Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH2:27][CH2:26][C:10]3([O:15][CH2:14][CH2:13][N:12]([C:16]([C:18]4[N:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[S:21][CH:22]=4)=[O:17])[CH2:11]3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH2:30][CH2:31][OH:32].FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH2:27][CH2:26][C:10]3([O:15][CH2:14][CH2:13][N:12]([C:16]([C:18]4[N:19]=[C:20]([CH:23]([CH3:24])[CH3:25])[S:21][CH:22]=4)=[O:17])[CH2:11]3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH2:30][CH:31]=[O:32]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(Cl)c(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(Cl)c(CC=O)c4)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(4-chloro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 75, step d) (0.152 g) in DCM (5 mL) was cooled in ice-water, treated with trifluoroacetic acid (0.049 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.205 g) was added, then the mixture was removed from the cooling bath and stirred at room temperature for 30 minutes. The solution was diluted with saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL) and the resulting mixture was stirred vigorously for 10 minutes. The mixture was then extracted twice with ethyl acetate, the combined organic phases were washed with brine, acidified with acetic acid (0.1 mL), dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude subtitled compound as a yellow gum. Yield 0.197 g.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[C:5]1[C:4](=[O:7])[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:2](=[O:1])[NH:6]1
Reactant: N#Cc1ccc(N2C(=O)CNC2=O)c2ccccc12
Reactant: O=Cc1cccc(O)c1
Product: N#Cc1ccc(N2C(=O)NC(=Cc3cccc(O)c3)C2=O)c2ccccc12

Procedure:
The title compound was obtained as an off-white solid (38.5 mg, 18.2%) from compound 1C and 3-hydroxybenzaldehyde in the same manner as that used in the preparation of Example 1 by acidifying the aqueous washings and recrystallization of the crude product from MeOH. LC/MS m/z 356 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([OH:25])=[O:24])[N:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl[CH2:31][S:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([O:25][CH2:31][S:32][CH3:33])=[O:24])[N:20]=[C:19]([C:26]([F:29])([F:27])[F:28])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3CC(=O)O)cc2)c1
Reactant: CSCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
A mixture of compound 38 (0.2 g, 0.471 mmol), chloromethylmethylsulfane (0182 g, 1.89 mmol) and potassium carbonate (0.324 g, 2.36 mmol) in DMF (5 mL) was stirred at room temperature for 1 h, then heated to 100° C. for 10 h. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine, dried over sodium sulphate and concentrated. The crude reaction mixture was purificated by prep HPLC to afford 41 (15 mg, 7%). LCMS: 485.20 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (s, 1H), 8.06 (d, 1H, J=7.2 Hz), 7.99 (d, 1H, J=8 Hz), 7.93 (d, 2H, J=8.4 Hz), 7.8-7.6 (m, 3H), 6.75 (s, 1H), 5.10-5.25 (m, 2H), 3.45-3.3 (m, 2H), 3.30 (s, 3H), 1.78 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=4)=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)cc(C)n1
Yield: 45.4 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (99 mg, 45%). MS (ISP) 437.2 [(M+H)+]; mp 236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19]C)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1cc2ccc(Cl)cc2[nH]c1=O
Agent: BrB(Br)Br
Product: O=c1[nH]c2cc(Cl)ccc2cc1-c1ccccc1O
Yield: 100.3 %

Procedure:
2-Amino-4-chlorobenzyl alcohol (2 g, 12.86 mmol) and 2-methoxyphenylacetic acid (4.70 g, 28.3mol) were reacted in a similar manner as described in Example 19 to give 7-chloro-3-(2-methoxyphenyl)-2(1H)-quinolone as fine white needles mp 235°-236° C. (MeOH). (Found: C, 67.49; H, 4.22; N, 4.93. C16H12ClNO2 requires C, 67.26; H, 4.23; N, 4.90%); δH (360 MHz, d6 -DMSO) 3.73 (1H, s, CH3) 6.97 (1H, dt, J=0.8 and 7.4 Hz, 5'-H) 7.08 (1H, d, J=8.3 Hz, 3'-H) 7.22 (1H, dd, J=8.4 and 2.1 Hz, 6-H) 2.27 (1H, dd, J=7.5 and 1.7 Hz, 6'-H) 7.34 (1H, d, J=1.8 Hz, 8-H) 7.37 (1H, dt, J=1.7 and 8.2 Hz, 4'-H) 7.70 (1H, d, J=8.4 Hz, 5-H) 7.87 (1H, s, 4-H) 11.87 (1H, br s, NH); m/z (EI+) 285 (M+). The quinolone (300 mg) and boron tribromide (3.15 ml, 1N solution in CH2Cl2) were reacted as described in Example 20 to give 286 mg of 7-chloro-3-(2-hydroxyphenyl)-2(1H)-quinolone as a yellow crystalline solid; mp 246°-248° C. (dec) (methanol). (Found: C, 66.43; H, 3.70; N, 5.17. C15H10ClNO2 requires C, 66.31; H, 3.71; N, 5.15%); δH (360 MHz, DMSO-d6) 6.87 (1H, t, J=8.2 Hz, 5'-H), 6.90 (1H, d, J=7.8 Hz, 3'-H), 7.22 (1H, dt, J=1.7 and 7.8 Hz, 4'-H), 7.26 (1H, dd, J=8.4 and 2.1 Hz, 6-H), 7.31 (1H, dd, J=8.2 and 1.7 Hz, 6'-H), 7.39 (1H, d, J=2.1 Hz, 8-H), 7.77 (1H, d, J=8.4 Hz, 5-H), 8.03 (1H, s, 4-H), 9.56 (1H, br s, OH), 12.14 (1H, br s, NH); m/z (EI+) 271 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]2[C@@H:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[Cl:25][CH2:26][C:27](O)=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]2[C@H:13]([O:14][C:27](=[O:28])[CH2:26][Cl:25])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Reactant: O=C(O)CCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](OC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.9 %

Procedure:
To a mixture of (3S,4S)-tert-butyl 3-(4-bromo-2-nitrophenylamino)-4-hydroxypyrrolidine-1-carboxylate (2.50 mmol, 1.0 g), chloroacetic acid (3.0 mmol, 300 mg) and triphenylphosphine (3.0 mmol, 850 mg) in tetrahydrofuran (40 mL) add diethylazodicarboxylate (3.0 mmol, 600 mg) and stir at room temperature for 12 h. Remove the solvent, add ethyl acetate (50 mL) to the residue and wash with water and brine. Dry over anhydrous sodium sulfate and evaporate. Purify the residue by column chromatography, eluting with 20% ethyl acetate in methylene chloride to obtain the title compound as a yellow solid (1.10 g, 98%). 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 8.20 (m, 1H), 7.60 (m, 1H), 6.82 (m, 1H), 5.55 (d, J=6.8 Hz, 1H), 4.32 (m, 1H), 4.13 (bd, J=8.2 Hz, 2H), 3.90 (m, 1H), 3.79 (m, 1H), 3.74 (dd, J=4.2, 10.4 Hz, 1H), 3.25 (t, J=7.20 Hz, 1H), 1.41 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:3][C@H:2]1[C:4]([OH:6])=[O:5].[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17])([O-:9])=[O:8].[OH-].[Na+]>CC(C)=O>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N@:1]1[CH2:3][CH:2]1[C:4]([OH:6])=[O:5])(=[O:18])=[O:17])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: O=C(O)[C@@H]1CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)C1C[N@@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 2 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
The liquid reaction mixture containing 9.21 g (106 mmol) of (S)-aziridine-2-carboxylic acid obtained in Example 1 was cooled to 2° C. and 150 mL of acetone was added thereto at an internal temperature of 2 to 5° C. While maintaining this solution at an internal temperature of −6 to −2° C., a mixture of 26.9 g (121 mmol) of 2-nitrobenzenesulfonyl chloride with 50 mL of acetone was added thereto over 1 hour. Then the reaction was continued as such for additional 2 hours. During the reaction, a 30 wt. % aqueous solution of sodium hydroxide was added to maintain the reaction system at pH 10.0 to 10.5 The obtained liquid reaction mixture contained 26.9 g (99 mmol) of (S)-N-2-nitrobenzenesulfonyl-aziridine-2-carboxylic acid (yield: 93%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:18]O>>[Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1Br

Procedure:
2-Bromo-4-nitrobenzoic acid (6.2 g, 25.3 mmol) was dissolved in MeOH (120 mL), and SOCl2 (5.5 mL, 75.9 mmol) was added dropwise at 0° C. The reaction mixture was refluxed for 6 h. The reaction solvent was concentrated to dryness. Residual SOCl2 was removed by co-evaporation with CH2Cl2 (×3). The solid was dried under vacuum to afford methyl 2-bromo-4-nitrobenzoate in 99.5% (6.52 g) yield as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (1H, s, Ar), 8.21 (1H, d, J=8.4 Hz, Ar), 7.91 (1H, d, J=8.4 Hz, Ar), 3.97 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.2, 149.2, 137.9, 131.7, 129.1, 122.1, 122.0, 53.1; MS (ESI) m/z Calcd for C8H6BrNO4 (M+): 259.0, Found: 260.1 (M+H+). Next, the nitro group of methyl 2-bromo-4-nitrobenzoate (6.38 g, 24.6 mmol) was chemoselectively reduced with 5 nCl2.2H2O (27.8 g, 123.2 mmol) in a manner similar to that described for compound 6 to deliver methyl 4-amino-2-bromobenzoate in 96.0% (5.41 g) yield as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.74 (1H, d, J=8.8 Hz, Ar), 6.90 (1H, d, J=1.6 Hz, Ar), 6.55 (1H, dd, J=8.8 Hz, 1.6 Hz, Ar), 4.06 (2H, s, NH2), 3.83 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.9, 150.4, 133.6, 124.1, 119.7, 119.6, 112.7, 51.8; MS (ESI) m/z Calcd for C8H8BrNO2 (M+): 229.0, Found: 230.1 (M+H+). Finally, a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) was added to methyl 4-amino-2-bromobenzoate (1.23 g, 5.38 mmol) and the resulting suspension was heated to 90° C., then stirred for 5 h at this temperature. The reaction mixture was cooled to 0° C. and a solution of NaNO2 (384 mg, 5.57 mmol) in H2O (5 mL) was added dropwise, then the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) that had been preheated to 90° C. The reaction mixture was stirred at 90° C. for 1 h, and then allowed to cool. The reaction mixture was partitioned between EtOAc (200 mL) and aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (35% EtOAc in hexanes) to afford compound 10 in 41.1% (508 mg) yield as a light brown solid. 1H-NMR (CDCl3, 400 MHz) δ 7.76 (1H, d, J=8.8 Hz, Ar), 7.09 (1H, s, Ar), 6.75 (1H, d, J=8.8 Hz, Ar), 3.84 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 166.2, 160.3, 133.5, 123.4, 122.1, 121.4, 114.3, 52.1; MS (ESI) m/z Calcd for C8H7BrO3 (M+): 230.0, Found: 231.0 (M+H+).
Reaction SMILES: N[N:2]1[C:7](=[O:8])[C:6]2[C:9]3[CH2:15][CH2:14][N:13]([C:16]([O:18]C(C)(C)C)=O)[CH2:12][C:10]=3[S:11][C:5]=2[N:4]=[C:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1.N([O-])=O.[Na+].[C:47](=O)([O-])O.[Na+]>C(O)(=O)C.O>[C:16]([N:13]1[CH2:14][CH2:15][C:9]2[C:6]3[C:7](=[O:8])[NH:2][C:3]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:42]=[CH:41][C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=5)[CH2:31][CH2:32]4)=[N:4][C:5]=3[S:11][C:10]=2[CH2:12]1)(=[O:18])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc(CCCCN4CCN(c5ccc6ccccc6n5)CC4)n(N)c(=O)c23)C1
Reactant: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCc2c(sc3nc(CCCCN4CCN(c5ccc6ccccc6n5)CC4)[nH]c(=O)c23)C1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
In a mixture of 5 ml of acetic acid with 2 ml of water 60 mg of 3-amino-7-tert-butoxycarbonyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-pyrido[4′3′:4,5]thieno[2,3-d]pyrimidin-4-one was dissolved, and into the solution, a solution of 10 mg of sodium nitrite in 2 ml of water was dropped under cooling with ice. After 30 minutes' stirring, the reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and the resulting precipitate was extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography to provide 52 mg (99%) of 7-acetyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-pyrido[4′3′:4,5]thieno-[2,3-d]pyrimidin-4-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>CC(C)=O>[C:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)(=[O:29])[CH3:28]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g; 0.01 mole) in acetone (60 ml) at -10° was treated with triethylamine (1.11 g; 0.011 mole). Then acetyl chloride (0.86 g; 0.011 mole) was added, dropwise, during 5 minutes at -10°.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1.N1C=CC=CC=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Cl:3])=[CH:10][N:11]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: ClCc1ccc(Cl)nc1

Procedure:
85 ml of thionyl chloride are added cautiously to 14.4 g (0.1 mol) of 6-chloro-pyridine-3-methanol. 8.1 g (0.1 mol) of pyridine are then added dropwise and the mixture is heated under reflux until gas evolution is complete. Excess thionyl chloride is removed in vacuo and the residue is poured onto ice. The precipitate is filtered off with suction and dried. Yield 10.6 g (65.5% of theory), m.p.: 38°-40° C. The crude product can be used further without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1F)([O-:9])=[O:8]>>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)([O-:9])=[O:8]
Reactant: Nc1cccs1
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=[N+]([O-])c1ccccc1Nc1cccs1

Procedure:
Both paths start with a Gewald reaction to form appropriately substituted 2-amino-thiophenes (a). This type of reaction is described in Chem. Ber. 1965, 98, 3571-3577; Chem. Ber. 1966, 99, 94-100. The second step involves the reaction of 2-aminothiophene with 2-nitro-1-fluorobenzene (b), to give a 2-(2-nitro-anilino)thiophene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:35]([O:37][CH3:38])=[O:36])[CH2:34][CH:33]=[CH:32][CH2:31]2)=[CH:26][CH:25]=1>C(Cl)Cl>[Br:20][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:35]([O:37][CH3:38])=[O:36])[CH2:34][CH:33]=[CH:32][CH2:31]2)=[CH:26][CH:25]=1
Reactant: COC(=O)C1(c2ccc(CO)cc2)CC=CC1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(CBr)cc2)CC=CC1

Procedure:
To a solution of triphenylphosphine (8.03 g, 30.6 mmol) in 100 ml CH2Cl2 at 0° C. was added dropwise bromine (1.45 ml, 28.1 mmol). After 15 minutes at 0° C. a white precipitate formed and a solution of the product of Step 3, above, (5.93 g, 25.5 mmol) in 30 ml CH2Cl2 was added dropwise. After 1 hour the solvent was removed in vacuo and the residue was taken up in ether to precipitate the triphenylphosphine oxide formed in the reaction. After filtration, evaporation and SGC (5% EtOAc-hexanes) the title compound (5 g) was obtained as a colorless oil which crystallized on standing.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH3:5][O:6][C:7](=[CH:9][CH3:10])[CH3:8]>P(=O)(O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:5][O:6][C:7]([O:4][CH2:1][C:2]#[CH:3])([CH2:9][CH3:10])[CH3:8]
Reactant: CC=C(C)OC
Reactant: C#CCO
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Product: C#CCOC(C)(CC)OC
Reaction time: 2 h
Yield: 102.2 %

Procedure:
A mixture of 130 mg (0.3 μmol) of phosphoric acid (19% w/w in acetone) and 22.80 g (399 mmol) of propargyl alcohol is filled into a dropping funnel. 53.5 g (598 mmol) of 2-methoxy-but-2-ene (96.2% GC) was transferred into a second dropping funnel. Both solutions were added simultaneously within 30 minutes to the cooled flask (8° C.). The internal temperature was maintained between 8° C. and 12° C. during the addition of the reactants. The reaction mixture was held at 10° C. for about 2 hours. The reaction mixture was neutralized with 0.5 g of sodium carbonate and concentrated under reduced pressure (40° C., 80 mbar). The crude product was analyzed by GC. 58.0 g of crude 2-methoxy-2-prop-2-ynyloxy-butane were obtained with a purity of 85.5% (yield 96.9% based on propargyl alcohol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH:12]=[O:13])[CH3:11])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[CH2:12][OH:13])[CH3:2]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C=C(C)C=CC=C(C)CO
Temperature: 10 °C
Reaction time: 2 h

Procedure:
36 g. of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester are dissolved in 600 ml. of absolute ethanol. The solution is treated portionwise with 1.8 g. of sodium borohydride. The mixture is stirred for 2 hours at 10° C., then poured onto ice water and 3 n aqueous hydrochloric acid and extracted with ether. The ether extract is washed successively with water, a saturated aqueous sodium bicarbonate solution and once more with water, dried over sodium sulfate and evaporated. There is obtained 8-hydroxy-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl ester, which is processed further as follows:
Reaction SMILES: [Cl:1][C:2]1[C:15]([NH:16][C:17]2[NH:18][C:19]3[C:20]([N:34]=2)=[N:21][C:22]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=3)=[C:14]([Cl:35])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:15]([NH:16][C:17]2[NH:18][C:19]3[C:20]([N:34]=2)=[N:21][C:22]([O:29][CH2:30][CH:31]([F:32])[F:33])=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=3)=[C:14]([Cl:35])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1cc2[nH]c(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)nc2nc1OCC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3nc(OCC(F)F)c(C(=O)O)cc3[nH]2)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of N-{2,4-dichloro-3-[6-methoxycarbonyl-5-(2,2-difluoro-ethoxy)-1H-imidazo[4,5-b]pyridin-2-ylamino]-benzyl)-2,2-dimethyl-propionamide (9.80 g, 12.0 mmol) and 1 N NaOH (40 ml) in MeOH (40 ml) is stirred overnight at rt and 45 min at reflux. Then the mixture is concentrated, acidified with 1 N aq. HCl-solution and the precipitate is filtered, dried and purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:19][CH3:20])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 1-chloroisoquinolin-4-ol (1.0 g, 5.5 mmole) in acetonitrile (10 mL) was added K2CO3 (2.3 g, 16.7 mmole) followed by ethyl iodide (0.87 mL, 11.0 mmole) at room temperature. The reaction mixture was stirred at room temperature for overnight. Solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced. The resulting residue was purified by silica gel chromatography to afford 1-chloro-4-ethoxyisoquinoline (700 mg, 62%) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.26-8.24 (m, 2H), 7.79 (s, 1H), 7.76-7.26 (m, 2H), 4.29-4.24 (q, J=6.8 Hz, 2H), 1.58-1.1.54 (t, J=6.8 Hz, 3H); MS: MS m/z 207.7 (M++1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C.O>C1COCC1>[CH3:20][O:19][N:18]([CH3:17])[C:11]([CH:8]1[CH2:7][CH2:6][C:5]2([O:1][CH2:2][CH2:3][O:4]2)[CH2:10][CH2:9]1)=[O:13]
Reactant: CNOC
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCC2(CC1)OCCO2
Yield: 98.4 %

Procedure:
Ethyl 1,4-dioxaspiro[4,5]decane-8′-carboxylate (6.28 g, 29.3 mmol) obtained in Step 1 was dissolved in THF, and N,O-dimethylhydroxylamine hydrochloride (4.30 g, 44.1 mmol) was added thereto, followed by stirring. In an atmosphere of argon at −30° C., a 2.0 mol/L solution of isopropylmagnesium chloride in THF (44.1 mL, 88.2 mmol) was added dropwise to the reaction mixture, followed by stirring at −5° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford N-methoxy-N-methyl-1,4-dioxaspiro[4,5]decane-8-carboxamide (6.61 g, 99%).