Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][CH:13]2[NH:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([CH:8]1[CH2:14][CH:13]2[N:15]([CH2:32][CH2:31][CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:25][CH:26]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(CC2CC3CCC(C2)N3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: c1ccc(COc2ccc(CCCN3C4CCC3CC(Cc3ccccc3)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.6 %

Procedure:
A mixture of 0.18 g of 3-benzyl-8-aza-bicyclo[3.2.1]octane, 0.30 g of 3-(4-benzyloxy-phenyl)-propionaldehyde, 5 mL of 1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography eluting with 80:20 EtOAc:MeOH gave 0.28 g of 3-benzyl-8-[3-(4-benzyloxy-phenyl)-propyl]-8-aza-bicyclo[3.2.1]octane as a 2:1 mixture of exo:endo isomers. Hydrogenation at 1 atm over 0.2 g of 10% Pd/C in 50 mL of ethanol gave 0.17 g of 4-[3-(3-benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-phenol as a 2:1 mixture of exo:endo isomers: MS (m+1)=336.4; 1H NMR (400 MHz, CDCl3) 7.25-7.1 (complex, 5H), 6.8 (d, 2H), 6.5 (d, 2H), 3.35 (br s, 2H), 2.75 (d, 0.6 H), 2.5-2.3 (complex, 5.4 H), 2.1 (m, 2H), 1.95 (m, 1H), 1.85 (m, 3H), 1.5 (m, 3H), 1.4 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH3:3].[CH3:11][N:12]([CH3:19])[CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH2:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH3:1][C:2]([CH3:10])([C:4](=[O:9])[CH2:5][C:6](=[N:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][N:12]([CH3:19])[CH3:11])[CH3:7])[CH3:3]
Reactant: CN(C)CCOCCN
Reactant: CC(=O)CC(=O)C(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(CC(=O)C(C)(C)C)=NCCOCCN(C)C
Reaction time: 72 h

Procedure:
In a 100 mL round bottom flask equipped with a magnetic stirrer, 8 g 2,2-dimethylhexane-3,5-dione was combined with 1.1 equivalents of 2-(2-(dimethylamino)ethoxy)ethylamine, anhydrous sodium sulfate and anhydrous diethyl ether and stirred over three days under nitrogen. The ether was removed on a rotary evaporator and the residue was vacuum distilled through a Vigreux column to yield 9.7 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)(O)[CH3:14])[CH:7]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][CH:6]3[C:5]=2[CH:4]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8](/[CH:12]=[C:13](\[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)/[CH3:14])[C:7]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C1CN(C)CCC1N2CC(C)(O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)c1c(n2/C=C(/C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(8-Methoxy-2-methyl-2,3,4,4a-tetrahydro-1H-pyrido[4,3-b]indol-5(9bH)-yl)-2-(pyridin-4-yl)propan-2-ol (500 mg, 1.4 mmol) was dissolved in thionylchloride (5 mL) was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (4 mL) and stirred for 5 min. Powdered KOH (798 mg, 14.2 mmol) was added and stirring was continued at RT for additional 5 min. The reaction mixture was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was cooled at RT, diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated and purified the compound by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.25 (d, 2H), 7.0 (m, 4H), 6.90 (d, 1H), 6.70 (d, 1H), 3.90 (m, 2H), 3.80 (s, 3H), 3.0 (t, 2H), 2.70 (s, 3H), 2.62 (m, 2H), 1.95 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:25]=1)[N:7]=[C:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]([C:12]([O:14]CC)=[O:13])=[CH:11]2.[OH-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:25]=1)[N:7]=[C:8]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11]2
Reactant: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=Nc2cc(Br)ccc2C=C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
To a solution of (1E,4E)-ethyl 8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate (15.0 g, 36.7 mmol) in THF (195 mL) at −15° C. was slowly added 1N aq NaOH (55.0 ml, 55.0 mmol) over 10 min. The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was poured into ice-cold water (500 mL). The pH of the mixture was carefully adjusted to 5-6 with 0.5 N aq HCl (˜260 mL). The resulting mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with brine, dried over MgSO4, filtered while rinsing with EtOAc, and concentrated under reduced pressure to give the crude material that was triturated with MeCN (20 mL). The solids were filtered off and dried under reduced pressure to afford 7.56 g (54%) of the desired product. The filtrate was concentrated under reduced pressure again to give the second crude material that was triturated with MeCN again to afford additional 1.33 g (9.5%) of the product. Total 8.89 g (64%) of (1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylic acid was obtained. MS APCI(+) m/z 381, 383 (M+1, Br pattern) detected.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]3[CH2:35][CH2:34][CH:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:32][CH2:31]3)[N:24]=2)[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]3[CH2:31][CH2:32][CH:33]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH2:34][CH2:35]3)[N:24]=2)[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(NS(C)(=O)=O)CC3)n2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)NC1CCC(Nc2nccc(-n3ccc4c(N5CCC(O)C5)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.3 %

Procedure:
N-[4-(4-{4-[3-(t-butyl-dimethylsilanyloxy)-pyrrolidin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide (0.35 mmol) was mixed with TBAF (10 eq, 3.5 mL) in anhydrous THF (15 mL) and allowed to stir for 1.5 h at RT, and then heated to 68° C. The reaction mixture was washed with NH4Cl/H2O, extracted into EtOAc (6×15 mL), and further washed with H2O (6×30 mL). The product was isolated via chromatography (prep. TLC in NH4OH/MeOH/DCM) as N-[4-(4-{4-[3-(hydroxy)-pyrrolidin-1-yl]-indol-1-yl}-pyrimidin-2-yl-amino)-cyclohexyl]-methanesulfonamide (Compound 311, 35 mg).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([OH:30])=[C:25]([Br:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:44])[C@H:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)O>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([O:30][C@H:35]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([OH:44])=[O:33])=[C:25]([Br:31])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3,5-dibromo-biphenyl-4-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 87-89° C.; MS m/e 696 (M+);
Reaction SMILES: C(=O)([O-])OC1C=CC(S(N2C3C(=CC=C(F)C=3)NC(=O)[C@@H]2CC)(=O)=O)=CC=1.IC.[CH2:30]([C@@H:32]1[N:41]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([F:52])[CH:39]=2)[N:34]([CH2:53]CC)[C:33]1=[O:56])[CH3:31]>>[CH2:30]([C@@H:32]1[N:41]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)(=[O:43])=[O:44])[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([F:52])[CH:39]=2)[N:34]([CH3:53])[C:33]1=[O:56])[CH3:31]
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Agent: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Solvent: CI
Product: CC[C@H]1C(=O)N(C)c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl carbonate (see Example 20) was treated with iodomethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−14° (c=0.0041 G/ML, DMSO); MS (ESI) m/z 365 ([M+H]+); MS (ESI) m/z 363 ([M−H]−); HRMS: calcd for C17H17FN2O4S, 364.0893; found (ESI+), 365.09603.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[C:1]([NH:4][CH:5]([C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)c1ccco1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(C)=O)C(=O)c1ccco1
Yield: 40.6 %

Procedure:
2.6 g of N-acetyl-(2-furylcarbonyl)methylamine, 0.74 g of 61% sodium hydride and 2.9 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 1.6 g of ethyl 3-acetylamino-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 41%
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:3]=1>C(O)(=O)C.[Zn]>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:5]3[C:6](=[N:7][CH:2]=[CH:3][C:4]=3[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[S:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: Fc1ccc(-c2csc3nc(Cl)cc(NCc4ccccn4)c23)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Fc1ccc(-c2csc3nccc(NCc4ccccn4)c23)cc1

Procedure:
[6-Chloro-3-(4-fluoro-phenyl)-thieno[2,3-b]pyridin-4-yl]-pyridin-2-ylmethyl-amine (40 mg, 0.1 mmol) was dissolved in acetic acid (3 ml). Zinc powder (71 mg, 1 mmol) was added and the mixture refluxed for 6 hr. On cooling, the mixture was filtered through celite and the solids washed with further portions of acetic acid (3×5 ml). The acetic acid extracts were neutralized with saturated sodium bicarbonate solution and extracted with DCM (2×50 ml). The extracts were combined, dried over sodium sulfate and concentrated. The residue was purified on silica (ethyl actetate/hexane 20-40%) to give [3-(4-fluoro-phenyl)-thieno[2,3-b]pyridin-4-yl]-pyridin-2-ylmethyl-amine as a white solid. Yield=5.5 mg (15.2%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1)=[O:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCCC1.[CH2:27]([O:29][CH:30]([O:36][CH2:37][CH3:38])[C:31](OCC)=[O:32])[CH3:28].Cl>O1CCCC1>[F:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:31](=[O:32])[CH:30]([O:36][CH2:37][CH3:38])[O:29][CH2:27][CH3:28])[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(F)c1
Reactant: CCOC(=O)C(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)CC(=O)c1cc(F)cc(F)c1
Reaction time: 1 h

Procedure:
At −78° C., a tetrahydrofuran (20 ml) solution of 3,5-difluoroacetophenone (8.86 g) was added to a tetrahydrofuran (180 ml) solution of 1 N lithium hexamethyldisilazide/tetrahydrofuran solution (68 ml), and stirred at the same temperature for 1 hour. At −78° C., ethyl diethoxyacetate (12.2 ml) was added to the reaction liquid, and stirred overnight at room temperature. At 0° C., 2 N hydrochloric acid (60 ml) was added to the reaction liquid, and extracted with ethyl acetate. The extract was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off to obtain the entitled compound (16.5 g).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35]3)=[CH:28][CH:27]=1>>[OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11](/[CH:14]=[C:35]3\[C:36](=[O:41])[NH:37][C:38]4[C:34]\3=[CH:33][C:32]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[CH:40][CH:39]=4)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: COc1ccc(-c2ccc3c(c2)CC(=O)N3)cc1
Product: COc1ccc(-c2ccc3c(c2)/C(=C/c2[nH]c4c(c2C)C(=O)N(C[C@@H](O)CN2CCOCC2)CC4)C(=O)N3)cc1
Yield: 87.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 5-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-2-[5-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 21 (53 mg, yield 87.2%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1>C(O)C.[Pt].[H][H]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: CN1CCCC1=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pt]
Solvent: CCO
Product: CN1CCCC1Cc1ccc(N)cc1

Procedure:
Reduce 8.5 g of 1-methyl-2-(4-nitrobenzylidene)pyrrolidine in ethanol with platinum/hydrogen. Remove the catalyst and solvent and recrystallize from n-hexane to obtain 3.6 g (49% of theory) of title compound (m.p. 59° to 61°).
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>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:6][C:7]1[C:8]([C:4]#[C:3][C@@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H](C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](C)O)c21

Procedure:
Using Method C above, (S)-but-3-yn-2-ol (38 mg, 0.54 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (16 mg, 0.01 mmol) and CuI (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was obtained after silica gel column with a 0-10% MeOH in CH2Cl2 gradient and trituration with Et2O. (Yield 21 mg, 50%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH2:14][CH:15]1[O:19][CH2:18][O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C>[O:19]1[CH:15]([CH2:14][CH2:13][NH:5][C:4]2[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=2[CH2:1][CH3:2])[CH2:16][O:17][CH2:18]1
Reactant: ClCCC1COCO1
Reactant: CCc1cccc(CC)c1N
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: CCc1cccc(CC)c1NCCC1COCO1

Procedure:
2,6-Diethylaniline (0.3 mole, 5-β-chloroethyl-1,3-dioxolane (0.3 mole), potassium carbonate (0.3 mole) and tetraethylammonium chloride (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of 4 hours. After this time the mixture is filtered to yield the desired product N-(1,3-dioxolan-5-ylethyl)-2,6-diethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](B(O)O)=[C:4]([CH3:12])[CH:3]=1.[F-].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([CH3:12])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(Cl)cc(C)c1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(C)cc(Cl)cc1C

Procedure:
Ethyl 4-chloro-2,6-dimethylphenylacetate was prepared by the general experimental method from 4-chloro-2,6-dimethylphenylboronic acid (186 mg, 1.00 mmol). This involved using 290 mg [5 mmol] of KF and 418 mg [2.5 mmol] of ethyl bromoacetate. After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 4-chloro-2,6-dimethylphenylacetate is obtained as a colourless liquid in a yield of 68% of theory. 1H NMR (400 MHz, CDCl3): δ=7.02 (s, 2H), 4.13 (q, J=0.7 Hz, 2H), 3.62 (s, 2H), 2.29 (s, 6H), 1.23 (t, J=7.2 HZ, 3H) ppm; 13C NMR (101 MHz, CDCl3): δ=170.8, 139.0, 132.2, 131.6, 130.3, 127.9, 113.6, 60.8, 35.0, 20.1, 14.2 ppm; MS (70 eV), m/z (%): 226 (22) [M+], 180 (9), 153 (100), 115 (17), 91 (11); IR (NaCl): ν=2980 (m), 1733 (s), 1328 (w), 1155 (m), 1030 (m) cm−1; elemental analysis: (theor): C=63.58, H=6.67, (exp): C=63.30, H=6.78.
Reaction SMILES: [C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:3].[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[C@@H:30]2[O:36][C@H:35]([CH2:37][OH:38])[C@@H:33]([OH:34])[C@@H:31]2[OH:32])=[C:23](N)[N:22]=1.P([O-])([O-])([O-])=O>>[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[C@@H:30]2[O:36][C@H:35]([CH2:37][OH:38])[C@@H:33]([OH:34])[C@@H:31]2[OH:32])=[C:23]([OH:3])[N:22]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc(O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1
Reaction time: 2 h

Procedure:
A suspension of 10 mg/ml of an adenosine deaminase enzyme (prepared from intestinal calf mucosa) was assayed to have an activity of 210 μ moles/min. at 38° C. To a solution of 191 mg. of 2,6-diamino-9-(β-D-arabinofuranosyl)purine in 800 ml of a 1 millimole phosphate buffer of pH 7.1 was added 50 micrograms of adenosine deaminase. After two hours at 38° C. the reaction mixture was freeze dried. The resulting powder was extracted with hot methanol which was filtered and evaporated to give a solid. This solid was triturated with methanol, filtered and the methanol evaporated. The solid was dissolved in 25 ml. of warm methanol and cooled to crystallize the product, 2-amino-6-hydroxy-9-(β-D-arabinofuranosyl)purine, m.p. < 300° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:25])[CH2:4][CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:27]([O:25][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)=[CH:10][C:11]=2[C:2]([CH3:1])([CH3:26])[CH2:3][CH:4]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OC(C)=O)cc1
Temperature: 80 °C

Procedure:
To 200 mg (0.51 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonapth-2-yl)ethynyl]benzoate (Compound 1) was added 0.13 ml (1.5 mmol) of acetic anhydride and 10 mg (0.05 mmol) of p-toluenesulfonic acid. The mixture was heated at 80° C. for 12 hours, cooled to room temperature and concentrated in vacuo to an oil. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a light yellow powder.
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.[Bi](Cl)(Cl)Cl>CO>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Bi](Cl)Cl
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of sulfolane were added 2.72 g of 7-ACA, 19 g of bismuth trichloride and 1.1 g of methanol. The mixture was heated at 60° C. for 35 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. The resulting precipitate was filtered off. To the filtrate was added 30 ml of water while cooling on ice. Then, the filtrate was adjusted to pH 3.5 with sodium bicarbonate at a temperature of from 0° C. to 5° C., thereby to form a white crystalline precipitate. The resulting precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.76 g. The yield of the desired product was 31 %.
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19]([C:20]3[CH2:21][CH2:22][O:23][CH2:24][CH:25]=3)[N:12]2[N:11]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19]([CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:12]2[N:11]=1
Reactant: [H][H]
Reactant: O=c1[nH]c(COCc2ccccc2)nn2c(C3=CCOCC3)ncc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]c(CO)nn2c(C3CCOCC3)ncc12
Yield: 143.7 %

Procedure:
To a solution of compound 6 (650 mg, 1.14 mmol) in MeOH (30 mL) was added Pd(OH)2/C (120 mg). The reaction mixture was stirred under 50 psi of hydrogen at 70° C. until LC-MS showed that the starting material was almost consumed. The suspension was filtered through celite and washed with MeOH (20 mL×2) and the filtrate was concentrated in vacuo to afford compound 7 (410 mg, 85% yield) as a white solid. LC-MS: m/z 251.3 [M+H]+.