Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH3:24][S:25]([O:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])[CH:5]=[CH:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=C1C=CC(=NO)S1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C1C=CC(=C(C#N)c2ccccc2)S1
Yield: 77.2 %

Procedure:
5 g (22 mmol) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-phenyl-acetonitrile are dissolved in 50 ml of THF and cooled in an ice bath. After adding 4.6 ml (33 mmol) of triethylamine to the solution, 1.9 ml (24 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred while cooling in an ice bath for 30 min. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 5.2 g (77%) of (5-Methylsulfonyloxyimino-5H-thiophen-2-ylidene)-phenyl-acetonitrile are obtained in the form of greenish brown crystals having a melting point of 160-162° C. (dec.).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[F:32]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([F:32])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2F)CC1
Temperature: 40 °C

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.3012 g, 0.0007895 mol) was dissolved in methylene chloride (5.00 mL, 0.0780 mol) in a capped 40 mL vial equipped with a magnetic stir bar. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.249 g, 0.000789 mol) was added followed by zirconium tetrachloride (0.184 g, 0.000789 mol) and the mixture was heated overnight at 40° C. The reaction mixture was cooled to room temperature then concentrated to dryness under reduced pressure, adsorbed onto silica gel and purified by flash chromatography (0-55% EtOAc in hexanes) to give 131.3 mg of the title compound (42% yield).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:39])[C:17]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[CH:19][C:18]=1[O:31]CC1C=CC=CC=1.[H][H]>C(O)(C)C.O.[C].[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:39])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[OH:31]
Reactant: COc1ccc(CCNCC(O)c2ccc(OCc3ccccc3)cc2OCc2ccccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(CCNCC(O)c2ccc(O)cc2O)cc1OC
Yield: 92.7 %

Procedure:
0.6 g of α-(3,4-dimethoxyphenethylaminomethyl)-2,4-dibenzyloxybenzylalcohol oxalate is suspended in a mixture of 40 ml of isopropanol and 10 ml of water. 0.2 g of 10 % palladium-carbon are added to the suspension. Then, the mixture is subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature for 2 hours under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, whereby 0.39 g of α-(3,4-dimethoxyphenethylaminomethyl)-2,4-dihydroxybenzylalcohol oxalate is obtained as amorphous powder. Yield: 93 %
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[S:11][C:12]([Cl:21])=[C:13]([Cl:20])[C:14]=1/[CH:15]=[CH:16]/[C:17](=[O:19])[CH3:18]>CS(C)=O.[Cl-].[Na+].O>[Cl:9][C:10]1[S:11][C:12]([Cl:21])=[C:13]([Cl:20])[C:14]=1[C@@H:15]1[CH2:4][C@H:16]1[C:17](=[O:19])[CH3:18]
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)/C=C/c1c(Cl)sc(Cl)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
To a stirred mixture of solid sodium hydride (55-65% in oil; 1.5 g; 34 mmol) and trimethylsulfoxonium iodide (7.6 g; 34 mmol) under nitrogen was added in one portion a solution of (E)-4-(2,4,5-Trichloro-thiophen-3-yl)-but-3-en-2-one (7.0 g; 27 mmol) prepared as described in example P33 in dry dimethylsulfoxide (300 mL). The reaction is slightly exothermic and gas evolution is observed. The reaction mixture was stirred for 10 minutes at ambient temperature then poured on water (600 ml) and brine (100 ml) then extracted with dichloromethane (3×300 ml). Combined organic layers were washed with water (2×800 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by chromatography over silica gel (eluant: cyclohexane/ethyl acetate 90:10) to afford 2.7 g (37% of theory) of trans-1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethanone as a yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:9]=2[N:10]=1)C.[BH4-].[Na+]>C1COCC1.CCO>[Br:15][C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([CH2:5][CH2:4][OH:3])=[N:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)Cc1nc2cc(Br)ccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCCc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5-Bromo-benzothiazol-2-yl)-acetic acid ethyl ester (1.25 g, 4.2 mmol) was dissolved in THF (20 mL) and EtOH (5 mL) under N2. Then 0.24 g of NaBH4 was dissolved in EtOH (3 mL) and added to the above solution. The reaction mixture was stirred at room temperature for 2 hours. After the completion the mixture was quenched with water and extracted with CH2Cl2. The aqueous layer was extracted again with more CH2Cl2. The combined methylene chloride layer was dried over anhydrous MgSO4 and filtered. Removal of solvent gave crude product with a yield of 1.11 g. The crude product was used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.CCN(C(C)C)C(C)C.[N-:35]=[N+:36]=[N-:37].[Na+]>C(Cl)Cl.CCOC(C)=O.O.CN(C=O)C>[N:35]([CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:36]=[N-:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)COCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of (S)-tert-butyl 1-(benzyloxy)-3-hydroxypropan-2-ylcarbamate (1.89 g, 6.4 mmol) in DCM (50 mL) was added MsCl (0.55 mL, 7.04 mmol) and DIEA (1.27 mL, 7.68 mmol). The mixture was stirred at RT for 30 min. The mixture was diluted with DCM (300 mL), washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF (20 mL). To this DMF solution was added NaN3 (1.25 g, 19.2 mmol) and the mixture was heated to 80° C. for 6 h. LCMS indicated the completion of the reaction. The mixture was cooled to RT, water (20 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The rude was purified on silica gel column to give (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-ylcarbamate (1.5 g, 73% for 2 steps).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.O.O.[I:22](O)(=O)(=O)=O.S([O-])(O)=O.[Na+]>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:22])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)Cc1cc(I)ccc1-2
Temperature: 75 °C
Yield: 382.7 %

Procedure:
A mixture of 2-bromofluorene (compound 19) (25.0 g, 0.1020 mol), glacial acetic acid (250 cm3), concentrated sulphuric acid (3 cm3) and water (20 cm3) became homogeneous on heating to 75° C. Periodic acid dihydrate (H5IO6, 4.56 g, 0.0200 mol) and pulverised 12 (10.2 g, 0.0402 mol) were added. The initial deep-purple colour changed to a brown during 2 h of heating and stirring at 75° C. Upon dilution with sodium hydrogensulphite (2.50 g) in water (25 cm3), the colour changed to yellow. The solution was subsequently diluted with water (500 cm3) and cooled to 0° C. to give a yellow precipitate. The excess liquid was decanted and the solid filtered off, washed repeatedly with cold ethanol (4×50 cm3), aqueous NaOH (5% solution, 4×50 cm3) and with water (4×50 cm3) to leave a yellow powder. The product was recrystallised from a solvent mixture of DCM and ethanol to yield a yellow powder (28.4 g, 74.9%). Melting point/° C.: 185.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:40](Cl)(=[O:43])[CH2:41][CH3:42].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:40](=[O:43])[CH2:41][CH3:42])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CCC(=O)Cl
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 56.5 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (70.8 mg, 0.12 mmol) in dichloromethane (1 mL) was added propanoyl chloride (11.5 mg, 0.12 mmol). Triethylamine (50 mg, 0.50 mmol) was added and the resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 42.4 mg (56%) of the title compound as off white solid. MS (ES) m/e 625.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>O1CCCC1>[C:32]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3)c2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cc2s1
Yield: 46.2 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.23 mmol) produced in Example A12(iv), tetrahydrofuran (20 mL), acetyl chloride (0.12 mL, 1.69 mmol) and triethylamine (1.0 mL, 7.18 mmol) as starting materials, and in the same manner as in Example A38, the title compound (50 mg, 46%) was obtained as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([C:32]3[CH:41]=[CH:40][C:35]4[O:36][CH2:37][CH2:38][O:39][C:34]=4[CH:33]=3)[CH:23]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+]>>[C:44]([CH2:43][CH2:42][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:25]=[C:24]([C:32]3[CH:41]=[CH:40][C:35]4[O:36][CH2:37][CH2:38][O:39][C:34]=4[CH:33]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])([OH:46])=[O:45]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCCO4)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCCO3)c1
Yield: 69.7 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-(2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-methanesulfonyl-phenoxy]-hexyl}-phenoxy)-butyric acid ethyl ester (330 mg, 0.47 mmol) and 1.0 N aqueous sodium hydroxide (4.74 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-methanesulfonyl-phenoxy]-hexyl}-phenoxy)-butyric acid (210 mg, 69%) as a white solid: ES(+)-HRMS m/e calcd for C34H40O10S (M+Na)+ 663.2234, found 663.2229.
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:15])=[C:10]([Mg]Br)[CH:11]=2)[C:6]([CH3:17])([CH3:16])[CH:5]1[CH3:18])([CH3:3])[CH3:2].[Mg].BrC1C=C2C(C(C)(C)C(C)C2C(C)C)=CC=1C.S(=O)(=O)(O)O.CN(C)[CH:44]=[O:45]>>[CH:44]([C:10]1[CH:11]=[C:12]2[C:7]([C:6]([CH3:17])([CH3:16])[CH:5]([CH3:18])[CH:4]2[CH:1]([CH3:3])[CH3:2])=[CH:8][C:9]=1[CH3:15])=[O:45]
Reactant: CN(C)C=O
Reactant: Cc1cc2c(cc1[Mg]Br)C(C(C)C)C(C)C2(C)C
Agent: Cc1cc2c(cc1Br)C(C(C)C)C(C)C2(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Product: Cc1cc2c(cc1C=O)C(C(C)C)C(C)C2(C)C

Procedure:
40 ml Bromine is added at 10° C. to a solution of 100 g 1-isopropyl-2,3,3,5-tetramethyl indan (obtained according to Example I or II) and 1 ml pyridine in 50 ml carbon tetrachloride. Then the reaction mixture is stirred during one hour and poured out into an aqueous solution of approximately 25 g sodium thiosulphate. The organic layer is separated, washed with 25% sodium hydroxide and evaporated. The residue is distilled under diminished pressure yielding 105 g 6-bromo-1-isopropyl-2,3,3,5-tetramethyl indan. B.p. 145°-150° C./1 mm Hg. 25 g Dimethyl formamide is added to a solution of 1-isopropyl-2,3,3,5-tetramethyl-6-indanyl magnesium bromide, prepared from 9 g magnesium and 100 g of the 6-bromo indan obtained above. The reaction mixture is then heated to reflux during 30 min., poured out into a mixture of ice and diluted sulphuric acid and extracted with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure yielding 30 g 6-formyl-1-isopropyl-2,3,3,5-tetramethyl indan. B.p. 135° C./1 mm Hg.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8](Cl)[N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H].O.O.O.C([O-])(=O)C.[Na+]>CO.[Pd]>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1ncc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
12.0 g (18.1 mmol) of 2-n-butyl-4-chloro-1-[(2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-1H-imidazole-5-carboxaldehyde in 150 ml of methanol are hydrogenated at 25° C. for 1.5 h at a hydrogen pressure of about 3 bar in the presence of 1. 2 g of palladium on active carbon (5%) and 2.46 g (18.1 mmol) of sodium acetate trihydrate. The solution is then filtered off from the catalyst and concentrated, and the residue is chromatographed on silica gel 60 using ethyl acetate/petroleum ether (1:1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][N:6]([CH3:8])[N:7]=1.[CH3:9][NH2:10]>>[CH3:9][NH:10][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH3:8])[N:7]=1
Reactant: CN
Reactant: Cn1nnc(CCl)n1
Product: CNCc1nnn(C)n1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To 5-(chloromethyl)-2-methyl-2H-tetrazole (136.8 mg, 1.032 mmol), was added methylamine (4.00 mL of 2M solution in THF, 8.00 mmol). This was stirred for 16 hours at 45° C. A white precipitate formed in the reaction and it was allowed to continue stirring for another 24 hours at room temperature before being concentrated in vacuo and successively azeotroped with THF, triethylamine, methanol, and then DCM. 1H NMR (600 MHz, CDCl3) δ 2.23 (s, 3H), 3.80 (s, 2H), 4.29 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:22]
Reactant: CC(C)(C)Nc1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(C(=O)CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a stirred solution of 7.91 g (53.0 mmol) tert-Butyl-phenyl-amine (Biehl, Smith, Reeves, J. Org. Chem., 1971, 13, 1842) and 5.36 g (58.3 mmol, 1.1 equiv) Et3N in 60 mL DCM is added 11.77 g (58.3 mmol, 1.1 equiv) Bromoacetyl bromide in 40 mL DCM dropwise over 45 minutes at 0° C. The reaction mixture is stirred 3 h at 0° C., diluted with 200 mL DCM, washed with 1N HCl (2×150 mL), dried (MgSO4), and concentrated in vacuo. The crude product is filtered through a pad of 15 g silica gel eluted with 300 mL DCM. The filtrate is concentrated in vacuo to give 12.40 g (45.9 mmol) of 2-Bromo-N-tert-butyl-N-phenyl-acetamide as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.45-7.21 (m, 12H), 7.08 (t, 1H), 6.90 (m, 1H), 4.30 (d, 1H, J=16.4), 3.85 (d, 1H, J=16.6), 3.59 (d, 1H, J=12.0), 3.49 (d, 1H, J=11.9), 1.43 (s, 9H); TLC Rf =0.24 (EtOAc/Hexanes, 1:1).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+].Cl>CS(C)=O.O1CCCC1.O>[CH2:23]([O:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][OH:7])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCBr
Reactant: COC(CO)CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCOCC(CO)OC
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
In a mixture of 30 ml of dimethyl sulfoxide (DMSO) and 30 ml of tetrahydrofuran (THF) were dissolved 10.9 g of 2-methylglycerol and 10 g of 1-bromopentadecane, and 7.7 g of powdered KOH was added at room temperature. The mixture was stirred vigorously for 30 minutes, refluxed for 3.5 hours, poured into 400 ml of water, neutralized with concentrated hydrochloric acid with ice-cooling, and extracted three times with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The oily residue (10 g) was purified by silica gel column chromatography [silica gel: 110 g; eluent: n-hexane-chloroform (2:3)] to give 4.6 g of the above-identified alcohol compound.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:33][CH2:34][CH2:35][NH:36][S:37]([C:40]2[C:41]3[CH:42]=[CH:43][N:44]=[CH:45][C:46]=3[CH:47]=[C:48](Br)[CH:49]=2)(=[O:39])=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:33][CH2:34][CH2:35][NH:36][S:37]([C:40]2[C:41]3[CH:42]=[CH:43][N:44]=[CH:45][C:46]=3[CH:47]=[C:48]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:49]=2)(=[O:39])=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C(NCCNS(=O)(=O)c2cc(Br)cc3cnccc23)c2ccc(OC)cc2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(NCCNS(=O)(=O)c2cc(-c3ccccc3)cc3cnccc23)c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
Add tetrakis(triphenylphosphine)palladium (0.816 g, 0.706 mmol) to a degassed mixture of phenylboronic acid (0.1.72 g, 14.1 mmol), cesium carbonate (9.20 g, 3.5928.2 mmol), and 7-bromo-isoquinoline-5-sulfonic acid (2-{[bis-(4-methoxy-phenyl)-methyl]-amino}-ethyl)-amide (3.93 g, 7.06 mmol) in toluene (75.0 mL) and water (100.0 mL). Warm to 100° C. for 2 hours, and cool to room temperature. Dilute with toluene (100 mL), separate layers, wash sequentially with water and brine, then dry with anhydrous MgSO4, filter and evaporate. Apply the residue to a cation exchange cartridge, wash the cartridge with methanol, and then elute with 2M methanolic ammonia. Evaporation affords the title compound (2.25 g, 58%). 1H NMR (DMSO): δ9.56 (s, 1H), 8.78(d, J=1.8 Hz, 1H), 8.70(d, J=6.2 Hz, 1H), 8.75(d, J=2.0 Hz, 1H), 8.45 (d, J=6.2 Hz, 1H), 7.91(d of t J1=1.3 Hz, J=7.0 Hz, 2H), 7.62(t of t, J1=1.7 Hz, J2=7.4 Hz, 2H), 7.53 (t of t, J1=1.3 Hz, J2=7.4 Hz, 1H), 7.04 (d of t, J1=1.7 Hz, J2=8.8 Hz, 4H), 6.72 (d of t, J1=1.7 Hz, J2=8.8 Hz, 4H), 4.44 (s, 1H), 3.68(s, 6H), 3.01 (t, J=6.1 Hz, 2H), 2.35 (t, J=5.9 Hz, 2H). LCMS: m/z 554 (M+H)+, 552(M−H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:6]=2[N:7]=1)[CH3:2]>[Pd].CO>[CH2:1]([C:3]1[O:4][C:5]2[C:6](=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc2c([N+](=O)[O-])cccc2o1
Agent: [Pd]
Solvent: CO
Product: CCc1nc2c(N)cccc2o1

Procedure:
2-ethyl-4-nitro-1,3-benzoxazole is hydrogenated under a pressure of 8 bars in the presence of 10% palladium on carbon (0.01 eq.) using methanol as a solvent. The catalyst is separated by filtration and the methanol is eliminated under reduced pressure. The residue is taken up in ethyl ether in order to produce a pale violet solid which is collected by filtration and dried. Melting point: 46° C.