Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=CC=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2[S:45]C(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.S1C=CC=C1S(Cl)(=O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[S:45][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1cccs1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 87.8 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (600 mg, 1.8 mmol) and thiophene-2-sulfonyl chloride (331 mg, 1.1 mmol) the title compound was obtained (760 mg, 87.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (d, J=5.3 Hz, 1H), 7.51-7.57 (m, 2H), 7.29-7.38 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.17 (br, 1H), 6.98-7.03 (m, 1H), 6.88 (d, J=5.3 Hz, 1H), 3.27-3.37 (m, 1H), 1.43 (d, J=7.1 Hz, 6H). MS (ES+): 477 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C([O-])(O)=O.[Na+].[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:21](ON1C(=O)CCC1=O)=[O:22])[CH:18]([CH3:20])[CH3:19]>O.CC#N>[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:21]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:22])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 5 °C

Procedure:
H-Gln-OH (2 eq.) and NaHCO3 (2 eq.) were dissolved under stirring in water at maximum 45° C. and then cooled to about 5° C. Z-Val-OSu (1 eq.) was dissolved in MeCN and added in the aqueous solution in such way that the temperature did not rise above 10° C. The mixture was stirred for at least 1 h at ±5° C. before being warmed to room temperature for at least two hours. The peptide solution was concentrated under vacuum, diluted with water and washed twice with AcOEt. The aqueous phase was then diluted with i-BuOH and the pH was adjusted to 2.5 with a solution of KHSO4. DCM was then added to extract the peptide into the organic phase which was washed with a 5% weight NaCl solution and finally with water. The organic phase was collected and concentrated under reduced pressure until water content in the evaporates was <1% weight. The concentrate was diluted with hot isopropyl acetate and left to cool to 25° C. under gentle stirring to crystallize the peptide. The solid was recovered by filtration, once washed with AcOiPr at 25° C. and dried under vacuum until AcOiPr content in the peptide was ≦5% weight. After drying under vacuum not less than 70% of Z-Val-Gln-OH was recovered.
Reaction SMILES: C(OC(=O)[N:10]([C:15]1[N:44]=[C:18]2[N:19]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[C:20]([CH3:33])=[C:21]([C:31]#[N:32])[C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:17]2[N:16]=1)[S:11]([CH3:14])(=[O:13])=[O:12])C1C=CC=CC=1>CO.[Pd]>[C:31]([C:21]1[C@@H:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[N:17]2[N:16]=[C:15]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[N:44]=[C:18]2[N:19]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:20]=1[CH3:33])#[N:32]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(C(=O)OCc3ccccc3)S(C)(=O)=O)nc2N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NS(C)(=O)=O)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(methylsulfonyl)carbamate (16.0 mg, 11 μmol) was dissolved in degassed methanol (2 ml). After addition of a catalytic amount of palladium on activated carbon (10%), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 0.5 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (8.5 mg, 71% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].C(C1C=CC=C(C(C)C)C=1C1NC=C[N+]=1C1C(C(C)C)=CC=CC=1C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=1
Reactant: COc1ccc(Br)c(C(F)(F)F)c1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1-c1[nH]cc[n+]1-c1c(C(C)C)cccc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(N2CCCCC2)c(C(F)(F)F)c1
Temperature: 150 °C

Procedure:
To a solution of 1-Bromo-4-methoxy-2-trifluoromethyl-benzene (500 mg, 1.961 mmol) in 1,4-dioxane (8 mL) is added sequentially: piperidine (2 eq., 3.921 mmol, 0.41 mL), Pd2dba3 (2 mol %, 0.039 mmol, 36 mg), KtOBu (1.5 eq., 2.941 mmol, 330 mg) and 1,3-(Bis(2,6-di-iso-propylphenyl)-imidazolium chloride (iPrHCl, 4 mol %, 0.078 mmol, 33 mg). The resulting reaction mixture is heated in a sealed tube at 150° C. oil bath for 12 hours. After cooling to room temperature, the reaction mixture is concentrated. The residue obtained is partially purified by silica gel chromatography (9:1 hexanes/EtOAc) to give crude 1-(4-Methoxy-2-trifluoromethyl-phenyl)-piperidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:6]=[CH:5]2.C([Li])CCC.CON(C)[C:28]([C:30]1[CH:35]=[C:34]([Cl:36])[N:33]=[CH:32][N:31]=1)=[O:29]>C1COCC1>[Cl:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]([C:28]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=2)[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:6]=[CH:5]3)=[O:29])[CH:35]=1
Reactant: Cc1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Reactant: CON(C)C(=O)c1cc(Cl)ncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: -75 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 0.34 g (1.00 mmol) 5-bromo-7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole in 10 mL THF were cooled to −75° C., mixed with 0.70 mL (1.1 mmol) of a 1.6 molar n-butyllithium solution and stirred for 1 h at −75° C. Then 0.25 g (1.1 mmol) 6-chloro-pyrimidine-4-carboxylic acidmethoxy-methyl-amide, dissolved in a little THF, were added dropwise. The cooling bath was removed and the mixture was heated to 0° C. and stirred for a further hour in the ice bath. The mixture was stirred with saturated sodium hydrogen carbonate solution, extracted with EtOAc, the organic phase was dried and evaporated down. The residue was purified by flash chromatography.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([O:19][CH2:20][CH3:21])(=[O:18])[C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].N1C=CN=C1>CN(C)C=O>[Si:1]([O:11][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([O:19][CH2:20][CH3:21])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H](O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 31.4 g of t-butyldimethylsilyl chloride in 200 ml of dimethylformamide was added dropwise to a solution of 25 g of ethyl (R)-(-)-mandelate and 28.4 g of imidazole in 600 ml of anhydrous dimethylformamide, and the resulting mixture was stirred overnight at 40° C. The dimethylformamide solvent was then removed by distillation under reduced pressure, and the residue was mixed with water and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:10 by volume mixture of ethyl acetate and hexane as the eluent,. The title compound was obtained as a liquid, boiling at 129° C./3.5 mmHg (466 Pa) by distillation in vacuo. [α]D23 -40.8° (c=1.07, chloroform)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])(=[O:21])=[O:20])=[CH:15][C:14]=2[O:30][CH3:31])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:31][O:30][C:14]1[CH:15]=[C:16]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]#[N:29])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=1[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COc1cc(S(=O)(=O)c2ccccc2C#N)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(S(=O)(=O)c2ccccc2C#N)ccc1C1CCNC1

Procedure:
3-[4-(2-Cyano-benzenesulfonyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was deprotected following the procedure described in Example 1. The free amine base was converted in the corresponding hydrochloride salt by addition of a small excess of HCl in 1,4-dioxane: MP=247.8-249.1° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([OH:16])[CH2:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:18]1([CH2:17][C:5]([OH:16])([CH2:6][C:7]([CH3:8])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:15])[CH2:4][OH:3])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)C(O)(CC1CCCCC1)CC(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(CC(O)(CO)CC1CCCCC1)c1ccccc1

Procedure:
Analogously to Example 1, 290 mg of 2-cyclohexylmethyl-2-hydroxy-4-methyl-4-phenylpentanoic acid-ethyl ester is converted with 76 mg of lithium aluminum hydride into 160 mg of product.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:20][C:17]([F:18])([F:19])[C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[N:8]([CH2:7][C:6]([OH:21])=[O:5])[N:9]=1
Reactant: CC(C)(C)OC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetic acid tert-butyl ester was dissolved in a solution of DCM (30 mL) and TFA (30 mL), and the resulting mixture stirred at RT for 30 min, before concentration in vacuo to afford the title compound (4.50 g). This was used directly in the next step without any further purification.
Reaction SMILES: B(F)(F)F.CC[O:7]CC.[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.B.O1CCCC1.[Cl-].[Cl-].[Ca+2].OO.[O-]S([O-])=O.[Na+].[Na+].[OH-].[Na+]>O1CCCC1.Cl.C(OC)(C)(C)C.CO>[CH2:10]([N:17]1[CH2:18][CH2:19][C@@H:20]([CH:23]([CH3:25])[CH3:24])[C@H:21]([OH:7])[CH2:22]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOCC
Reactant: CC(C)C1=CCN(Cc2ccccc2)CC1
Agent: B
Agent: Cl
Agent: FB(F)F
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
Add boron trifluoride etherate (4.6 mL, 36.2 mmol) slowly to a solution of 1-benzyl-4-isopropyl-3,6-dihydro-2H-pyridine (6.7 g, 30.2 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under a nitrogen atmosphere. Stir the mixture for 15 minutes and then dropwise add borane-tetrahydrofuran complex (1M in tetrahydrofuran, 42.3 mL, 42.2 mmol). Allow the mixture to reach ambient temperature and stir for 6 hours. Then add slowly borane-tetrahydrofuran complex (24.1 mL, 24.1 mmol) and stir the mixture overnight. Cool the mixture at 0° C. and add methanol (54 mL) slowly. Stir the mixture at ambient temperature for one hour. Cool the mixture to 0° C. and add a solution of 10% CaCl2 in HCl (0.2M) slowly until the mixture has a pH of 1-2. Stir the mixture at ambient temperature for 1.5 hours. Cool the mixture at 0° C. and add a solution of 35% hydrogen peroxide (3.1 mL, 36.2 mmol). Stir the mixture at ambient temperature over the weekend. Add an aqueous solution of 10% Na2SO3 (15 mL) and methyl tert-butyl ether (50 mL). Add NaOH (5M) to pH 11-12. Separate the organic layer and extract the aqueous layer with methyl tert-butyl ether. Combine the organic layers and wash with brine; dry over MgSO4; filter; collect the filtrate; then remove the solvent under vacuum. Purify the residue by chromatography on a silica gel cartridge eluting with hexane:ethyl acetate (100% to 50% hexane) to obtain the title compound (2.6 g, 37%). MS (m/z): 234 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:19]([OH:20])[C@@H:18]([CH3:21])[C:16](=[O:17])[C:15]([CH3:23])([CH3:22])[C@@H:14]([OH:24])[CH2:13][C:11](=[O:12])[O:10][C@H:9](/[C:25](/[CH3:33])=[CH:26]/[C:27]2[N:31]=[C:30]([CH3:32])[S:29][CH:28]=2)[CH2:8][CH:7]=[C:6]([CH3:34])[CH2:5][CH2:4][CH2:3]1.CC1(C)O[O:37]1>>[CH3:1][C@@H:2]1[C@H:19]([OH:20])[C@@H:18]([CH3:21])[C:16](=[O:17])[C:15]([CH3:22])([CH3:23])[C@@H:14]([OH:24])[CH2:13][C:11](=[O:12])[O:10][C@H:9](/[C:25](/[CH3:33])=[CH:26]/[C:27]2[N:31]=[C:30]([CH3:32])[S:29][CH:28]=2)[CH2:8][C@@H:7]2[O:37][C@:6]2([CH3:34])[CH2:5][CH2:4][CH2:3]1
Reactant: CC1=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Reactant: CC1(C)OO1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of desoxyepothilone B (0.0022 g, 0.0041 mmol) in CH2CI2 (0.25 mL) at −50° C. was added dimethyldioxirane (0.1 mL, 0.0095 mmol) dropwise. The resulting solution was stirred at −50° C. for 1 h. The dimethyldioxirane and solvent were removed by a stream of N2. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 1:1) gave 0.0015 g (70%) of epothiolone B (2) as a pale yellow oil which was identical with an authentic sample in 1H NMR, IR, mass spectrum, and [α]D.
Reaction SMILES: C([BH3-])#N.[Na+].[O:5]=[C:6]1[CH2:15][N:14]2[C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][C:17]=3[C:12]3[C:13]2=[C:8]([CH:9]=[CH:10][CH:11]=3)[NH:7]1.[OH-].[NH4+].[OH-].[Na+]>FC(F)(F)C(O)=O>[O:5]=[C:6]1[CH2:15][N:14]2[C@H:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][C@H:17]3[C:12]3[C:13]2=[C:8]([CH:9]=[CH:10][CH:11]=3)[NH:7]1
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2CC(=O)N4)C1
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
Sodium cyanoborohydride (4.0 g; 65 mmol) was added, in small portions, to a vigorously stirred solution of ethyl 2,3,9,10-tetrahydro-2-oxo-1H-pyrido[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (11.97 g, 40 mmol) in trifluoroacetic acid (125 mL) cooled in an ice-water bath, under nitrogen. After the addition was complete, the mixture was stirred for 30 min and then poured slowly into ammonium hydroxide (300 mL) containing ice followed by the addition of enough 1N sodium hydroxide to make the mixture basic. The mixture was extracted with dichloromethane (2×) and the extract was washed with water, dried over magnesium sulfate, and evaporated to dryness to yield 10.89 g (90%) of ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as an off-white powder, m.p. 167-168° C. (dec., sinters at 70° C.). 1H NMR (CDCl3, 300 MHz) δ 1.28 (t, J=7 Hz, 3H), 1.81-1.95 (m, 2H), 3.13-3.22 (m,1H), 3.23-3.39 (m, 1H), 3.44 (d, J=14.7 Hz, 1H), 3.41-3.51(m, 1H), 3.80-3.95 (m, 1H), 3.98 (d, J=14.7 Hz, 2H), 4.16 (q, 2H), 6.59 (d, J=7.7 Hz, 1H), 6.74 (t, J=7.7 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 8.17 (s, 1H) ppm. MS (CI): 302 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([Mg]Br)=[N:6][CH:7]=1.C1C[O:13][CH2:12]C1.CN(C=O)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:13])=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1ccc([Mg]Br)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(C=O)nc1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To the 0.25 M 5-methyl-2-pyridinylmagnesium bromide of THF solution (20 mL, 5 mmol), DMF (0.773 mL, 10 mmol) was added at room temperature under argon. The reaction mixture was stirred for 10 min. and concentrated in vacuo. The residue was quenched with saturated ammonium chloride and dichloromethane. The organic layer was dried and the product was purified by silica gel column chromatography with 20% ethyl acetate in hexanes to give 379 mg (62.6%) of the title compound. GC-MS (M+): 121.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C:15]([C:39](OCC)=[O:40])=[CH:14][CH:13]=1)=O)C>C1COCC1>[OH:9][CH2:10][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C:15]([CH2:39][OH:40])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c2cc(-c3ccc(OCCC(C)CCCC(C)C)cc3)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCOc1ccc(-c2ccc3c(CO)ccc(CO)c3c2)cc1
Reaction time: 3 h

Procedure:
Under argon atmosphere and with cooling in ice, 10.0 ml of THF solutions of LiAlH4 (1.0M) was added to 6-(4-(3,7-dimethyloctyloxy)phenyl)naphthalene-1,4-dicarboxylic-acid diethyl ester 1.42 g in THF solution, and stirred at a temperature as it was, for 3 hours.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[C:7]([O:24][CH3:25])=[CH:8][C:9]([CH:21]([CH3:23])[CH3:22])=[C:10]([CH:20]=1)[O:11][C:12]1[C:13]([NH2:19])=[N:14][C:15]([NH2:18])=[N:16][CH:17]=1.[Mn]([O-])([O-])(=O)=O.[Ba+2]>C(Cl)Cl>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[C:6]1[C:7]([O:24][CH3:25])=[CH:8][C:9]([CH:21]([CH3:23])[CH3:22])=[C:10]([CH:20]=1)[O:11][C:12]1[C:13]([NH2:19])=[N:14][C:15]([NH2:18])=[N:16][CH:17]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C1=NCCN1
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1ncc[nH]1
Yield: 79.6 %

Procedure:
To a solution of 5-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-isopropyl-4-methoxy-phenoxy]-pyrimidine-2,4-diamine (0.033 g, 0.096 mmol) in dry methylene chloride (25 ml) was added barium manganate (0.4 g, 1.56 mmol). The reaction mixture refluxed over night, after which more of barium manganate (0.1 g) was added, and the mixture was refluxed for another 6 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified with preparative TLC (8% methanol in methylene chloride/0.1% concentrated ammonium hydroxide) to yield 5-[5-(1H-imidazol-2-yl)-2-isopropyl-4-methoxy-phenoxy]-pyrimidine-2,4-diamine as pale yellow solid (0.026 g, 41%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:34]=[CH:33][C:22]4[C:23](=[O:32])[CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[O:26][C:21]=4[CH:20]=3)=[CH:11][C:6]=2[O:5][CH:4]=[CH:3]1.C(=O)(O)[O-].[Na+].O>C(O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:34]=[CH:33][C:22]4[C:23](=[O:32])[CH:24]=[C:25]([C:27]([OH:29])=[O:28])[O:26][C:21]=4[CH:20]=3)=[CH:11][C:6]=2[O:5][CH:4]=[CH:3]1
Reactant: CCOC(=O)c1cc(=O)c2ccc(OCCCCCOc3ccc4c(=O)ccoc4c3)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(=O)c2ccc(OCCCCCOc3ccc4c(=O)ccoc4c3)cc2o1
Reaction time: 0.5 h

Procedure:
A mixture of 5 parts of the ethyl ester from (b), 5 parts of sodium bicarbonate, 70 parts by volume of water and 20 parts by volume of ethanol was warmed and stirred on a steam bath for 30 min. The cooled aqueous solution on acidification gave 4.6 parts of the required acid, m.p. 228°-232° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl[C:20]([C:22]1[CH:41]=[CH:40][C:25]([CH2:26][CH2:27][N:28]([CH3:39])[C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:24][CH:23]=1)=[O:21]>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:29]([N:28]([CH3:39])[CH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([C:20]([NH:1][C:2]2[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:21])=[CH:41][CH:40]=1)=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)c1cccc(N)c1O
Reactant: CN(CCc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(CCN(C)C(=O)OCc3ccccc3)cc2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a stirred solution of 4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzoic acid (2.0 g, 6.38 mmol) in anhydrous dichloromethane (30 mL) was added dropwise thionyl chloride (1.52 g, 12.76 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give benzyl 4-(chlorocarbonyl)phenethyl(methyl)carbamate. To a stirred solution of methyl 3-amino-2-hydroxybenzoate (0.71 g, 4.25 mmol) and pyridine (0.19 mL, 10.2 mmol) in anhydrous toluene (20 mL) was added dropwise a solution of benzyl 4-(chlorocarbonyl)phenethyl(methyl)carbamate (1.7 g, 5.1 mmol) in anhydrous toluene (5 mL). After the addition, the mixture was stirred at room temperature 30 min, then 80° C. for 1 h. The mixture was diluted with toluene, washed with water (30 mL×3), 1N hydrochloric acid (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography ((silica gel, petroleum ether/ethyl acetate 15:1 to 4:1), to obtain methyl 3-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzamido)-2-hydroxybenzoate (1.9 g, yield 97%) as yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.82-2.87 (m, 5H), 3.49-3.53 (t, J=7 Hz, 2H), 3.94 (s, 1H), 4.98-5.06 (d, J=32 Hz, 2H), 6.98-7.02 (t, J=8 Hz, 1H), 7.26-7.39 (m, 7H), 7.66-7.68 (d, J=7.6 Hz, 1H), 7.89-7.91 (m, 2H), 7.94-7.96 (d, J=8 Hz, 1H), 9.61 (s, 1H), 10.92 (s, 1H); LC-MS (ESI) m/z: 463 (M+1)+.
Reaction SMILES: [CH:1]12[CH:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]1[CH2:4][NH:3][CH2:2]2.Br[CH2:16][CH2:17][OH:18].C(Cl)(Cl)Cl.CO>C(#N)C>[OH:18][CH2:17][CH2:16][N:3]1[CH2:2][CH:1]2[CH:5]([CH:6]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:4]1
Reactant: OCCBr
Reactant: CC(C)(C)OC(=O)NC1C2CNCC21
Solvent: CO
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1C2CN(CCO)CC21
Temperature: 70 °C
Yield: 46 %

Procedure:
A mixture of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (T. F. Braish et al. Synlett, 1996, page 1100 and T. Norris et al. J. Chem. Soc. Perkin I, 2000, page 1615-1622), 2-bromoethanol (669 mg, 3.36 mmol) and N,N-ethyldiisopropyl amine (0.087 mL) in acetonitrile (9 mL) was heated in the microwave at 70° C. for 30 minutes. Chromatography on silica gel with chloroform/methanol (20:1) gave 376 mg (46%) of the product.