Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Cl-].[Zr+4:5].[C:6]1([CH:12]([CH3:14])C)[CH:11]=[CH:10]C=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[Al]>Cl.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].ClCCl>[Cl-:1].[Cl-:1].[CH-:10]1[CH:11]=[CH:6][CH:12]=[CH:14]1.[CH-:10]1[CH:11]=[CH:6][CH:12]=[CH:14]1.[Zr+2:5]
Reactant: [Zr+4]
Reactant: CC(C)c1ccccc1
Agent: [Fe+2]
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Product: [Zr+2]
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
17.5 g (0.075 mol) of zirconium tetrachloride are added at 60° C. under nitrogen over 30 minutes to a stirred mixture of 129.7 g (1.265 mol) of cumene, 27.9 g (0.15 mol) of ferrocene, 26.6 g (0.199 mol) of aluminium chloride and 0.7 g (0.025 mol) of aluminium powder. The reaction mixture is heated and then stirred for 1.5 hours at 110° C., cooled to 25° C., and then slowly poured into a cold mixture of -10° C. of 200 ml of dichloromethane and 50 ml of 32% hydrochloric acid. The mixture is then diluted with a further 200 ml of 5% hydrochloric acid under nitrogen and the two phases are separated. The lower dichloromethane phase containing zirconocene dichloride is concentrated by rotary evaporation and the residual solid is dried under a high vacuum, affording 13 g of zirconocene dichloride [59.4% of theory, sublimed 50.5%, m.p. 195° C. (dec.)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18](OCC)=[O:19])=[C:16](/[CH:23]=[CH:24]/[N:25](C)C)[N:15]=[C:14]([S:28][CH3:29])[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH4+].[OH-]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]3[C:18](=[O:19])[NH:25][CH:24]=[CH:23][C:16]=3[N:15]=[C:14]([S:28][CH3:29])[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOC(=O)c1c(/C=C/N(C)C)nc(SC)nc1Nc1cc(OC)cc(OC)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Nc2nc(SC)nc3cc[nH]c(=O)c23)cc(OC)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 56.5 %

Procedure:
The crude of (E)-ethyl 4-(3,5-dimethoxyphenylamino)-6-(2-(dimethylamino)vinyl)-2-(methylthio)pyrimidine-5-carboxylate (3.16 g) was dissolved in 45 mL EtOH. To the solution was added 30% NH4OH solution (5.2 mL), the reaction mixture was stirred at 75-85° C. for 10 hours. The mixture was cooled to room temperature. The solids formed from the solution were filtered. The filtrate was condensed under reduced pressure resulting in the solid residue. The residue was recrystallized from ethyl acetate. The combined solids were dried under reduced pressure yielding light yellow solids (1.47 g). MS m/z: 344.9 (M+H)+.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:55])[C@H:10]([O:24][C:25]1[C:30]([Br:31])=[CH:29][C:28]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]4[CH:53]=[CH:52][CH:51]=[CH:50][C:40]=4[S:41][C:42]=3[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:27][C:26]=1[Br:54])[CH2:11][CH2:12][N:13]1C(=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].CO.Cl>O>[CH2:43]([C:42]1[S:41][C:40]2[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=2[C:38]=1[C:35]1[CH:36]=[CH:37][C:32]([C:28]2[CH:27]=[C:26]([Br:54])[C:25]([O:24][C@@H:10]([C:9]([O:8][CH3:7])=[O:55])[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:1]([OH:3])=[O:4])=[C:30]([Br:31])[CH:29]=2)=[CH:33][CH:34]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC(=O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](CCNC(=O)c1ccccc1C(=O)O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 624.3 %

Procedure:
Potassium carbonate (0.01 g) was added into a mixture of (2R)-2-[4′-(2-benzyl-benzo[b]-thiophen-3-yl)-3,5-dibromo-biphenyl-4-yloxy]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (0.5, 0.063 mmol), methyl alcohol (10 mL), and water (0.5 mL). The reaction mixture was stirred at room temperature for 24 hours, poured into water, acidified with HCl (2 N), and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acidic silica gel (hexanes/EtAOc 4:1) gave white solid (0.32 g, 63% yield): mp 95-97° C; MS m/e 811 (M+);
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:3]1=[O:33].C(O)(=[O:36])C.[Se](=O)=O>O1CCOCC1>[OH:36][CH2:22][C:5]1[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:3](=[O:33])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=1[C:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: Cn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(CO)n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To a solution of 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 1) (50.0 mg) in dioxane (1.0 ml) were added acetic acid (0.5 ml) and selenium dioxide (74.0 mg) and the resulting mixture was stirred with heating under reflux for six hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-(6-hydroxymethyl)-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (3.7 mg).
Reaction SMILES: Cl[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[SH-:19].[Na+].Cl>C(O)C>[SH:19][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(S)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 14 g. (.05 moles) of α, 2'-dichloro-4-biphenylylacetic acid and 5 g. of sodium hydrosulfide in 100 ml. of absolute ethanol and under a nitrogen atmosphere is stirred for 15 hours. The mixture is then acidified with 6 N hydrochloric acid. The solvent is removed in vacuo and the residue is extracted into ether, washed with water, saturated sodium chloride solution, dried and evaporated to dryness to obtain α-mercapto-2'-chloro-4-biphenylylacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2)([O-])=O.[H][H]>[Ni].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2
Reactant: [H][H]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1

Procedure:
A solution of 3.63 g (14.9 mmol) of 1,2-dihydro-6-nitro-2-oxo-3-quinolinecarboxylic acid and 200 ml of dimethylformamide is hydrogenated using 1 g of Raney nickel catalyst at 52 psi and 23° until the required amount of hydrogen uptake is obtained. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is treated with ethanol and 3.0 g of the desired product and is filtered.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1>>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CCC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CCC(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
The crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propionamide (42 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 19.8 mg of 162. MS (Q1) 409 (M)+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]([CH:45]=O)=[CH:37]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1CCCCC1>CO>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38](/[CH:45]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])=[CH:37]2)(=[O:34])=[O:35])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1cn(S(=O)(=O)c2ccc(Cl)cc2)c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(Cl)cc4)c4ccccc24)C3=O)CC1
Yield: 86.3 %

Procedure:
tert-Butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 and 1-(4-chlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.0918 g, 0.287 mmol) were stirred overnight at room temperature in methanol (1.2 mL) in the presence of piperidine (0.00244 g, 0.0287 mmol). The reaction mixture was further added with methanol (1 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(4-chlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.161 g, 86%).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:29])(=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:30]>C(O)(=O)C>[Br:1][C:14]1[C:9]([C:8]2[N:4]([CH3:3])[C:5]([CH3:30])=[N:6][CH:7]=2)=[N:10][C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:29])(=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:20][CH:21]=2)=[N:12][CH:13]=1
Reactant: BrBr
Reactant: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Solvent: CC(=O)O
Product: COCCNS(=O)(=O)c1ccc(Nc2ncc(Br)c(-c3cnc(C)n3C)n2)cc1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
Bromine (8 μl, 0.14 mmol) was added to a solution of 4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Example 35; 52 mg, 0.13 mmol) in glacial acetic acid (2 ml) heated at 60° C. The mixture was heated at 60° C. for 4 hours, then the solvent was removed by evaporated. The residue was dissolved in DCM (20 ml), washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), dried (Chemelut column 1005) and purified by flash chromatography eluting with DCM/2% methanolic ammonia (100:0 increasing in polarity to 97:3) to yield the title compound (37 mg, 60%) as a white foam NMR 2.40 (s, 3H), 3.06 (q, 2H), 3.20 (s, 3H), 3.36 (t, 2H), 3.68 (s, 3H), 5.00 (t, 1H), 7.56 (s, 1H), 7.67 (d, 2H), 7.73 (d, 2H), 7.80 (s, 1H), 8.53 (s, 1H); m/z 483.
Reaction SMILES: C(OC(N[C@H](C(NC[C@@H](NC(OC(C)(C)C)=O)C(C)C)=O)CC1C=CC=CC=1)=O)C1C=CC=CC=1.Cl.[NH2:37][C@:38](NC(OC(C)(C)C)=O)([CH:62]([CH3:64])[CH3:63])[CH2:39][NH:40][C:41](=[O:61])[C@H:42]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[C:90]([NH:97][C@H:98]([C:103](O)=[O:104])[CH2:99][CH:100]([CH3:102])[CH3:101])([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91].C1CCC(N=C=NC2CCCCC2)CC1>Cl.O1CCOCC1.CN(C=O)C.C(Cl)Cl>[CH2:47]([O:46][C:44]([NH:43][C@H:42]([C:41]([NH:40][CH2:39][C@@H:38]([NH:37][C:103](=[O:104])[C@H:98]([CH2:99][CH:100]([CH3:101])[CH3:102])[NH:97][C:90]([O:92][C:93]([CH3:94])([CH3:95])[CH3:96])=[O:91])[CH:62]([CH3:64])[CH3:63])=[O:61])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:45])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)[C@@](N)(CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)[C@@H](CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
(2S)-1-(N-benzyloxycarbonyl-L-phenylalanylamino)-2-(tert-butoxycarbonylamino)-3-methylbutane (0.730 g, 1.51 mmol) was dissolved in 15 ml of 4N solution of anhydrous hydrochloride in dioxane. The reaction mixture was stirred during 0.5 h at room temperature, then evaporated under reduced pressure. The residual oil was triturated with anhydrous diethyl ether (50 ml). The obtained solid was filtered off under reduced pressure, washed with anhydrous diethyl ether (3×10 ml) and dried under vacuum over potassium hydroxide. The resulted (2S)-2-amino-1-(N-benzyloxycarbonyl-L-phenylalanylamino)-2-(tert-butoxycarbonyl-amino)-3-methylbutane hydrochloride (0.622 g, 1.48 mmol) was dissolved in 14 ml DMF/DCM (5:9 v/v) mixture, then triethylamine (412 μl, 2.96 mmol), HOBt (0.200 g, 1.48 mmol) and Boc-L-leucine (0.342 g, 1.48 mmol) were added to the solution. The mixture was cooled on ice bath and DCC (0.336 g, 1.63 mmol) was added in small portions during 0.5 h, with vigorous stirring. Stirring on ice bath was continued during additional 1 h, then the reaction mixture was left at room temperature overnight. The precipitated DCU was filtered off, washed with DMF (5 ml) and the combined filtrates were evaporated under reduced pressure. The solid residue was dissolved in 250 ml of ethyl acetate and the solution was washed with 1 M hydrochloric acid (3×80 ml), water (100 ml), 1 M sodium bicarbonate (3×80 ml) and saline (3×80 ml). The organic layer was dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was dissolved in hot toluene and precipitated with petroleum ether, yielding 0.795 g (90%) of (2S)-1-(N-benzyloxycarbonyl-L-phenylalanylamino)-2-(N-tert-butoxycarbonyl-L-leucylamino)-3-methylbutane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14]C(OCC2C=CC=CC=2)=O)[C@H:10]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28]2)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28]2)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
In a dry 500-mL Paar flask charged with 10 wt % palladium on carbon (0.050 g) and (3R,4R)-4-benzyloxycarbonylamino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (0.25 g, 0.451 mmol) was added methanol (15 mL). The reaction mixture was hydrogenated at 48 psi for 18 hours with vigorous shaking. The reaction mixture was filtered through a plug of celite. The plug was washed with 20 mL of methanol and the combined filtrates were concentrated in vacuo to give a white solid (0.183 g, 97%). 1H NMR (300 MHz, CDCl3), δ: 8.11 (bs, 2H), 7.15 (m, 2H), 6.97 (t, 2H, J=8), 4.23 (bm, 3H), 3.88 (m, 1H), 3.67 (bs, 1H), 3.13 (m, 1H), 2.60 (bm, 5H), 2.31 (bd, 1H, J=12), 1.74 (bm, 6H), 1.47 (2s, 9H), 1.20 (m, 1H). MS (ESI), m+/z: (M+H)+=420.3.
Reaction SMILES: [CH:1]1([N:5]2[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:22]1([O:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>C(OCC)(=O)C.[Pd].CO>[C:22]1([O:28][C:29](=[O:30])[NH:10][C:8]2[N:7]=[CH:6][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH:9]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cn(C2CCC2)cn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cn(C2CCC2)cn1)Oc1ccccc1
Temperature: -78 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
A Parr hydrogenation bottle was charged with 1-cyclobutyl-4-nitro-1H-imidazole (Preparation 1, 3 g, 18 mmol) and ethyl acetate (70 mL) followed by 10% Pd on carbon (1.2 g) under a nitrogen atmosphere. The mixture was hydrogenated for 6 h under 50 psi H2 at 23° C. The mixture was then filtered through a pad of celite which was rinsed with dry methylene chloride (140 mL) into a flame-dried flask. The resulting solution was cooled to −78° C. and diisopropylethylamine (2.3 g, 18 mmol) was added followed by the dropwise addition of phenylchloroformate (2.5 g, 16.2 mmol). After 30 min, methanol (9 mL) containing acetic acid (1.8 mmol) was added. The reaction mixture was transferred to a separatory funnel, was diluted with ethyl acetate (200 mL), and was washed with water (2×). The aqueous layers were extracted with ethyl acetate (2×10 mL). The organic layers were combined, were washed with brine (2×), and were then dried (MgSO4), filtered, and concentrated in vacuo. The crude product was adsorbed onto silica gel and was purified by silica gel chromatography (1:1 hexanes-ethyl acetate) to afford 3 g (65% yield) of (1-cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester; 1H NMR (400 MHz, CDCl3) δ 7.4–7.3 (m, 2H), 7.22–7.18 (m, 3H), 4.5 (m, 1H), 2.46–2.30 (m, 4H), 1.83 (m, 2H); MS (AP/CI): 258.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11]2[C:16]([C:17]=1[O:18]CC1C=CC=CC=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]>[Pd].CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(CC(C)C)c2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(CC(C)C)c2ccccc2c1O
Reaction time: 24 h
Yield: 90.2 %

Procedure:
A mixture of 4-Benzyloxy-1-isobutyl-isoquinoline-3-carboxylic acid butyl ester (125 mg, 0.32 mmol), Pd/C (50 mg, Aldrich, 10 wt % Pd) and EtOAc (15 ml) were stirred at ambient pressure and temperature under an H2 atmosphere for 24 h. The mixture was then filtered through a pad of celite. Concentration of the filtrate in vacuo yielded the title compound as a yellowish oil (87 mg); MS-(+)-ion M+1=302.2.
Reaction SMILES: O.[OH-].[Li+:3].C[O:5][C:6](=[O:19])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[CH:11]=[N:10][CH:9]=1>C1COCC1.O>[Li+:3].[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[C:8]2[CH2:7][C:6]([O-:19])=[O:5]
Reactant: COC(=O)Cc1cncc2ccc(Br)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])Cc1cncc2ccc(Br)cc12

Procedure:
Sodium borohydride (1.12 g, 29.6 mmol) is added portionwise to a cooled (0° C.) solution of 6-bromoisoquinoline[J Chem Soc Perkin Trans 2, 1998, 437] (1.544 g, 7.42 mmol) in acetic acid (10 ml) and acetic anhydride (3 ml). After heating at 60° C. for 4 hours, the mixture is cooled, evaporated and diluted with water. After adjustment to pH10 with potassium carbonate and extraction with ethyl acetate, the combined organic phases are washed twice with 0.5N HCl and brine, then dried over sodium sulphate. Evaporation affords 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone, MH+ 253. Glyoxylic acid (0.812 g, 8.80 mmol) is added to mixture of 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone (1.50 g, 5.90 mmol) in 6N HCl (20 ml). The reaction is heated at 100° C. for 2 hours, cooled to RT and washed with ethyl acetate. After evaporation, the residue is taken into methanol (20 ml), concentrated sulphuric acid (10 drops) is added and the mixture heated at reflux for 14 hours. After partial evaporation of the solvent, the resultant solid is collected by filtration, washed with methanol and dried to afford (6-bromo-isoquinolin4-yl)-acetic acid methyl ester hydrochloride, MH+ 281. Lithium hydroxide hydrate (8.5 mg, 0.20 mmol) is added to a cooled (0° C.) solution of (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (50 mg, 0.18 mmol) in 3:1 THF-water (3 ml). After 1 hour the solvent is evaporated to afford (6-bromo-isoquinolin-4-yl)-acetic acid lithium salt, MH+ 266.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].OC[C:16]([CH2:21][OH:22])([CH2:19][OH:20])CO>>[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:12][CH2:13][C:16]2([CH2:19][O:20][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])[O:22][CH2:21]2)[CH2:1][O:2]1)#[N:11]
Reactant: COC(CCCCCCC#N)OC
Reactant: OCC(CO)(CO)CO
Product: N#CCCCCCCC1OCC2(CO1)COC(CCCCCCC#N)OC2
Yield: 112.5 %

Procedure:
The condensation reaction of 11.9 g of 7-cyanoheptanal dimethylacetal and 4.35 g of pentaerythritol was carried out to obtain 13.6 g of 3,9-bis(6-cyanohexyl)-2,4,8,10-tetraoxaspiro[5.5]undecane, which was then subjected to catalytic reduction to form 8.6 g of 3,9-bis(7-aminoheptyl)-2,4,8,10-tetraoxaspiro[5.5]undecane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=1[F:14].[NH3:19].[BH4-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:19])=[CH:8][C:7]=1[F:14]
Reactant: N
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: NCc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(3,4-difluorophenoxy)-3-fluorobenzaldehyde (300 mg, 1.19 mmol) and 7 M NH3 in MeOH (10 mL) was added titanium isopropoxide (0.712 mL, 2.38 mmol). The reaction mixture was stirred overnight at rt. Then, NaBH4 (54.0 mg, 1.43 mmol) was added in portions. The mixture was stirred at rt for 4 h, and quenched with water and filtered. The organic part was extracted with ethyl acetate. Combined organic portions were dried over Na2SO4, filtered and concentrated. Purification via Biotage reverse phase chromatography (acetonitrile/water, 5%-95% with 0.25% TFA) afforded the title product (100 mg) as a white solid.
Reaction SMILES: [CH2:1]([S:11](Cl)(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC.[OH-].[Na+]>[CH2:1]([S:11]([NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCS(=O)(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCCCCCCS(=O)(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of decanesulfonyl chloride (0.8571 g, 3.56 mmol) in ether (7.5 ml) was added to a solution of L-phenylalanine (0.7441 g, 4.40 mmol) in 10 ml of 1.0 N sodium hydroxide and stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and the aqueous phase was separated and acidified to pH 1 with 6 N hydrochloric acid. The resulting precipitate was extracted into ethyl acetate and the extract was washed with water and dried with magnesium sulfate. Evaporation of the ethyl acetate gave an oil which crystallized (see Table 1). Yield 0.245 g; FABMS m/z 370(M+H)+, 392(M+Na)+, Calculated for C19H32NO4S, 370.20; C19H31NO4SNa, 392.19.