Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:11]=2[NH:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH2:33](I)[CH3:34]>>[CH2:1]([CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:11]=2[N:10]([CH2:33][CH3:34])[C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1ccccc1)C(=O)N2
Reactant: CCI
Solvent: CI
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1ccccc1)C(=O)N2CC
Yield: 65 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 3-benzyl-8-ethoxy-7-methoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIbb), and methyl iodide by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. F: 228–230° C. 1H-NMR (CDCl3, 300 MHz): d 1.03–1.08 (m, 3H, NCH2CH3), 1.50–1.54 (m, 3H, OCH2CH3), 3.59–3.65 (m, 3H, 1HNCH2+CH2Bn), 3.70 (s, 3H, OCH3), 3.77–3.83 (m, 1H, 1CH), 4.12–4.18 (m, 2H, OCH2), 4.30–4.41 (m, 1H, 1HNCH2), 6.62 (s, 1H Ar), 6.79 (s, 1H Ar), 7.22–7.59 (m, 10H Ar).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:23])[CH2:15][CH2:14]1.C[O-].[Na+].[BH4-].[K+]>CO>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH:22]([OH:23])[CH2:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][CH:13]([O:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[CH2:18][CH2:17]2)=[CH:29][CH:28]=1
Reactant: O=C(CCCN1CCC(Oc2ccc3ccccc3c2)CC1)c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: OC(CCCN1CCC(Oc2ccc3ccccc3c2)CC1)c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
To 8.0 g (0.02 mole) of 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone HCl in 50 ml of methanol is added 1.1 g (0.02 mole) of sodium methoxide and then 2.7 g (0.05 mole) of potassium borohydride and the mixture stirred at room temperature for 2 hours. The methanol is removed at reduced pressure on a steam bath after which 50 ml of 10% sodium hydroxide solution is added. The mixture is stirred for 15 minutes and 100 ml of chloroform is added. Stirring is continued for 1/2 hour. The chloroform layer is separated and combined with two 25 ml chloroform extracts of the aqueous phase, washed with water and with brine, dried over MgSO4, filtered and concentrated to a solid. The solid material is recrystallized from ethanol/water to give α-(4-fluorophenyl)-4-(2-naphthalenyloxy)-1-piperidinebutanol.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([O:4][CH2:3][CH:2]3[CH2:5][CH2:6][CH2:7][NH:1]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: OC[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OCC3CCCN3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of prolinol (0.0243 g, 2.27 mmol) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1–2% MeOH—CHCl3) to afford the title compound E22 as an off-white solid (0.35 g, quantitative). mp 84–86 ° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 24.67 min, 99.59% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[C:39]1[CH:47]=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH:47]([C:39]1[NH:38][C:46]2[C:41]([CH:40]=1)=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCC=Cc1cc2ccccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a suspension of heptyl-triphenyl-phosphonium bromide in THF was added LiHMDS in THF and the mixture was stirred for 30 minutes and then the solution of 1H-indole-2-carbaldehyde was added to the reaction mixture and stirred for 3 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]1[C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]1[C:21](=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CSc1ccc2cc(C(=O)C(C)C)n(CCNC(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1ccc2cc(C(=O)C(C)C)n(CCN)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 143.4 %

Procedure:
To a solution of tert-butyl(2-(2-isobutyryl-6-(methylthio)-1H-indol-1-yl)ethyl)carbamate (200 mg, 0.53 mmol) in CH2Cl2 (9 mL) at 0° C. was added TFA (1 mL). The reaction mixture was stirred at rt for 1 h. The mixture was concentrated (T<25° C.), treated with water (5 mL), adjusted to pH=11 with sat. NaHCO3 and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated to afford 1-(1-(2-aminoethyl)-6-(methylthio)-1H-indol-2-yl)-2-methylpropan-1-one (210 mg, 100% yield) as a colorless oil. LC-MS MS (ESI) m/z 258.8 [M−18+H]+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[N:28]=[C:21]2[C:22]([CH:26]=O)=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1.O>O1CCCC1>[CH3:17][C:18]1[N:28]=[C:21]2[C:22](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1
Reactant: Cc1nc2c(C=O)cccn2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccn2nc(C)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (1.42 g, 35.5 mmol) in tetrahydrofuran (35 mL) was added a solution of ethyl diethylphosphonoacetate (7.10 mL, 35.5 mmol) in tetrahydrofuran (5.0 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde (5.20 g, 32.3 mmol) in tetrahydrofuran (60 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (6.30 g, yield 84%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11](Cl)[C:12](Cl)=[C:13](Cl)[C:14]=1Cl)[C:8]([OH:10])=[O:9].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)[C:12]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[C:13]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)[C:14]=1[S:27][C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(O)=NCCO
Reactant: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2c(Sc3ccc(C)cc3)c(Sc3ccc(C)cc3)c(C(O)=NCCO)c(C(=O)O)c2Sc2ccc(C)cc2)cc1

Procedure:
2 g (6.08 millimols) of tetrachlorophthalic acid N-2-hydroxyethylimide, 3.1 g (24.93 millimols) of p-thiocresol, 5.08 g (36.78 millimols) of potassium carbonate and 20 ml of N,N-dimethylformamide are stirred at 25° C. for 1 hour. After evaporation, the residue is acidified with dilute HCl solution and extracted with methylene chloride. After recrystallisation from toluene/cyclohexane, 3.21 g (78% of theory) of the title compound are obtained; melting point 161°-2° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:21])([O-])=O.CC(O)=O>C1COCC1.[Zn]>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:21]
Reactant: O=[N+]([O-])c1cc(Oc2ccnc3ccccc23)ccc1O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc(Oc2ccnc3ccccc23)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Nitro-4-(quinolin-4-yloxy)-phenol (Step A, 200 mg) was dissolved in THF (50 mL) at 0° C. and AcOH (0.88 mL) was added followed by zinc dust (2.3 g). The mixture was stirred at RT for 1.5 h and filtered through a Celite® pad. The solvent was evaporated, the residue was dissolved in CH2Cl2 and washed with 1M NaOH. The organic phases were dried, filtered and evaporated to give the title compound as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:37])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 4-(isoxazol-5-yl)aniline (60 mg, 0.375 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(isoxazol-5-yl)phenylamino)pyrazine-2-carbonitrile (4 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(isoxazol-5-yl)phenylamino)pyrazine-2-carbonitrile (4 mg, 0.010 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.25 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (3 mg). MS 430.4 (M+H); UV 202.3, 234.0, 274.4, 331.8 nm; t 0.483 min.
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:3]1.[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:21]([N:8]([CH:5]1[CH2:6][CH2:7][C:2]([OH:1])([CH3:20])[CH2:3][CH2:4]1)[C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:22]
Reactant: CC=O
Reactant: COC(=O)c1cccc(NC2CCC(C)(O)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cccc(C(=O)OC)c1C)C1CCC(C)(O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 3-((4-hydroxy-4-methylcyclohexyl)amino)-2-methylbenzoate (1.4 g, 5.05 mmol) and acetaldehyde (0.7 ml, 13 mmol) in 20 ml of dichloroethane was added acetic acid (1.7 mL, 30 mmol) and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (3.2 g, 15 mmol) was added and the mixture was stirred at room temperature for overnight. The reaction mixture was neutralized with sat. NaHCO3 and extracted with DCM. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and the residue purified by silica gel column chromatography to afford the title compound (1.42 g, 94%).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14]=1[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1)=[O:23])=[O:11])(C)(C)C>FC(F)(F)C(O)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22]([C:14]2[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:13]=2[NH:12][C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:32])=[O:5])=[O:11])=[O:23])=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 104.6 %

Procedure:
N-{[(2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-benzofuran-3-yl)amino]carbonyl}-β-alanine t-butyl ester (1.71 g) obtained in Example 11(1) is dissolved in trifluoroacetic acid (15 ml), and the mixture is stirred at room temperature for 1 hour and 45 minutes. The reaction solution is concentrated in vacuo to reduce the volume by about half. To the residue is added diisopropyl ether and the precipitates are collected by filtration to give the title compound (1.57 g). ESI-MS M/Z:401/403[M−H]−
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[N:4]([CH3:31])[N:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>CCO>[CH3:31][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[C:10]2[CH:2]=[N:3]1
Reactant: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccnc21
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cn1ncc2c(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccnc21

Procedure:
In analogy to GP 6, reaction of 171 mg of 1-[4-(3-Amino-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (0.4 mmol, 1 eq.) with 63 μL concentrated sulphuric acid and 68 mg sodium nitrite (2.5 eq.) in 3.75 mL EtOH yielded the desired product.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])[CH:4]=[O:5])[CH3:2].[Li+].[BH4-]>CO.C1COCC1>[OH:5][CH2:4][C:3]([CH2:1][CH3:2])=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])=[C:10]2[C:14]([CH2:13][O:12][C:11]2=[O:20])=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18]
Reactant: CCC(C=O)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.2 %

Procedure:
A solution of 2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal (1.3g, 3.30 mmol) in methanol (10 mL) and THF (10 mL) was cooled to 0° C. A solution of CeCl3 (8.25 mL, 0.4M, MeOH: H2O, 9:1) was added, followed by LiBH4 (1.66 mL, 3.30 mmol of a 2M solution in THF). The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for an additional 40 minutes whereupon TLC indicated complete consumption of starting aldehyde. The reaction was worked up by addition of aqueous 1N HCl and the product was extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 948 mg (73%) of the product as colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.07 (t, 3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.13 (s, 3H), 2.38-2.50 (m, 2H), 3.77 (s, 3H), 3.99 (s, 2H), 4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.34 (t, J=7.2 Hz, 1H) ppm.
Reaction SMILES: O[C:2]1([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH2:6][C:5](=[O:16])[CH:4]=[CH:3]1.[CH3:25][CH2:26][O:27]CC.C(=O)(O)[O-].[Na+].C(=O)=O>C(OC(=O)C)(=O)C>[C:26]([O:16][C:5]1[CH:4]=[CH:3][C:2]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:7]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH:6]=1)(=[O:27])[CH3:25]
Reactant: CCOCC
Reactant: CC1(CCC2CC(=O)C=CC2(O)C#Cc2ccccc2)OCCO1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C#Cc2ccccc2)c(CCC2(C)OCCO2)c1
Temperature: 25 °C

Procedure:
4-Hydroxy-5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-4-(phenylethynyl)-2-cyclohexen-1-one (3.0 g, 9.2 mmole, prepared in a manner similar to that in Example 7b) was dissolved in acetic anhydride (25 mL) and stirred at RT under argon. After stirring 5 hr at RT, the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to RT, poured into about 100 mL of ether, about 200 mL of saturated sodium bicarbonate added and the solution stirred. After evolution of CO2 was complete, solid sodium bicarbonate was added cautiously until foaming ceased. The layers were separated, the aqueous layer extracted twice with 100 mL portions of ether, the ether layers combined, washed with two 100 mL portions of sodium bicarbonate solution, two 100 mL portions of ether, the ether layers combined, washed with two 100 mL portions of saturated sodium bicarbonate solution, two 100 mL portions of water and 75 mL of saturated brine. After drying over anhydrous sodium sulfate, the organic layer was filtered and concentrated in vacuo to give 3.2 g of the title compound, a dark orange oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:25][C:26]1[C:31]2=[C:32]([C:47]3[S:48][C:49]4[C:55]([O:56][CH3:57])=[CH:54][C:53]([CH3:58])=[CH:52][C:50]=4[CH:51]=3)[C:33]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])=[C:34]([CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:30]2[N:29]=[CH:28][N:27]=1>ClCCl.N1C=CC=CC=1.CO>[NH2:25][C:26]1[C:31]2=[C:32]([C:47]3[S:48][C:49]4[C:55]([O:56][CH3:57])=[CH:54][C:53]([CH3:58])=[CH:52][C:50]=4[CH:51]=3)[C:33]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])=[C:34]([CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH:1]=[O:3])[CH2:40][CH2:41]3)[N:30]2[N:29]=[CH:28][N:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C)cc2cc(-c3c(CNC(C)=O)c(CN4CCNCC4)n4ncnc(N)c34)sc12
Solvent: CO
Solvent: ClCCl
Solvent: O=CO
Product: COc1cc(C)cc2cc(-c3c(CNC(C)=O)c(CN4CCN(C=O)CC4)n4ncnc(N)c34)sc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic acid anhydride (304 μl, 3.16 mmol) and formic acid (145 μl, 3.16 mmol) were stirred first 2 h at 50° C. and then overnight at rt. Subsequently, the mixture was diluted with dichloromethane (3.1 ml), and 663 μl of this solution were added to a solution of Example 63 (160 mg, 226 μmol) in pyridine (54 μl). The mixture was stirred at rt for 2 h, then diluted with methanol (1 ml), and stirring was continued at 40° C. for another 2 h. After evaporation, the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) affording 74 mg (61% of th.) of title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:25])[C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH:12]1[CH2:26][CH2:27][C:9]2([O:28][CH2:29][CH2:30][OH:31])[CH2:10][CH2:11]1)=[O:5])C.[H-].[Na+].[CH3:34]I>CN(C=O)C>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:25])[C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH:12]1[CH2:26][CH2:27][C:9]2([O:28][CH2:29][CH2:30][O:31][CH3:34])[CH2:10][CH2:11]1)=[O:5]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(OCCO)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC12CCC(CC1)Cn1c2nc(C(=O)OC)c(OCc2ccccc2)c1=O
Reaction time: 0.25 h
Yield: 7.8 %

Procedure:
To a solution of 5-benzyloxy-1-(2-hydroxy-ethoxy)-6-oxo-3,7-diazatricyclo[7.2.2.02,7]trideca-2,4-diene-4-carboxylic acid ethyl ester (105 mg, 0.245 mmol) in DMF (1 mL) was added 60% NaH (15 mg, 0.37 mmol) and the mixture stirred at room temp. for 15 min. under N2. After H2 gas evolution had ceased, MeI (0.031 mL, 0.490 mmol) was added and the mixture stirred at room temperature overnight. The mixture was concentrated and the residue was taken up in ethyl acetate (10 mL), washed with water followed by brine, then dried (Na2SO4) and concentrated to provide 85 mg of a crude oil which was purified by C-18 reverse phase column chromatography (YMC AQ, 18-22-26-30-34% CH3CN/H2O with 01% trifluoroacetic acid) to provide 8 mg (0.019 mmol, 8% yield) of the title compound as an amber film: HPLC: retention time=2.30 min (area percent=91%); LC/MS: m/z 429 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 1.66-1.70 (2H, m), 1.87-2.02 (2H, m), 2.12 (4H, t, J=7.5 Hz), 2.46 (1H, brs), 3.39 (3H, s), 3.62 (2H, t, J=4.7 Hz), 3.73 (2H, d, J=4.7 Hz), 3.84 (3H, s), 4.07 (2H, d, J=3.7 Hz), 5.26 (2H, s), 7.31 (1H, t, J=7.0 Hz), 7.36 (2H, t, J=7.3 Hz), 7.48 (2H, d, J=7.6 Hz).
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)[CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[CH3:40][C:5]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)[CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:18][CH:19]=1)([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2cccc(-c3cccs3)c2)nc1CCOc1ccc(OC(C)(Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
2-Methyl-2-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-3-phenyl-propionic acid ethyl ester (24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-Methyl-2-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-3-phenyl-propionic acid as colorless needles after drying at 50° C. under vacuum for 6 h: 1H NMR(400 MHz, CDCl3) δ 8.22 (t, 1H, J=1.56 Hz), 7.87 (d, 1H, J=7.82 Hz), 7.66-7.64 (m, 1H), 7.45 (d, 1H, J=7.82 Hz), 7.41-7.40 (m, 1H), 7.31-7.25 (m, 6H), 7.09 (dd, 1H, J=5.08 Hz, J=3.52 Hz), 6.84 (d, 2H, J=9.38 Hz), 6.76 (d, 2H, J=9.38 Hz), 4.17 (t, 2H, J=6.45 Hz), 3.30 (d, 1H, J=13.69 Hz), 3.15 (d, 1H, J=13.69 Hz), 3.01 (t, 2H, J=6.45 Hz), 2.40 (s, 3H), 1.35 (s, 3H); HRMS (ES+) m/z exact mass calculated for C32H30NO5S 540.1857, found 540.1857.