Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[I-:2].Cl[CH2:4][Si:5]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.N1C=CN=N1>CC(C)=O>[I:2][CH2:4][Si:5]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [I-]
Reactant: CCOc1ccc([Si]2(CCl)CCCC2)cc1
Agent: [Na+]
Agent: c1c[nH]nn1
Solvent: CC(C)=O
Product: CCOc1ccc([Si]2(CI)CCCC2)cc1

Procedure:
In the same apparatus as Example 1, 7.2 g (0.048 mol) of NaI was added and dissolved with 90 ml of acetone. To the flask, 8.13 g (0.032 mol) of 1-chloromethyl-1-(4-ethoxyphenyl) -1-silacyclopentane was added, and then the mixture was reacted under reflux for 5 hrs. After filtering the produced NaCl off and evaporating to remove acetone, the residue was extracted with n-hexane. The hexane solution was treated with dilute aqueous solution of Na2S2O3 and dried on anhydrous MgSO4, and filtered to remove the solvent. After confirming by NMR analysis that the halogen exchange reaction was completely carried out, the following triazole substitution reaction was directly carried out without any purification.
Reaction SMILES: C[O:2][P:3]([CH2:19][CH:20]([C:25](=[O:36])[NH:26][C@H:27]([C:32](=[O:35])[NH:33][CH3:34])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH:22]([CH3:24])[CH3:23])([CH2:5][N:6]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18])=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:23][CH:22]([CH3:24])[CH2:21][CH:20]([C:25](=[O:36])[NH:26][C@H:27]([C:32](=[O:35])[NH:33][CH3:34])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:19][P:3]([CH2:5][N:6]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18])(=[O:2])[OH:4]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)C=C(c2ccccc2)C1=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)C=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
0.1 g of [(RS) -4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl][(2-phenylmaleimido)methyl]phosphinic acid methyl ester was dissolved in 1 ml of dichloromethane and 2 ml of trifluoroacetic acid were added. The mixture was stirred at room temperature for 2 hours and the solvent was then removed by evaporation. The residue was taken up in 30 ml of acetone/ dichloromethane (1:1) and the solution was evaporated to give 95 mg of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl) butyl]carbamoyl]pentyl][(2-phenylmaleimido)methyl]phosphinic acid in the form of a tan colored foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[C:16]1([N:22]=[C:23]=S)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C.[Pd]>[C:16]1([NH:22][C:23]2[O:1][C:2]3[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=3[N:8]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: S=C=Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(Nc3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
In ethanol (10 ml) was dissolved methyl 3-hydroxy-4-nitrophenylacetate (592 mg, 2.81 mmol), followed by the addition of 5% palladium/carbon (194 mg). The resulting mixture was subjected to catalytic hydrogenation overnight under stirring at room temperature and normal pressure. After removal the catalyst from the reaction mixture by filtration through Celite under reduced pressure, the filtrated cake was washed with ethanol (30 ml). The filtrate was stirred at room temperature. After addition of phenyl isothiocyanate (370 μl, 3.09 mmol) and stirring at room temperature for one hour, mercuric oxide (yellow) (1.1 g, 5.07 mmol) was added. The reaction mixture was heated under reflux for 3 hours. The mixture was then cooled and the insoluble matter was filtered out under reduced pressure. The filtrate was distilled under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby methyl 2-phenylaminobenzoxazol-6-acetate (480 mg, 61%) was obtained as a white solid from chloroform-ethyl acetate (10:1, v/v) eluate fractions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:14]=[N:15][C:16]([F:20])=[C:17]([Cl:19])[CH:18]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:19][C:17]1[CH:18]=[C:13]([C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]=[C:10]([C:21]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=[O:23])[CH:11]=2)[CH:14]=[N:15][C:16]=1[F:20]
Reactant: O=C(O)c1cc(-c2cnc(F)c(Cl)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cnc(F)c(Cl)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
21 mg (0.06 mmol) of the compound of Example 63A is reacted analogously to the synthesis of the compound of Example 1 with 8 mg (0.07 mmol) of 4-imidazolinone-hydrochloride. 15 mg (59% of theory) of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=[O:8].[CH2:13]([NH2:16])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH:16][CH2:13][CH:14]=[CH2:15])=[O:8]
Reactant: C=CCN
Reactant: O=C(Cl)C=Cc1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C=CCNC(=O)C=Cc1cccc(F)c1
Reaction time: 72 h

Procedure:
A solution of 3-fluorocinnamoyl chloride (3.7 g) in dry toluene (35 ml) was added with stirring to allylamine (8 ml) in dry benzene (100 ml). The reaction mixture was allowed to stand at room temperature for three days. After evaporation of the solvents under reduced pressure the residue was triturated with water containing a small amount of sodium carbonate and washed with water. Recrystallization from ethanol: water gave 3-fluoro-N-allylcinnamamide (3.3 g), m.p. 84.5-87° C. as fine white needles. Elemental analysis, nmr and ir spectra were consistent with the structure assignment.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH:30](=[O:33])[CH2:31][CH3:32].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:30]([OH:33])[CH2:31][CH3:32])[CH3:2]
Reactant: CCC=O
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(O)CC)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 20 g (70.6 mmol) dibenzylamino-acetic acid ethyl ester in 240 ml tetrahydrofuran was stirred at −78° C. with 38.8 ml (77.6 mmol) lithium diisopropylamide (2M in heptane) for 30 minutes. 5.83 ml (77.6 mmol) Propionaldehyde in 5 ml tetrahydrofurane were added and stirring was continued overnight. The mixture was allowed to warm to room temprature, water was added and most of the organic solvent was removed by distillation. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1/5 yielded as first eluting fraction 6.85 g (28%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester, MS m/e (%): 342.3 (M+H+, 100) and as second eluting fraction 6.15 g (26%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester, MS m/e (%): 342.2 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]([NH2:26])([CH3:25])[CH3:24]>CN1C(=O)CCC1.C(Cl)Cl>[C:23]([NH:26][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)(C)N
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Yield: 21.4 %

Procedure:
A solution of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (1) (125 mg, 0.42 mmol) and 2-methylpropan-2-amine (154 mg, 2.10 mmol) (Sigma-Aldrich) in NMP (0.84 mL) was heated in a sealed tube at 165° C. for 2.5 d. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. brine (4×100 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give 2-(2-(tert-butylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (30 mg) (0.09 mmol, 21% yield) as a yellow oil which was slightly impure. This material was dissolved in MeOH (˜20 mg/mL) and injected (2×1.0 mL) onto the Shimadzu preparatory LC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% MeCN/water with 0.1% TFA); the pure fractions were combined, basicified with NaHCO3 (saturated, aq.), extracted with CHCl3/IPA(3:2), separated, dried over Na2SO4, and concentrated via rotary evaporation to give 2-(2-(tert-butylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (340) (19 mg, 0.08 mmol, 14% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.62 (s, 9H) 2.99 (t, J=6.94 Hz, 2H) 3.65 (td, J=6.85, 2.35 Hz, 2H) 4.84 (s, 1H) 5.71 (br. s., 1H) 6.56 (d, J=9.00 Hz, 1H) 7.10 (d, J=1.76 Hz, 1H) 7.21 (t, J=7.73 Hz, 1H) 7.38 (d, J=7.63 Hz, 1H) 7.75 (d, J=9.00 Hz, 1H) 7.96 (d, J=7.63 Hz, 1H) 13.24 (br. s., 1H). MS (ESI, pos. ion) m/z: 353.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a solution of tert-butyl 5-((5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.66 g, 4.01 mmol) in DCM (20 mL) was added a solution of HCl in EtOAc (20 mL, 80 mmol). The reaction mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with saturated Na2CO3 aqueous solution, then extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a beige solid (505.2 mg, 40.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])=[O:18])/C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>NC(N)=S.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][C:17](=[O:18])[C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:25]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)/C(=C/c1ccc(Br)cc1)C(=O)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(N)=S
Solvent: Cc1ccccc1
Product: O=C1CC(c2ccc(Br)cc2)Oc2ccccc21
Yield: 65.1 %

Procedure:
Prepared according to general procedure using E-tert-butyl 3-(4-bromophenyl)-2-(2-hydroxyphenylcarbonyl)prop-2-enoate (81.0 mg, 0.20 mmol), thiourea catalyst III (14 mg, 0.020 mmol) in 2.0 mL toluene for 38 h at −25° C. and p-toluenesulfonic acid (19 mg, 0.10 mmol) for 36 h. Purification via column chromatography with 10% EtOAc/hexanes afforded 39.5 mg (65%) of 8 as a white solid in 92% ee. mp=115-116° C. [α]D: +50.4 (EtOH, c=0.5). Analytical data for 8: IR (film) 1691.8, 1604.8, 1465.1, 1304.6, 1222.9 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J=7.5 Hz, 1H), 7.58-7.36 (AA′BB′, 4H), 7.52 (t, J=8.0 Hz, 1H), 7.09-7.05 (m, 2H), 5.45 (dd, J=13.2, 2.4 Hz, 1H), 3.00 (dd, J=16.8, 13.3 Hz, 1H), 2.88 (dd, J=16.8, 2.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 191.7, 161.5, 138.0, 136.6, 132.3, 128.1, 127.3, 123.0, 122.1, 121.1, 118.3, 79.1, 44.8; LRMS (electrospray): Exact mass calcd for C15H11BrO2 [M]+, 301.99, 303.99. Found [M+1], 305.5.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[O:14][C:13](=O)[NH:12][C:11](=[O:17])[C:10]=3[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH3:19]>>[C:1]1([CH:7]2[C:15]3[NH:19][C:13](=[O:14])[NH:12][C:11](=[O:17])[C:10]=3[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CC2
Reactant: N
Solvent: O
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1ccccc1
Yield: 100 %

Procedure:
A solution of 7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (3.751 g, 16.36 mmol) in concentrated ammonia in water (80 mL, 16.36 mmol) was heated in a 350 mL high-pressure flask for 5 h. The solvent was removed in vacuum to give 7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (3.73 g, 16.34 mmol, 100% yield) as brown solid. LC-MS (M+H)+=229.1. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 7.34 (2H, t, J=7.5 Hz), 7.26 (1H, t, J=7.3 Hz), 7.18 (2H, d, J=7.3 Hz), 5.39 (1H, br s), 4.14 (1H, d, J=7.3 Hz), 2.43-2.68 (2H, m), 1.80-1.88 (2H, m).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:30])[NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Br[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41]>O>[C:3]([O:7][C:8](=[O:30])[N:9]([CH2:10][CH:11]1[C:20]2[C:15](=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)CCCBr
Reactant: CC(C)(C)OC(=O)NCC1CCCc2c(Oc3ccc(C#N)cn3)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C#N)cn3)cccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
Add NaH (60% oil suspension, 30 mg, 0.750 mmol) to a solution of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid tert-butyl ester (Intermediate 22, 189 mg, 0.500 mmol) and DMF (5 ml) stirring at ambient temperature under nitrogen. After 20 minutes, add 1-bromo-4-methylpentane (247 mg, 1.50 mmol) and heat the mixture at 60° C. overnight. After cooling, pour the mixture into water and extract with EtOAc (2×). Wash the extract with water and brine before drying ((MgSO4) and concentrating. Purify on silica gel (20% EtOAc/Hexane) to obtain 111 mg of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamic acid tert-butyl ester as a colorless glass.
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])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][CH:22]=1
Reactant: BrCc1ccc(Oc2ccccc2)cc1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(C)nc(O)c(Cc3ccc(Oc4ccccc4)cc3)c2cc1OC
Temperature: 140 °C
Reaction time: 0.83 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (152 mg, 693 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.38 mL, 0.76 mmol) at RT followed by 1-(bromomethyl)-4-phenoxybenzene (191 mg, 726 μmol) and the mixture was stirred at 140° C. for 50 min under microwave irradiation then at 160° C. for 50 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:3) gave 43 mg of 6,7-dimethoxy-1-methyl-4-(4-phenoxybenzyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (3 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(4-phenoxybenzyl)isoquinolin-3-ol hydrochloride 5 as a brown solid (47 mg, 15% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8](O)/[CH:9]=[CH:10]/[C:11]1[N:12]([CH:29]([CH3:31])[CH3:30])[C:13](=[O:28])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3][C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.O>ClCCl>[OH:1][CH:2]1[CH2:7][CH:8](/[CH:9]=[CH:10]/[C:11]2[N:12]([CH:29]([CH3:31])[CH3:30])[C:13](=[O:28])[C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:5][C:4](=[O:6])[CH2:3]1
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc2c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)n1c(/C=C/C2CC(O)CC(=O)O2)c(-c2ccc(F)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of a 1:1 mixture of the erythro- and threo-diastereoisomers of (E)-3,5-dihydroxy-7-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]hept-6-enoic acid (0.35 g; prepared as described in Example 5) in dichloromethane (25 ml) was treated with dicyclohexylcarbodiimide (0.18 g) and the resulting solution was stirred at room temperature for 1 hour. The solution was treated with water (20 ml), and stirred for 30 minutes. The layers were then separated and the aqueous phase was extracted with dichloromethane (210 ml). The combined extracts were dried over magnesium sulphate and evaporated to dryness. The resulting residue was triturated with diethyl ether (10 ml) and the insoluble material was filtered off. Evaporation of the ethereal solution gave a pale yellow solid, which was triturated with petroleum ether (b.p. 60°-80° C.; 10 ml) and filtered, to give (E)-4-hydroxy-6-[2-{4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl}ethenyl]-3,4,5,6-tetrahydro-2H-pyran-2-one, in the form of a pale yellow solid (0.21 g), m.p. 151°-154° C. [Elemental analysis: C, 70.8; H, 5.74; N, 3.35%; calculated: C, 71.24; H, 5.74; N, 3.32%].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)([O-])=O.[H][H].[C:19](O)(=[O:21])[CH3:20]>[Pt]>[C:19]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)(=[O:21])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(OC(F)C(F)(F)F)cc1
Reactant: [H][H]
Reactant: CC(=O)O
Agent: [Pt]
Product: CC(=O)Nc1ccc(OC(F)C(F)(F)F)cc1

Procedure:
23.9 g (0.1 moles) 4-nitrotetrafluoroethoxybenzene are dissolved in 75 ml glacial acetic acid and reduced at 50°-60° C. in the presence of platinum with hydrogen at normal pressure. After receiving 7.4 1 hydrogen the catalyst was filtered off and the filtrate is heated 1 hour with 75 ml acetic anhydride accompanied by reflux. The reaction mixture is then concentrated in a vacuum to 1/3 the original solvent quantity and poured onto 1 l ice water. The acetyl amino compound first precipitates as an oil which crystalizes overnight. 23.5 g (94% theoretical yield) of almost colorless crystals with a melting range of 114°-115° C. are obtained.
Reaction SMILES: Br[C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].C([Li])(C)(C)C.CN(C)[CH:22]=[O:23]>O1CCCC1>[CH:22]([C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)=[O:23]
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)cnc1O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Under nitrogen, the compound from Step A above (48.8 g, 202 mmol) was added in small portions to a suspension of sodium hydride (8.9 g, 220 mmol) in anhydrous tetrahydrofuran (500 mL). After complete addition of the intermediate, the reaction mixture was cooled to −78° C. and treated with tert-butyllithium (260 mL, 444 mmol) added dropwise via syringe. After stirring for 5 min, N,N-dimethylformamide (50 mL, 707 mmol) was added slowly, maintaining the temperature below −50° C. The resultant mixture was allowed to slowly warm to room temperature over 10 h. The mixture was quenched with 2N hydrochloric acid and then diluted with ethyl acetate (1000 mL). The organic layer was separated, washed with saturated brine, dried over magnesium sulfate and evaporated in vacuo. The desired product was precipitated out of a mixture of ethyl acetate and hexanes and filtered to yield a light brown solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][N:16]([CH3:22])[CH2:17][CH2:18][C:19](O)=[O:20])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>ClC(Cl)C>[ClH:25].[CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][N:16]([CH3:22])[CH2:17][CH2:18][C:19]([Cl:25])=[O:20])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CN(CCC(=O)O)CCC1c2ccccc2-c2ccccc21
Solvent: CC(Cl)Cl
Product: CN(CCC(=O)Cl)CCC1c2ccccc2-c2ccccc21
Product: Cl

Procedure:
A solution of 3-{[2-(9H-fluoren-9-yl)-ethyl]-methyl-amino}-propionic acid (11.4 g) in dichloroethane (115 ml) is treated with thionyl chloride (7.71 g) at room temperature for 5′ and at 60° for 1 hour. About 20 ml volatiles are removed under reduced pressure. 100 ml diethyl ether are added and the mixture kept at 5° over night for crystallization. The crystals are collected by filtration, washed with dichloroethane/diethylether and dried. M.p. 120°-123°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([OH:21])=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:22])=[O:10].ClC1C=CC=C(C(OO)=[O:31])C=1.CCCCCC>C(Cl)(Cl)Cl.CS(C)=O>[CH3:1][N:2]1[C:6]([S:7]([CH3:8])=[O:31])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([OH:21])=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:22])=[O:10]
Reactant: CSc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)O)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc2n(c1C(=O)c1ccc(S(C)=O)n1C)CCC2C(=O)O
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A solution of 0.2 g of 5-(1-methyl-5-methylthio-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid in 20 ml chloroform and a few drops of dimethylsulfoxide was treated with 0.1 g of m-chloroperbenzoic acid (MCPBA) and stirred overnight. Hexane was then added carefully, and the mixture was cooled and the resulting yellow crystals was collected by filtration to give 195 mg of 5-(1-methyl-5-methylsulfinyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid. m/e 334.