesulphonyl chloride (0.097 g) in pyridine (5 ml) and the resultant solution was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with hydrochloric acid (1M), water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane (5%) to give ethyl 2-benzenesulphonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.076 g) as a pale yellow solid.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:16]>>[Na+:16].[C:1]1([NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([O-:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])/C=C\C(=O)Nc1ccccc1

Procedure:
Aniline (1 mol) and maleic anhydride (1.0 mol) were subjected to an addition reaction at 20 to 30° C. for 2.5 hours to give N-phenylmaleamidic acid. Then, the resulting N-phenylmaleamidic acid was neutralized with sodium hydroxide under cooling to give an N-phenylmaleamidic acid sodium salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:21]([NH2:22])=[C:20]([O:28][CH3:29])[CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)CCC>[F:17][C:18]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: Clc1nccc(-c2cnn3c2CCCC3)n1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 37.5 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (Intermediate 128, 3.6857 g, 15.70 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 2.92 g, 15.70 mmol) and p-toluenesulfonic acid hydrate (3.29 g, 17.28 mmol) in 2-pentanol (100 mL) was stirred at 85° C. under an atmosphere of N2 for 1.5 h. The mixture was then concentrated in vacuo and the resulting reside was dissolved in CH2Cl2 (250 mL). This solution was washed with sat. NaHCO3 (2×100 mL), water (100 mL), and sat. brine (100 mL). The organic solution was concentrated in vacuo to give crude product. Purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 provided an orange solid. This material was triturated with CH3OH to give a solid which was collected by filtration and dried in vacuo to give the title compound (2.26 g, 37%) as a yellow solid; 1H NMR: 1.75-1.86 (2H, m), 1.92-2.04 (2H, m), 3.09 (2H, t), 4.02 (3H, s), 4.12 (2H, t), 7.13 (1H, d), 7.35 (1H, d), 8.14 (1H, s), 8.25 (1H, s), 8.42 (1H, d), 9.02 (1H, d); m/z: ES+ MH+ 385.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:21]([O:23]C(C)(C)C)=[O:22])=[C:14]([CH2:19][Br:20])[CH:15]([Br:18])[S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:21]([OH:23])=[O:22])=[C:14]([CH2:19][Br:20])[CH:15]([Br:18])[S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
A mixture of 12.5 g of t-butyl 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylate-1-oxide and 50 ml of trifluoroacetic acid was stirred at room temperature for 15 minutes and was then evaporated to dryness under vacuo. 25 ml of dichloromethane were added to the residue and evaporation to dryness was repeated. A 1:1 mixture of ether and heptane was added to the residue and the formed crystals were vacuum filtered and washed with the same mixture to obtain 9.6 g of 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylic acid-1-oxide as an almost colorless solid, having the following characteristics:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32]CC)=[O:31])=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=3)=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Oc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (0.73 g dissolved in 25 mL water) is added to a solution of 7-(4-ethoxycarbonyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (3.00 g) in ethanol (100 mL). The resulting suspension is stirred at 45° C. overnight. The solution is concentrated and the aqueous residue is adjusted to pH value 2-3 using 1 M hydrochloric acid. Then dichloromethane is added and the mixture is stirred for 10 min. The organic phase is separated and the aqueous phase is extracted with dichloromethane twice. The combined organic phases are dried (Na2SO4) and concentrated. The residue is purified by chromatography on silica gel (petrol ether/ethyl acetate/acetic acid 50:50:0.5) to furnish the title compound as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[N:7][O:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:4].Cl>CO>[C:3]([C:5]1[C:6]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[N:7][O:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([OH:4])=[O:2]
Reactant: CCCCCCc1onc(-c2c(F)cccc2F)c1C(=O)OC
Agent: Cl
Solvent: CO
Product: CCCCCCc1onc(-c2c(F)cccc2F)c1C(=O)O
Temperature: 50 °C
Yield: 77.2 %

Procedure:
4-Methoxycarbonyl-5-hexyl-3-(2,6-difluorophenyl)isoxazole (0.30 g, 0.88 mmol) was dissolved in methanol (10 ml), 5N NAOH (1 ml) was added, and the mixture was heated at 50° C. for 2 h. Upon cooling to room temperature, HCl was added until pH 1. Extraction with ethyl acetate and subsequent washing of the organic fraction (brine), drying (MgSO4), filtering, and concentrating afforded the desired 4-carboxy-5-hexyl-3-(2,6-difluorophenyl)isoxazole (0.21 g, 72%) that was used without further purification.