Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:20])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Solvent: ClCCl
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Yield: 98.2 %

Procedure:
A 250 ml three-necked flask with magnetic stirrer, thermometer and condenser was charged with 15.4 g (64.7 mmol) of 3,5-diacetoxybenzoic acid, 10 ml of thionyl chloride and 80 ml of CH2Cl2. The mixture was refluxed for 3-5 hours. Then the solvent and remaining thionyl chloride were distilled off. Fresh CH2Cl2 was added and distilled off again. The crude solid was dissolved in 120 ml toluene, and the solution was filtered. Evaporated the solvent out and dried the product at room temperature under 1 mbar. 16.3 g of 3,5-diacetoxybenzoyl chloride were obtained as a white solid. The yield was 98.2%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)C1CC(=O)N(c2ccc(F)cc2)C1
Product: CCOC(=O)C1CC(=O)N(c2ccc(F)cc2)C1
Temperature: 0 °C

Procedure:
1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (unknown amount) was dissolved in 20 ml ethanol and cooled to 0° C. HCl gas was bubbled into the solution until the solution became red in color. The reaction was allowed to warm to room temperature and stir ovenight. The solvent was removed to yield ethyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (M+1=251.93).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.OO.C(=O)([O-])[O-:31].[K+].[K+]>C(O)(=O)C.O>[CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([S:23]([CH3:24])=[O:31])[CH:20]=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1
Reactant: COc1ccc(SC)cc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(S(C)=O)cc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reaction time: 0.5 h

Procedure:
3.0 gm of 7,7-dimethyl-2-(2-methoxy-5-metylmercapto-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione were dissolved in 60 ml of glacial acetic acid and then 0.88 ml of 30% hydrogen peroxide were slowly added dropwise at room temperature. After stirring for 30 minutes, the solution was neutralized with an aqueous saturated potassium carbonate solution, diluted with water and extracted with chloroform. The residual crude product obtained after evaporation of the chloroform was purified on a silicagel column (eluant: chloroform with increasing content of acetone).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:5][O:4]1)[CH3:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:6]([N:13]([CH2:5][CH:3]([OH:4])[CH2:1][CH3:2])[CH2:5][CH:3]([OH:4])[CH2:1][CH3:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: CCC1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Product: CCC(O)CN(Cc1ccccc1)CC(O)CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.4 %

Procedure:
To a stirred solution of 2-ethyloxirane, 103 (621 mg, 8.61 mmol, R=ethyl) in DCM (60 mL) was added benzylamine (996 mg, 9.30 mmol) followed by scandium triflate (341 mg, 0.693 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at rt for 20 h after which time the completed reaction was quenched with saturated NaHCO3 (20 mL), extracted three times with DCM (10 mL each), and the combined organic layers was dried over MgSO4, filtered and concentrated to dry. The crude product was purified over silica gel (Biotage 25 g, eluting with a 10:10:0.1 ratio of heptanes:EtOAc:TEA) to provide 1,1′-(benzylazanediyl)bis(butan-2-ol), 104 (658 mg, 2.628 mmol, 30.4% yield, R=ethyl) after concentration of the combined desired fractions and drying in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=4[Cl:30])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 79.8 %

Procedure:
A solution of [(R)-(8-(2,6-dichlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.6 g, 1.25 mmol) in ethyl acetate/ethanol (10/10 mL) was added platinum(IV) oxide (45 mg, 0.198 mmol) and the mixture hydrogenated at 45 psi of hydrogen for 2 hours. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure. Chromatography with 0–15% ethyl acetate in hexanes afforded 0.48 g (80%) of [(R)-8-(2,6-dichlorophenyl)-6-fluorochroman-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. [α]D25=+9.51° (c 5.3 mg/0.7 mL MeOH); MS (ES) m/z 498.0 ([M+NH4]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.S(=O)(=O)(O)O.[I:21]N1C(=O)CCC1=O.O>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([I:21])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: Oc1ccc(-c2cccc(F)c2)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Oc1cc(Cl)c(-c2cccc(F)c2)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
2-Chloro-3′-fluorobiphenyl-4-ol (Preparation 69, 500 mg, 2.25 mmol) was dissolved in dichloromethane (5 mL) and acetic acid (5 mL). Concentrated sulfuric acid (0.05 mL) was added followed by N-iodosuccinimide (480 mg, 2.13 mmol) and the reaction stirred at room temperature for 18 hours. A further portion of N-iodosuccinimide (50 mg, 0.22 mmol) was added and stirring continued at room temperature for 3 hours. Water and dichloromethane were added and the two layers separated. The organic layer was washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% ethyl acetate in heptane) to afford the title compound (496 mg, 63%) as a yellow oil that solidified on standing.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)#[CH:10]>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]#[C:10][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#Cc1ccc(CCCCCC)cc1
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CCCCCCc1ccc(C#Cc2ccc(N)cc2)cc1
Temperature: 85 °C
Reaction time: 22 h
Yield: 87 %

Procedure:
To a stirred solution of 4-iodoaniline (10.0 g, 45.6 mmol, Aldrich) and 1-eth-1-ynyl-4-hexylbenzene (10.0 g, 53.0 mol, Maybridge) in anhydrous acetonitrile (200 mL) under nitrogen was added CuI (0.43 g, 2.2 mmol), TEA (14.0 g, 138 mmol) followed by Pd(PPh3)2Cl2 (1.6 g, 2.2 mmol). The reaction mixture was stirred at 85° C. for 22 hours. The solvent was removed under reduced pressure. The residue was diluted with Et2O (200 mL) 20 and washed with water and brine. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by chromatography Wet ether/EtOAc 4/1) to give 11.0 g (87%) of the title compound as a pale yellow solid. TLC-Pet ether/EtOAc (4/1): Rf=0.4. HPLC purity >98%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH:8]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2cc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(n2cc(N)cn2)CC1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A solution of tert-Butyl 4-(4-nitro-1H-pyrazol-1-yl)azepane-1-carboxylate (4.5 g, 15.5 mmol) in methanol (250 mL) was hydrogenated (3 bars) in presence of Palladium on Carbon (10%, 2 g) at RT. After 3 h, the reaction mixture was filtered through a celite pad and concentrated under reduced pressure to give the title compound as a brown solid (3.8 g, 95%). 1H NMR: (400 MHz, DMSO-d6) δ 6.99 (s, 1H), 6.86 (s, 1H), 4.05 (m, 1H), 3.94 (m, 2H), 3.85 (m, 2H), 2.85 (brs, 2H), 1.86 (m, 2H), 1.65 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][CH:11]([C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[CH2:12][CH3:13]>C1COCC1>[CH3:10][CH:11]([C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]2[C:21]3=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]3[CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[CH2:12][CH3:13]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCC(C)c1ccc(OCc2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)c1ccc(OCC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 117 mg) in THF (dry) (4 mL) was added 2-chloroethanesulfonyl chloride (0.185 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-{[4-(1-methylpropyl)phenoxy]methyl}pyridin-2-amine (150 mg) in THF (dry) (4 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 1 day. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and crystallized from THF/IPE to give the title compound (34.9 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[Si]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CC(C)(C)[Si](C)(C)N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Temperature: 60 °C
Yield: 84.6 %

Procedure:
0.5 g (1.85 mmol) of 1-ethyl-6-fluoro-7-chloro-4-oxo1,4-dihydro-quinoline-3-carboxylic acid (II, R1 : ethyl; X: chloro) and 1.1 g (5.5 mmol) of 1-(t-butyldimethylsilyl) piperazine (R2 : hydrogen, R3 and R4 : methyl; R5 : t-butyl) are added to 5 ml of pyridine and then heated at 60° C. A solution of 1.73 g (5.5 mmol) of tetrabutylammonium fluoride trihydrate in 5 ml of pyridine is added dropwise to the reaction mixture. After completion of addition, the reaction mixture is heated at 80° C. for 2 hours and then distilled under reduced pressure (10 mmHg, 60° C.). The residue is added with water and then stirred to afford a crystal. After filtering and drying, 0.50 g of a solid product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[Cl:11][C:12]1[C:13]([F:25])=[C:14]([S:21](Cl)(=[O:23])=[O:22])[C:15]([F:20])=[C:16]([Cl:19])[C:17]=1[F:18]>>[Cl:11][C:12]1[C:13]([F:25])=[C:14]([S:21]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:2]([OH:1])[CH:3]=2)(=[O:23])=[O:22])[C:15]([F:20])=[C:16]([Cl:19])[C:17]=1[F:18]
Reactant: COc1ccc(N)cc1O
Reactant: O=S(=O)(Cl)c1c(F)c(Cl)c(F)c(Cl)c1F
Product: COc1ccc(NS(=O)(=O)c2c(F)c(Cl)c(F)c(Cl)c2F)cc1O

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 of WO 97/3-677, beginning with 3-hydroxy4-methoxyaniline and 3,5-dichloro-2,4,6-trifluorophenylsulfonyl chloride (Example A, above).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]3[NH2:32])[CH2:20]2)=[N:17][CH:18]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]3[NH:32][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH2:20]2)=[N:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=C=Nc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ncc([N+](=O)[O-])cn2)C1
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ncc([N+](=O)[O-])cn2)C1
Yield: 51.7 %

Procedure:
1-((1R,2R)-2-((S)-1-(5-Nitropyrimidin-2-yl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea (17.5 mg, 0.031 mmol, 51.5% yield) was synthesized as described in General Procedure F using phenyl isocyanate (7.15 mg, 0.060 mmol) and (1R,2R)—N1-((S)-1-(5-nitropyrimidin-2-yl)piperidin-3-yl)cyclohexane-1,2-diamine (32.9 mg, 0.060 mmol). Anal. Calcd. for C22H29N7O3 m/z 439.5, found: 440.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 10.25 (br. s., 1H), 8.90 (d, J=6.60 Hz, 1H), 8.78-8.59 (m, 2H), 7.23-7.123 (m, 4H), 6.98 (t, J=6.87 Hz, 1H), 6.56 (br. s., 1H), 4.27 (d, J=12.09 Hz, 1H), 4.12-3.92 (m, 2H), 3.88-3.73 (m, 1H), 3.64 (br. s., 1H), 3.21 (br. s., 1H), 3.02-2.77 (m, 3H), 2.20-2.00 (m, 2H), 1.92 (ddd, J=7.01, 3.44, 3.30 Hz, 1H), 1.80 (d, J=10.99 Hz, 2H), 1.63 (d, J=14.29 Hz, 3H), 1.35-1.11 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:23])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 2.60 g (14.6 mmol) of 4-morpholinoaniline in 20 ml of methylene chloride were added 14.07 ml (105 mmol) of triethylamine and 3.53 g (17.5 mmol) of 4-nitrophenyl chloroformate under ice-cooling, followed by stirring at room temperature for 7 hours. After the solvent was evaporated, water was added to the residue, and the precipitated crystals were collected by filtration, washed water, and dried to give 4-morpholino-N-(4-nitrophenoxycarbonyl)aniline.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:17].FC(F)(F)C(O)=O>>[O:17]=[C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][N:14]=[CH:13][CH:12]=2)[N:7]1[CH2:6][CH:2]=[O:1]
Reactant: O=c1ccc2ccncc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)ccc2ccncc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To 3.1 g of 1-(1,3-dioxolan-2-ylmethyl)-1,7-naphthyridin-2(1H)-one, 30 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at 70 to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, then 30 mL of an 80% aqueous trifluoroacetic acid solution was added thereto, the mixture was stirred at 70 to 80° C. for 3 hours 30 minutes, and the temperature was increased to 75 to 85° C. and the mixture was stirred for 2 hours. Thereto was further added 30 mL of an 80% aqueous trifluoroacetic acid solution, and the mixture was stirred at 80 to 90° C. for 2 hours 30 minutes. The reaction mixture was cooled to room temperature, and then left overnight. The solvent was distilled off under reduced pressure, and the resultant residue was charged with chloroform and water and adjusted to pH 10.4 with a 20% aqueous sodium hydroxide solution. Sodium chloride was added thereto, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.5 g of (2-oxo-1,7-naphthyridin-1(2H)-yl)acetaldehyde as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:11]([C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[N+:12]=[N-:13]
Reactant: CCOC1OC(=O)C=C1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC1OC(=O)C=C1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
A mixture of 4-bromo-5-ethoxy-5H-furan-2-one (2.07 g, 10.0 mmol) and sodium azide (0.66 g, 10.2 mmol) in dimethylformamide (10 mL) was stirred at room temperature under nitrogen for 24 h. The reaction was diluted with ethyl acetate, was washed with 0° C. water and with brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:9 ethyl acetate:hexanes afforded 4-azido-5-ethoxy-5H-furan-2-one (1.04 g, 62% yield) as a pale yellow oil. 1H-NMR (500 MHz, CDCl3) δ 5.83 (s, 1H), 5.63 (s, 1H), 3.99 (m, 1H), 3.88 (m, 1H), 1.35 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[F:14][C:15]1[CH:16]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34](Cl)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:18]=[C:19]([F:26])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:19]1[CH:18]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:16]=[C:15]([F:14])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc3ccccc3c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 22.8 %

Procedure:
2-Naphthaleneboronic acid (44.7 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (14 mg, 23%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: Br[C:2]1(Br)[C:6]2[CH:7]=[N:8][C:9]([Cl:11])=[CH:10][C:5]=2[NH:4][C:3]1=[O:12]>C(O)(=O)C.CO.[Zn]>[Cl:11][C:9]1[N:8]=[CH:7][C:6]2[CH2:2][C:3](=[O:12])[NH:4][C:5]=2[CH:10]=1
Reactant: O=C1Nc2cc(Cl)ncc2C1(Br)Br
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Cc2cnc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 95.2 %

Procedure:
To a solution of 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (preparation 36d, 1.14 g, 3.49 mmol) in acetic acid (35 mL) was added zinc dust (2.23 g, 34.10 mmol) in one portion and the mixture was stirred at room temperature for 50 minutes. The mixture was diluted with methanol and filtered through a fine frit. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give the title compound (0.56 g, 91%) as a white solid.
Reaction SMILES: F.[Si]([O:9][CH2:10][CH2:11][C@H:12]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])/[C:13](/[CH3:21])=[CH:14]/[C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].O>C(OCC)C.C(#N)C>[Si:23]([O:22][C@H:12](/[C:13](/[CH3:21])=[CH:14]/[C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1)[CH2:11][CH2:10][OH:9])([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:25])[CH3:24]
Reactant: C/C(=C\c1csc(C)n1)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: C/C(=C\c1csc(C)n1)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
20 ml of aqueous hydrofluoric acid (40%) at 0° C. is added to a vigorously stirred solution of (S,4E)-1,3-di-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene 15 (13.255 g, 30.0 mmol) in 120 ml of diethyl ether and 120 ml of acetonitrile. Finely ground splinters of glass (133 mg) are added and the mixture is stirred for 2 h at 0° C. and analyzed by tic. If starting material can still be detected another portion of hydrofluoric acid (20 ml) is added and stirring is continued for 1 h. The reaction is quenched by carefully adding solid sodium bicarbonate (84.0 g, 1.0 mol) within 15 min at 0° C. After stirring for 30 min at 0° C. water is aaded until the salts dissolve (the pH is adjusted to 6-8 by further addition of sodium bicarbonate, if necessary). The mixture is extracted with dichloromethane (4×200 ml). The combined organic extracts are washed with brine (100 ml), dried over magnesium sulfate, and concentrated in vacuo. Purification of the residue by flash column chromatography (pentane/diethyl ether 4:1) affords (S,4E)-3-(tert-butyldimethylsilyloxy)-1-hydroxy-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene 16 (8.255 g, 84%) as a viscous, colourless oil.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[C:24]#[N:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N)(=[S:28])C>CN(C=O)C>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20](=[S:28])[NH2:21])=[CH:18][C:17]=1[C:24]#[N:25])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(C#N)c1
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1cc(C(N)=S)ccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A 4M HCl/1,4-dioxane solution was added to a DMF solution of 4-(benzyloxy)isophthalonitrile and thioacetamide, followed by stirring at 60° C. to obtain 4-(benzyloxy)-3-cyanobenzenecarbothioamide. AP: 291(Na).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([SH:14])=[N:12][N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].[Cl-].[Na+]>CN(C)C=O>[O:24]([C:22]([NH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([SH:14])=[N:12][N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(-n2nnnc2S)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-n2nnnc2S)c1)Oc1ccccc1
Yield: 92.8 %

Procedure:
After dissolving 391 g of 1-(3-aminophenyl)- 5-mercaptotetrazole hydrochloride in 800 ml of N,N-dimethylformamide in a nitrogen gas atmosphere, the mixture was cooled to a temperature below 0° C. After adding thereto 302 ml of pyridine, 294 g of phenyl chloroformate were added dropwise to the s-lution while cooling with stirring so that the liquid temperature was not over 0° C. After further stirring the mixture for one hour at a temperature below 0° C., the reaction mixture was added dropwise to 5 liters of a saturated aqueous sodium chloride solution followed by stirring for 30 minutes. Crystals formed were collected by filtration and washed with 2 liters of water to provide 495 g of the desired compound with a yield of 93%.