Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17](=[O:27])[C@H:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH3:19]>CS(C)=O>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][C@@H:18]([C:17]1([C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[F:9])[CH2:4][O:27]1)[CH3:19]
Reactant: C[S+](C)(C)=O
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Temperature: 15 °C
Yield: 91.2 %

Procedure:
To dimethyl sulfoxide (50 ml) was added 60% sodium hydride (0.833 g) in mineral oil. While stirring the mixture at about 15° C., trimethylsulfoxonium iodide (4.80 g) was added thereto, which was stirred for 15 minutes at room temperature. The reaction mixture was cooled with ice, to which was added a dimethyl sulfoxide solution (10 ml) of (2R)-2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (4.90 g). The resultant mixture was stirred for two hours at room temperature. The reaction mixture was poured into ice-water (120 ml), followed by extraction with ethyl acetate (150 ml, 100 ml, 100ml). Ethyl acetate layers were combined and washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml), followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (eluent: hexane-ethyl acetate=10:1) to afford 2-[(1R)-1-(3,4,5,6 -tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (4.70 g) as a pale yellow oily product.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH3:20])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.O>C1COCC1>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1c(OC)cc(CP(=O)(OCC)OCC)cc1OC
Reactant: O=Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OC)cc(C=Cc2ccccc2F)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl(3,5-dimethoxy-4-1-propylbenzyl)phosphonate (0.50 g, 1.5 mmol) in THF (10 mL) at 0° C. was added NaH (60% in mineral oil) (0.14 g, 3.5 mmol) under N2. After the addition was completed, the suspension was stirred at 0° C. for 1 h and then 2-fluorobenzaldehyde (0.2 mL, 1.9 mmol) in THF (10 mL) was added. The reaction was kept at 0° C. for 1 h and then at 50° C. for 5 h. The reaction was cooled to 0° C. Water (5 mL) was added slowly to quench the reaction followed by addition of 2N HCl (8 mL). The mixture was extracted with ether (3×20 mL). The extract was dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 5% ethyl acetate in hexane as eluent afforded 2-(3,5-dimethoxy-4-1-propylphenyl)-1-(2-fluorophenyl)ethene (1). (0.31 g, 68%) as a yellow crystal. 1HNMR (CDCl3, ppm): δ 1.34 (d, J=7.1 Hz, 6H), 3.60 (qint. J=7.1 Hz, 1H), 3.89 (s, 6H), 6.74 (s, 2H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2N.N([O-])=[O:16].[Na+].O>C(O)(=O)C>[OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:9](=[O:16])[NH:8][CH:7]=[N:6][C:5]1=2
Reactant: CC(O)Cn1cnc2c(N)ncnc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(O)Cn1cnc2c(=O)[nH]cnc21
Reaction time: 3 h

Procedure:
9-(2-Hydroxy-1-propyl)adenine (I, 4.0 g, 20.7 mmol) was suspened in 50% acetic acid (20 ml) and sodium nitrite (4 g, 58 mmol), was slowly added. The mixture was stirred at 25° for 3 hr. The resulting solution was evaporated to dryness and isopropanol added; this operation was repeated once. The solid residue was boiled in isopropanol and filtered. The filtrate was evaporated and crystallized by addition of acetone. Recrystallization was made from iso-propanol/methanol (98:2); a colorless crystalline product was obtained. Yield 3.3 g (82%); M.P. 244°-250°; uv (H2O; pH 5.5), λmax 250 nm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1c[nH]c2ccc(F)cc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1c[nH]c2ccc(F)cc12
Reaction time: 8 h
Yield: 93.5 %

Procedure:
Into a flask, (E)-3-(5-fluoro-1H-indol-3-yl)-acrylic acid methyl ester (2, 530.00 mg, 0.0024178 mol) was dissolved in 14.69 mL methanol. Palladium (10% on activated carbon, 25.73 mg, 0.0002418 mol) was added and the reaction was stirred under an atmosphere of hydrogen overnight. TLC analysis showed complete conversion to a new product. The mixture was filtered and concentrated under reduced pressure to provide the desired compound (3, 500 mg, 93.4%). 1H NMR consistent with desired compound. MS(ESI) [M+H+]+=222.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH2:17])([O-:3])=[O:2].[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:18][C:6]1[CH:7]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[NH2:17]
Reactant: Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1c(Br)cc(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
2-Nitro-4-phenoxy-phenylamine (2.3 g, 10 mmol) prepared in Preparation 1 was dissolved in DCM (30 mL), Br2 (720 ul, 35%) was added thereto at 0° C., and the mixture was stirred for 2 h. After completion of the reaction, saturated aqueous sodium thiosulfate solution was added. The resulting mixture was extracted with EtOAc, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (2.84 g, Yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:34])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([F:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:21])[CH3:34])=[CH:33][CH:32]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(F)cncc2F)s1
Reactant: CN(C)CCCOc1ccc(N)cc1
Product: CN(C)CCCOc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(F)cncc3F)s2)cc1

Procedure:
Prepared according to the procedure described for example 44 from 5-((3,5-difluoropyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid (25 mg, 0.79 mmol) and 4-(3-(dimethylamino)propoxy)aniline (26.7 mg, 0.79 mmol). The title compound was obtained as a solid (12 mg, 15%). MS m/z: 495.10, [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=O)[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[NH2:29]O>CO>[CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15]3[CH:16]=[C:17]([OH:19])[O:18][N:29]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)CC(=O)OC(C)(C)C)c2C1
Agent: Cl
Solvent: CO
Product: CCCN(CCC)C1CCc2cccc(-c3cc(O)on3)c2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Di-n-propylamino-8-(t-butoxycarbonylacetyl)-1,2,3,4-tetrahydronaphthalene (prepared as in Example 6) (1.0 g, 3.3 mmol) was taken up in 25 ml methanol. Ten equivalents of hydroxylamine hydrochloride (8.3 g, 33 mmol) were added and the reaction stirred at room temperature for 48 hours. The solution was filtered to remove unused hydroxylamine hydrochloride. The mixture was then concentrated and three crystallizations were performed from methanol/ethylacetate. The title compound (30 mg) was recovered.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][N:15]([C:17]2[S:18][C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH2:14][CH2:13][N:12]1[S:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=1)(=[O:32])=[O:31])=[O:10])C1C=CC=CC=1.C(O)(=O)C>CO.[C].[Pd]>[C:26]([O:25][C:23]([C:19]1[S:18][C:17]([N:15]2[CH2:14][CH2:13][N:12]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=3)(=[O:32])=[O:31])[C@@H:11]([C:9]([OH:10])=[O:8])[CH2:16]2)=[N:21][C:20]=1[CH3:22])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)OCc3ccccc3)C2)sc1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)O)C2)sc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of the compound (1.82 g) obtained in Step 5, 10% palladium carbon (250 mg) and acetic acid (4.0 ml) in methanol (50 ml) was stirred under a hydrogen atmosphere (4 atm) at room temperature for 3 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. 10% Palladium carbon (1.8 g), acetic acid (4.0 ml) and methanol (50 ml) were added again to the residue, and the mixture was stirred under a hydrogen atmosphere (4 atm) at room temperature for 30 min. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure (repeated 4 times). The obtained powder was suspended in water, collected by filtration and dried to give the title compound (1.24 g).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]([C:15]4[C:23]5[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]([CH3:28])[CH:16]=4)=[CH:14][C:7]=23)[CH2:3][CH2:2]1.[OH-].[K+]>>[CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]([CH3:28])[CH:16]=4)=[CH:14][C:7]=23)[CH2:2][CH2:3]1
Reactant: COc1cc2c(-c3cc4c(CNC5CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNC5CC5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 79.9 %

Procedure:
Cyclopropyl[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is prepared as described in Example 179a starting with 0.06 g of cyclopropyl[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.5 cm3 of 5N potassium hydroxide. 0.034 g of cyclopropyl[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:25][OH:26])[CH:13]=[N:14][C:15]=2[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])[CH2:5][CH2:4][O:3]1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([CH:35]([CH:42]2[CH2:44][CH2:43]2)[CH2:36][C:37]([O:39]CC)=[O:38])[CH:30]=1.[H-].[Na+].Cl>C1COCC1.O>[CH:42]1([CH:35]([C:31]2[CH:30]=[C:29]([O:26][CH2:25][C:12]3[CH:13]=[N:14][C:15]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=4[F:24])=[C:10]([O:9][CH2:8][CH:6]4[CH2:5][CH2:4][O:3][C:2]([CH3:27])([CH3:1])[CH2:7]4)[CH:11]=3)[N:34]=[CH:33][N:32]=2)[CH2:36][C:37]([OH:39])=[O:38])[CH2:44][CH2:43]1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2OCC2CCOC(C)(C)C2)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCC2CCOC(C)(C)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To a solution of (5-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy)-6-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)methanol (930 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (945 mg) in THF (20 mL) was slowly added, at 0° C., 60% sodium hydride (300 mg) by small portions, and the mixture was stirred at 60° C. for 3 hr. After cooling to 0° C., water (1.0 mL) was added to the reaction mixture, and the mixture was further stirred at 60° C. for 1 hr. The mixture was acidified with 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC (C18, mobile phase: water/acetonitrile (0.1% TFA-containing system)), and saturated aqueous sodium carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound (192 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(F)cc2c[nH]nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
(±)-tert-Butyl 4-((1-(5-fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (200 mg, 0.332 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 92.5 mg of (±)-5-fluoro-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-2H-indazole (74.9%). The crude amine (92.5 mg, 0.249 mmol) in dichloromethane (2.5 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (109 mg, 0.498 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (15%→30% EtOAc/Hex) to give 108 mg (92%) as white foam. 1H-NMR (CDCl3, 300 MHz) δ 9.68(bs, 1H), 7.90(s, 1H), 7.17-7.28(m, 3H), 7.01-7.10(m, 2H), 6.80(m, 1H), 4.48(q, J=6.0 Hz, 1H), 3.60-3.80(m, 2H), 3.36 (d, J=9 Hz, 1H), 3.25 (d, J=9 Hz, 1H), 2.90-3.10(m, 2H), 2.01-2.25(m, 2H), 1.68-1.87(m, 2H), 1.39-1.41(m, 12H); 13C-NMR (CDCl3, 76MHz) δ 161.5 (d, J=981 Hz), 157.4 (d, J=948 Hz), 154.8, 137.9, 134.2, 133.8, 128.6, 127.4, 123.7, 115.7, 115.4, 113.2, 112.9, 103.7, 103.4, 79.4, 78.5, 78.2, 60.27, 41.0, 32.3, 32.0, 28.33, 22.0; Mass spec.: 472.51 (MH)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2ccc3c(c2)OCCO3)c1
Yield: 92.9 %

Procedure:
To a stirred solution of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)-methanol (1.15 g, 3.80 mmol) in CH2Cl2 (20 ml) at rt was added activated MnO2 powder (1.65 g, 19 mmol) and kept adding 2˜3 equivalents of MnO2 every 3˜5 h until HPLC showed at least 98% conversion occurred. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,5-dimethoxy-phenyl)-methanone as an oil (1.06 g, 93%): 1HNMR (CDCl3) δ 7.42 (d, J=1 Hz, 1H, Ar), 7.38 (dd, J=1.88, 8 Hz, 1H, Ar), 6.92 (d, J=8 Hz, 1H, Ar), 6.88 (d, J=2 Hz, 2H, Ar), 6.64 (t, J=2 Hz, 1H, Ar), 4.36-4.29 (m, 4H, 2CH2), 3.82 (s, 6H, OCH3). The product was carried over to the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:16][O-:17].[Na+].[OH-].[Na+].O>CO>[CH3:16][O:17][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cnc(C(=O)O)cn1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
5-Chloropyrazine-2-carboxylic acid (5.0 g, 0.032 mol) was charged to a round-bottom flask equipped with a thermocouple, overhead stirrer and reflux condenser. Methanol (37.5 mL, 0.926 mol) was charged followed by conc. sulfuric acid (0.2 mL, 0.004 mol). The 3-neck flask was equipped with a heating mantle, and then the reaction mixture was heated to ca. 65.0° C. (T internal). The reaction mixture continued to stir at ca. 65.0° C. (T internal) for ca. 4 h. The reaction mixture cooled to ca. 25.8° C. (T internal). Methanol (12 mL, 0.31 mol) was charged and the slurry continued to stir at ca. 22.3° C. (T internal) for ca. 15 min then cooled to ca. 10.0° C. (T internal) under an atmosphere of nitrogen. 25% Sodium methoxide in methanol (1:3, Sodium methoxide:Methanol, 7.7 mL) was charged to flask while temperature remained below 30.0° C. (T internal). The reaction mixture was adjusted to 20.4° C. (T internal). After 30 min., sodium hydroxide (2.0 g, 0.04 mol) and water (37.5 mL, 2.08 mol) were combined to form a solution, and then the solution was charged to the reaction mixture. Water (50.0 mL, 2.78 mol) was charged and then the reaction mixture was heated to 40.0° C. (T internal) for ca. 60 mins. The heating mantle was removed, and then the reaction mixture cooled to ca. 25.4° C. (T internal). 38% aq. HCl Solution (38:62, hydrogen chloride:water, 4.0 mL) was added at a rate (ca. 5 min.) such that the temperature remained below 30.0° C. (T internal). The thick slurry was stirred for 1 h at ca. 21.4° C. (T internal), and then filtered over a sintered funnel. The solids were rinsed with water (10.0 mL, 0.555 mol) and dried under vacuum overnight to afford 5-methoxypyrazine-2-carboxylic acid (3.59 g). 1H NMR (500 MHz, DMSO) δ 13.24 (1H, br s), 8.79 (1H, d, J=1.2 Hz), 8.37 (1H, d, J=1.2 Hz), 3.98 (s, 3H); 13C NMR (125 MHz, DMSO) δ 165.36, 161.88, 143.88, 136.82, 135.55, 54.69.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[C:8](OC(=O)C)(=[O:10])[CH3:9].[OH-].[Na+]>CC(C)=O>[C:8]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])(=[O:10])[CH3:9]
Reactant: CN(C)CCCN
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)NCCCN(C)C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
A 51.1 g (0.50 mol) portion of N,N-dimethyl-1,3-diaminopropane was put into a flask and cooled to 5° C. while stirring in an atmosphere of nitrogen. Under ice-cooling, to this was added dropwise 51.1 g (0.50 mol) of acetic anhydride spending 1 hour. After completion of the dropwise addition, this was further stirred at 25° C. for 3 hours. Thereafter, the reaction mixture was again ice-cooled and 41.6 g (0.5 mol) of 48% sodium hydroxide aqueous solution was added dropwise thereto spending 15 minutes and then, after completion of the dropwise addition, 350 ml of acetone was added to the reaction mixture and allowed to stand at room temperature for 8 hours. Sodium acetate precipitated in the acetone solution was removed by filtration, acetone was evaporated under a reduced pressure and then 71 g of the remaining yellow oil was distilled under a reduced pressure to obtain the title compound as a transparent oil. Yield 62.4 g (0.433 mol; yield 86.8%, boiling point 116-118° C./0.64 kPa).
Reaction SMILES: C1(CO[C:9]2[CH:10]=[CH:11][CH:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18]CC[CH2:21][C:14]=32)C=CC=CC=1.C([O:33][CH2:34][CH3:35])(=O)C>C(O)C.[Pd]>[CH2:22]([CH:12]1[C:13]2=[C:14]3[CH2:21][CH2:35][CH:34]([OH:33])[CH2:18][C:15]3=[N:16][C:17]2=[CH:9][CH:10]=[CH:11]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCC1C=CC(OCc2ccccc2)=C2N=C3CCCCC3=C21
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC1C=CC=C2N=C3CC(O)CCC3=C21
Yield: 98.5 %

Procedure:
The hydrogenation of 1,2,3,4-tetrahydro-6-phenylmethoxy-9-octyl-9H-dibenzo[b,d]pyrrole from Example 63 was carried out at atmospheric pressure and at room temperature. Thus, 12.5 g of this material dissolved in 125 mL of absolute ethanol and 75 mL of ethyl acetate was hydrogenated in the presence of 0.6 g of 10% Palladium on carbon. The mixture was filtered on celite, the solvents evaporated in vacuo and the residue was chromatographed on silica gel to give 9.5 g (98.5%) of 1,2,3,4-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-3-ol as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:20]#[N:21])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30]>>[C:20]([C:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][CH2:2][N:23]([CH3:22])[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30])#[N:21]
Reactant: CNCCc1cccc(C(=O)OC)c1
Reactant: COC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Product: COC(=O)c1cccc(CCN(C)CCCC(C#N)(C(=O)OC)c2ccc(OC)c(OC)c2)c1

Procedure:
Reaction of 1b with 2d produced 3t. MS found M+H=469. The oxalate salt of 3t was recrystallized from ethyl acetate; mp 94-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Br:27]Br.C(O)(=O)C>C(Cl)(Cl)Cl>[Br:27][CH:10]([C:11](=[O:16])[C:12]([CH3:14])([CH3:13])[CH3:15])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)C(CC(=O)C(C)(C)C)c2ccc(Cl)cc2Cl)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)C(c2ccc(Cl)cc2Cl)C(Br)C(=O)C(C)(C)C)cc1

Procedure:
The bromination of 1-(2,4-dichlorophenyl)-1-p-toluenesulfonyl-4,4-dimethylpentan-3-one was carried out in the same manner as that of Example 3 but using 25 g of 1-(2,4-dichlorophenyl)-1-p-toluenesulfonyl-4,4-dimethyl-3-one, 9.2 g of bromine, 200 ml of acetic acid and 300 ml of chloroform, and 29 g of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-p-toluenesulfonylpentan-3-one was obtained.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[I:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH2:33][C:32]4[CH:35]=[CH:36][C:29]([I:28])=[CH:30][CH:31]=4)[CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:12](=[O:27])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=Cc1ccc(I)cc1
Reactant: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCNCC2
Agent: Cl
Product: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(I)cc1)CC2

Procedure:
Reductive amination using methyl 4-[4-(cyclohexylamino)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-1-yl]butanoate dihydrochloride and 4-iodo-benzaldehyde using a similar procedure as described in the preparation of intermediate I.1.d.1. LRMS (M+1)=567.5.