Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=[C:37]4[C:41](=[CH:42][C:32]2=3)[CH2:40][CH2:39][O:38]4)C1=O>>[O:38]1[CH2:37][CH2:41][CH2:42][CH2:32][CH:39]1[CH2:40][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(CC2CCCCO2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(tetrahydro-2H-pyran-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (45%) as a colorless solid: mp 158-166° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.31-7.25 (m, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.08-7.00 (m, 2H), 6.48 (s, 1H), 6.24 (s, 0.5H), 6.22 (s, 0.5H), 4.89 (d, J=9.0 Hz, 0.5H), 4.88 (d, J=9.0 Hz, 0.5H), 4.64 (d, J=9.0 Hz, 0.5H), 4.63 (d, J=9.0 Hz, 0.5H), 4.21-4.16 (m, 2H), 4.14-4.09 (m, 2H), 4.01-3.93 (m, 1H), 3.91-3.82 (m, 1H), 3.74-3.63 (m, 2H), 3.44-3.33 (m, 1H), 1.91-1.81 (m, 1H), 1.68-1.31 (m, 5H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.89, 177.80, 155.30, 155.27, 144.61, 143.25, 143.11, 138.34, 132.46, 132.35, 128.78, 128.73, 123.66, 123.64, 123.19, 123.17, 121.51, 121.45, 111.76, 111.62, 109.90, 109.77, 99.41, 99.36, 80.14, 75.75, 75.58, 68.57, 68.53, 64.63, 64.02, 58.08, 58.04, 45.83, 45.77, 29.70, 29.57, 25.88, 23.13; MS (ES+) m/z 394.2 (M+1); Anal. Calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.03; H, 5.97; N, 3.17.
Reaction SMILES: [CH3:1][C:2]#[CH:3].C(=O)=O.[CH2:7]([O:14][CH2:15][CH:16]([CH3:20])[CH2:17][CH:18]=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>CCCCCC.CCOCC.O1CCCC1>[CH2:7]([O:14][CH2:15][CH:16]([CH3:20])[CH2:17][CH:18]([OH:19])[C:1]#[C:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CC
Reactant: CC(CC=O)COCc1ccccc1
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC#CC(O)CC(C)COCc1ccccc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 72.8 ml. (0.146 mole) of 2 M n-butylithium solution in hexane and 420 ml. of anhydrous tetrahydrofuran was stirred and cooled to -50° C. while 112 ml. of liquified methylacetylene was added dropwise from a dry ice cooled addition funnel. After the addition was complete, the reaction mixture was allowed to warm to reflux temperature (8° C.) (dry ice condenser) and stirred at this temperature for 1 hour. The white slurry was then cooled to 0° C. and stirred while a solution of 14 g. (0.0728 mole) of rac. 4-benzyloxy-3-methylbutanal in 125 ml. of anhydrous tetrahydrofuran was added dropwise. After stirring at 0° C. for 1 hour, the mixture was slowly warmed to 40° C. and stirred at this temperature for 1 hour whereupon the reaction mixture was treated with saturated aqueous ammonium chloride. The product was isolated by ether extraction and worked up as in Example 1. There was obtained 15.4 g. of crude material which was chromatographed on 400 g. of silica gel. Elution with 2:1 parts by volume and 1:1 parts by volume hexane: ether afforded rac. 1-benzyloxy-2-methylhept-5-yn-4-ol as a yellow oil.
Reaction SMILES: C(OC[S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][S:17][C:16]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:11][C:10]=1[F:30])(=[O:8])=[O:7])(=O)C.C[O-].[Na+].C(OCC)(=O)C.Cl>O1CCCC1.CO>[F:30][C:10]1[CH:11]=[C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][S:17][C:16]=2[C:26]([O:28][CH3:29])=[O:27])[CH:13]=[CH:14][C:9]=1[S:6]([OH:8])=[O:7]
Reactant: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(S(=O)(=O)COC(C)=O)c(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(S(=O)O)c(F)c1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
The methyl 3-[4-[[(acetyloxy)methyl]sulfonyl]3-fluorophenyl]-4-phenyl-2-thiophenecarboxylate (2.75 g, 6.13 mmol) was dissolved in tetrahydrofuran (100 mL) and stirred at room temperature. 25% Sodium methoxide in methanol (3.0 mL) was added and the solution stirred for 5 min. The resulting slurry was poured into ethyl acetate (200 mL) and aqueous 1N hydrochloric acid (100 mL) was added. The solution was stirred and the layers allowed to separate. The organic layer was collected and the aqueous layer back extracted with ethyl acetate (100 mL). The organic layers were combined, extracted with brine, dried over sodium sulfate, and solvent removed at reduced pressure. The 2-methyl 3-(3-fluoro-4-sulfinophenyl)-4-phenyl-2-thiophenecarboxylate (1.87 g, 4.59 mmol) was isolated as a white solid.(77% yield). Mp 132.6-133.1° C. 1H NMR (CDCl3/300 MHz) 7.74-7.80 (1H, m), 7.55 (s, 1H), 6.80-7.28 (m, 6H), 3.74 (s, 3H). ESHRMS m/z 394.0586 (calcd for M+NH4+, 394.0583).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:23]=[C:22]([OH:24])[C:21]([CH3:25])=[CH:20][CH:19]=1.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[OH:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[C:11]3[CH:10]=[C:9]4[N:12]=[CH:13][N:14]=[C:8]4[CH2:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:19]=[CH:20][C:21]=1[CH3:25]
Reactant: Cc1ccc(N)cc1O
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: Cc1ccc(Nc2c(C#N)cnc3c2C=C2N=CN=C2C3)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A mixture of 0.15 g (0.66 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.1 g (0.78 mmol) of 5-amino-o-cresol and 0.075 g (0.66 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water, diethyl ether, methylene chloride, tetrahydrofuran and dried in vacuo to yield 0.17 g of 8-(3-hydroxy-4-methyl-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as white solid, mp 257–260° C. (dec).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21](OC)OC)[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[BH4-].[Na+]>C1COCC1>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][N:33]([CH2:34][CH2:35][N:36]([CH3:37])[CH3:38])[CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(OC)OC)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1ccccc1-3
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of methyl 3-cyclohexyl-1-(2,2-dimethoxyethyl)-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-1H-indole-6-carboxylate (0.16 M, 1 eq, from Step 3) in THF was added an equal volume of aqueous 1N HCl. The reaction was heated at 60° C. for 2.5 h and after cooling to RT was quenched by addition of NaOH (2N) and extracted into EtOAc (×3). The combined organic extracts were washed with brine before being dried over Na2SO4, filtered and concentrated in vacuo. The residue was re-dissolved in MeOH and acidified to pH 4 with glacial acetic acid. After stirring for 45 min, NaBH4 (8 eq) was added portionwise until cyclisation was complete as evidenced by LC-MS analysis. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted into EtOAc (×3). The combined organic extracts were washed with brine before being dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained as a pale yellow oil and taken on without further purification (quant.); MS (ES+) m/z 460 (M+H)+.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>C(Cl)Cl>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:13])[NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Reactant: Nc1nccs1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)Nc1nccs1)=C1SCS1
Yield: 62.9 %

Procedure:
The solution of isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate (10 g) and 2-aminothiazole (4.0 g) in methylene chloride (100 ml) was stirred at room temperature for 24 hrs. The reaction mixture was washed with 10% aqueous sodium hydroxide solution and water and then evaporated. The residue was chromatographed on silica gel column using methylene chloride as an eluent to afford the titled compound as a white solid (6.5 g, 63%).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([O:31][CH3:32])[CH:25]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][C@@H:7]2[CH2:8][C@@H:9]([OH:11])[CH2:10][N:6]2[CH3:4])=[C:16]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([O:31][CH3:32])[CH:25]=2)[CH:17]=1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(F)ccc2OCC[C@@H]2C[C@@H](O)CN2C)ccc1F
Yield: 84.4 %

Procedure:
551 mg of (2R,4R)-1-ethoxycarbonyl-2-[2-{4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl]phenoxy}ethyl]-4-hydroxypyrrolidine [prepared as described in step (a) above], 20 ml of tetrahydrofuran and 140 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrate thus obtained was purified by silica gel column chromatography, using a 3:2 by volume mixture of methylene chloride and methanol as the eluent, to give 405 mg (yield 84%) of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][C:29]([OH:31])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]([N:39]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN>CN(C)C=O.O1CCCC1.O>[CH2:32]([C:11]1[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:19]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:27][CH2:28][C:29]([NH:39][CH3:37])=[O:31])[CH:17]=2)[N:12]=1)[CH:33]([CH3:34])[CH3:35]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC(=O)O)cc23)cc1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)COc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
To a solution of {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}acetic acid (0.48 g, 1.0 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.2 mmol), 1-hydroxy-1H-benzotriazole (0.16 g, 1.2 mmol) and 1.0 M solution of methylamine in tetrahydrofuran (2 ml) and the mixture was stirred at room temperature for 12 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl {[2-isobutyl-6-[2-(methylamino)-2-oxoethoxy]-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.27 g, yield 55%) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:15]([OH:17])=O)[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:15]([Cl:21])=[O:17])[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: N#Cc1cc(C(=O)O)c2ccccc2c1C#N
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)Cl)c2ccccc2c1C#N

Procedure:
To a stirred solution of 3,4-dicyano-1-naphthoic acid (121 mg, 0.542 mmol) in dry DCM (5 mL) was added oxalyl chloride (80.0 mg, 0.63 mmol) and DMF (10 μL). After 3 h at room temperature DCM was removed in vacuo to afford 3,4-dicyano-1-naphthoyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br)#[N:2].[N-:11]=[N+:12]=[N-:13].[Na+]>C1COCC1.O>[N:11]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:1]#[N:2])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1CBr
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1CN=[N+]=[N-]
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of 90 g (459 mmol) 2-cyanobenzylbromide in 600 mL THF was added in one portion a solution of 36 g (553 mmol) sodium azide in 100 mL water. The two phase mixture was stirred at 23° C. for 18 hr. The THF layer was separated from the lower water layer and used in the next step without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C@@H:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1.[CH2:15](O)[CH3:16]>>[CH3:5][C@@H:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1
Reactant: CCO
Reactant: C[C@@H]1CCN[C@@H](C(=O)O)C1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1C[C@H](C)CCN1
Reaction time: 1 h

Procedure:
Thionyl chloride (128.6 g) added dropwise to a stirred suspension of (2R,4R)-4-methyl-2-piperidinecarboxylic acid (51.6 g) in absolute ethyl alcohol (690 ml) below 30° C. and stirring continued for 1 hr. at room temperature and then for 1 hr. under reflux. After evaporation of the solvent, the residue was dissolved in benzene (500 ml), washed with 5% K2CO3 solution (100 ml) and saturated NaCl solution (200 ml), and dried over anhydrous Na2SO4. Upon evaporation of benzene, the residue was distillated in vacuo to give ethyl (2R,4R)-4-methyl-2-piperidinecarboxylate (57.4 g), b.p. 83°-5° C./7 mm Hg, [α]D22 =-24.0 (C=5 in EtOH), Analysis Calcd. for C9H17NO2 (percent): C, 63.13, H, 10.00, N, 8.18 Found (percent): C, 63.20, H, 9.96, N, 8.12.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)=[O:23])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2].C(O)(=O)C.C(O)(=O)C.[C:66]1([Bi](C2C=CC=CC=2)C2C=CC=CC=2)[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.C(O)(=O)C.C(=O)(O)O.C1([Bi](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: c1ccc([Bi](c2ccccc2)c2ccccc2)cc1
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 120 h

Procedure:
To a stirred solution of 17-ethyl-20-fluoro-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1 eq) and Cu(OAc)2 (2.8 mg, 0.014 mmol, 0.11 eq) in CH2Cl2 (1 ml) in a 16 mL screw-cap vial equipped with a magnetic stir-bar is added triphenyl bismuth diacetate [prepared immediately prior to use by addition of acetic acid (0.030 mL, 0.504 mmol, 4 eq) to a suspension of triphenyl bismuth carbonate (127 mg, 0.253 mmol, 2 eq) in CH2Cl2 (1 ml)]. The reaction vessel is capped and the mixture stirred for five days. The reaction mixture is diluted with several milliliters of saturated aqueous NaHCO3 and extracted 4 times with CH2Cl2. The organic extracts are combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product is isolated by preparative TLC on silica gel to give the title compound.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[O:6]1)=[N+]=[N-]>[Pt]>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccccc3Cl)c2O1
Agent: [Pt]
Product: NCC1Cc2cccc(-c3ccccc3Cl)c2O1
Yield: 57 %

Procedure:
Treatment of (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.6 g, 6.26 mmol) with sodium azide (1.63 g, 25.05 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.17 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.05 g (57%) of (±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 60.71; H, 5.48; N, 4.55.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](N=O)[CH:8]=[C:7]([C:13](C)([CH3:15])[CH3:14])[C:6]=1[OH:17])(C)([CH3:3])[CH3:2].C(C1C=C(N=[O:28])C=C(C(C)C)C=1O)(C)C>>[CH:1]([C:5]1[C:6](=[O:17])[C:7]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:9](=[O:28])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Reactant: CC(C)c1cc(N=O)cc(C(C)C)c1O
Product: CC(C)C1=CC(=O)C=C(C(C)C)C1=O

Procedure:
If 2,6-ditert.butyl-4-nitrosophenol is replaced in this example by an equivalent quantity of 2,6-diisopropyl-4-nitrosophenol, an otherwise identical procedure gives 2,6-diisopropyl-benzoquinone monoxime p-toluenesulphonate of melting point 93° C.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:37])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](C2C=CC=CC=2N)=[CH:26][CH:25]=1)[NH:12]C(=O)C1C(Cl)=CC=CC=1Cl.CC(OC(C)=O)=O.CCN(C(C)C)C(C)C.CCOC(C)=O>C1COCC1>[CH3:8][O:9][C:10](=[O:37])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:12]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-aminophenyl)-L-phenylalanine methyl ester TFA salt (90 mg) was dissolved in dry THF (5 mL). Ac2O (60 μL) and DIEA (160 μL) were added and the mixture was stirred at room temperature for 12 h. EtOAc was added and the resulting mixture was extracted with water. The organic phase was dried (MgSO4) and evaporated to give N-(2,6-dichlorobenzoyl)-4-[2-(acetylamino)]phenyl]-L-phenylalanine methyl ester.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1.ClCCl.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:28][S:29]([O:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1)(=[O:31])=[O:30]
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C[C@H]1C[C@@H](COS(C)(=O)=O)OC(C)(C)O1
Reaction time: 2 h

Procedure:
2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (10.0 g), dichloromethane (150.0 mL), and triethylamine (17.0 mL) were added to a reactor. Methanesulfonyl chloride (4.7 mL) was added to the reaction mixture, which was then stirred for 2 hours. Water (200.0 mL) was added to the reaction mixture under stirring. The separated organic layer was washed with 0.5N hydrochloric acid solution (100.0 mL) and then concentrated under reduced pressure to obtain 2-[(4R,6S)-6-methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (13 g).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11]
Reactant: CN(C)c1cccc(O)c1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)c1cccc(OCCCCCCBr)c1

Procedure:
A mixture of 27.5 g. (0.2 mole) of m-dimethylaminophenol, 94 g. (0.39 mole) of 1,6-dibromohexane, 53.8 g. of powdered anhydrous potassium carbonate and 350 ml. of acetone was heated at reflux under nitrogen for two days. The reaction mixture was concentrated in vacuo and the residue partitioned between water and methylene dichloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled to remove unreacted 1,6-dibromohexane (b.p. 63° C., 0.2 mm.). The remaining material was dissolved in 5% sulfuric acid by warming on a steam bath, then filtered, cooled and made basic with sodium hydroxide. The product was extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated to a reddish brown oil, 52.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]#[N:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(Cl)cc23)C1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3ccc(Cl)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((7-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (660 mg, 1.77 mmol) in MeOH (5 mL) was added NH2NH2—H2O (5 mL) and the resulting mixture was heated to reflux for 2 hours. The solvent was subsequently removed to give the title compound as a yellow solid, which was used without further purification (710 mg). ESI-MS m/z [M+H]+ 405.