Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=1)C1C=CC=CC=1>CO.O>[CH2:20]([O:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH3:18])[C:11]([OH:27])=[O:10])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17]C)[CH:12]=3)[O:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[O:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc2oc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1c2cc(O)ccc2oc2c([N+](=O)[O-])ccc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 10 g of 1-chloro-7-methoxy-4-nitro-9H-xanthen-9-one and 84 ml of a 1M solution of boron tribromide in dichloromethane in 280 ml of dichloromethane was stirred at room temperature under an argon atmosphere for 16 hours, and then it was treated with 100 ml of methanol, and stirred for three hours. The mixture was filtered to give a light green solid. Recrystallization from chloroformmethanol afforded the title compound, mp 290°-292° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([NH2:39])(=[S:38])[CH3:37].C(=O)([O-])O.[Na+].C(O)C>O>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32]2[N:39]=[C:36]([CH3:37])[S:38][CH:33]=2)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cs1
Yield: 67.5 %

Procedure:
A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide (280 mg, 0.5 mmol), thioacetamide (41 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (15 mL) was refluxed for 1 hour. The reaction mixture was poured into water, neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. After the organic layer was washed with water and saturated brin, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (181 mg, 67.5%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[NH2:36][CH2:37][CH2:38][OH:39]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1[N:36]([CH2:37][CH2:38][OH:39])[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: NCCO
Reactant: CC(C)(C)C(=O)c1coc(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)C(=O)c1cn(CCO)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 11 h

Procedure:
To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (113 mg) in tetrahydrofuran (0.7 ml)-ethanol (0.7 ml) was added 2-aminoethanol (0.015 ml) and the mixture was stirred at 60° C. for 11 hr. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:1) to give 3-benzyloxy-5-(2,2-dimethylpropionyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (91 mg).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)#[N:4].[CH:18](OCC)=[O:19].C(O)(=O)C>COCCOC.CC(=O)OCC>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH:18]=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)#[N:4]
Reactant: CCOC(=O)CCc1ccc(C#N)cc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a suspension of NaH (1.102 g, 27.6 mmol) in DME (15 mL) was added dropwise a solution of ethyl 3-(4-cyanophenyl)propanoate (1.4 g, 6.89 mmol) and ethyl formate (2.77 mL, 34.4 mmol) in DME (15 mL). The reaction mixture was then stirred at room temperature overnight. It was neutralized with acetic acid (1.7 mL), then extracted with EtOAc. The organic phases were collected, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography, eluting with PE:EA=2: 1, to give the title compound as a pale yellow oil (1.3 g, 82% yield). LCMS: rt=2.47 and 3.13 min (a mixture of ketone and enol isomer), [M+H+]=232.2
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>O1CCCC1.O.O1CCCC1>[NH2:1][C:2]1[C:7]([NH:8][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)(=[O:18])=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1cccnc1N
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
2,3-Diaminopyridine (1.97 g, 18 mmol) was dissolved in a tetrahydrofuran/water mixture, followed by the addition of a solution of 1.90 g (9.0 mmol) of 3-chlorobenzenesulfonyl chloride in tetrahydrofuran. The obtained mixture was stirred at room temperature overnight and concentrated, followed by the addition of water and dichloromethane. The organic phase was recovered and put in a vessel and the inside wall of the vessel was scratched to precipitate crystals. The formed crystals were recovered by filtration to give 1.41 g of N-(2-amino-3-pyridinyl)-3-chlorobenzenesulfonamide. 530 mg (1.87 mmol) of the crystals was dissolved in methanol, followed by the addition of a 40% aqueous solution of chloroacetaldehyde (367 mg, 1.87 mmol). The obtained mixture was heated under reflux for 4 hours and concentrated to dryness. A small amount of methanol was added to the residue and the obtained mixture was filtered to give 373 mg of the title compound as a crystal.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C@@H:14]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]3[CH3:41])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.C([O-])(O)=O.[Na+]>[Fe].C(O)(=O)C>[NH2:1][C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:29]([F:32])([F:30])[F:31])[C:25]([F:27])([F:28])[F:26])=[CH:22][CH:23]=3)[C@@H:14]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]3[CH3:41])[CH2:13]2)(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc(N)s2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 68.1 %

Procedure:
A 5-mL vial was charged with 2-(4-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.060 g, 0.094 mmol, step 5), iron filings (0.0282 g, 0.505 mmol, Sigma-Aldrich, St. Louis, Mo.) and acetic acid (2 mL). The mixture was stirred at 50° C. for 40 min. Saturated aqueous NaHCO3 (20 mL) was added slowly and then the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (twice, 25 g of silica gel, 30 to 90% EtOAc in hexanes then 10 g of silica gel, 30 to 90% EtOAc in hexanes) to afford 2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.0386 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:19][C:4]1[CH:5]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:7]=[C:2]([CH3:1])[N+:3]=1[O-:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(CCc2ccc([N+](=O)[O-])cc2)cc(C)n1
Solvent: ClC(Cl)Cl
Product: Cc1cc(CCc2ccc([N+](=O)[O-])cc2)cc(C)[n+]1[O-]
Reaction time: 2 h

Procedure:
Compound (3) (22.82 g, 84.5 mmol) was dissolved in chloroform (100 ml), and 16 g (94 mmol) of m-chloroperbenzoic acid (mCPBA) was addedin small portions at RT over a period of 30 min. The mixture was stirred for an additional 2 h and after a negative TLC test for the starting material it was worked up by partitioning between sat. sodium hydrogen carbonate and chloroform. The combined chloroform extracts (3×200 ml) were evaporated yielding a light yellow solid material that was TLC pure.
Reaction SMILES: C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[C:23]([OH:26])(=[O:25])[CH3:24].C([O:29][C:30]([C:32]1[CH:33]=[N:34][NH:35][C:36]=1[N:37]1[C:41](=[O:42])[NH:40][C:39]([CH:43]([NH:55][C:56]2[CH:61]=[CH:60][C:59]([C:62](=[NH:64])[NH2:63])=[CH:58][CH:57]=2)[C:44]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[CH:46][C:45]=2[F:54])=[N:38]1)=[O:31])C>CN(C)C1C=CN=CC=1.C(#N)C>[C:23]([OH:26])(=[O:25])[CH3:24].[C:62]([C:59]1[CH:58]=[CH:57][C:56]([NH:55][CH:43]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[CH:46][C:45]=2[F:54])[C:39]2[NH:40][C:41](=[O:42])[N:37]([C:36]3[NH:35][N:34]=[CH:33][C:32]=3[C:30]([OH:31])=[O:29])[N:38]=2)=[CH:61][CH:60]=1)(=[NH:63])[NH2:64]
Reactant: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)c(OC)cc2F)[nH]c1=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1cc(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3[nH]ncc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
After adding 0.056 ml of triethylamine, 0.0015 g of 4-dimethylaminopyridine and 71 mg of di-t-butyl dicarbonate to a solution of 0.068 g of 5-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}-1H-pyrazole-4-carboxylic acid ethyl ester acetate in 4 ml of acetonitrile, the mixture was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure, and then 1 ml of methanol and 1 ml of a 5N aqueous solution of sodium hydroxide were added and the mixture was further stirred at room temperature for 6 hours. Next, 2 ml of acetic acid, 1 ml of water and 1 ml of methanol were added to the reaction mixture, which was then stirred and heated at 50° C. for 15 hours. After cooling, purification was performed by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 0.034 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:24]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:16]=[O:24])=[O:18])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Product: O=CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 72 h

Procedure:
1-(4-Benzyloxy-3-nitrophenyl)-2-bromoethanone (12.6 g) was dissolved in dimethyl sulphoxide (40 ml) and the solution was allowed to stand at room temperature for 3 days. The solution was poured onto ice and the product was collected as the hydrate (8.7 g). τ (d6DMSO) 4.58 (2H, s), 4.33 (1H, s), 2.25-2.65 (6H, m), 2.07 (2H, br), 1.30-1.87 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:4].[O:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.ClC(Cl)C(OC(=O)C(Cl)Cl)=O>C1(C)C=CC=CC=1>[O:13]=[C:11]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:9][C:8]#[C:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: c1ccoc1
Reactant: COC(=O)CCC#CCCC(=O)O
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCC#CCCC(=O)c1ccco1
Yield: 64.9 %

Procedure:
A mixture of 6-methoxycarbonyl-1-carboxy-3-hexyne [VI-1] (18.4 g, 0.1 mole), furan (13.6 g, 0.2 mole), dichloroacetic anhydride (28.8 g, 0.12 mole), boron trifluoride ether complex (3.2 g) and toluene (100 ml) is reacted at 20°-30° C. for 10 hours. After completion of the reaction, the reaction mixture is cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer is dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give 1-oxo-1-furyl-7-methoxycarbonyl-4-heptyne [VII-1] (15.2 g), b.p. 120°-125° C./0.3 mmHg.
Reaction SMILES: [CH3:1][C:2]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:18])([CH3:8])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:8][C:2]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:18])([CH3:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)n1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2ccccc2n1C(C)(C)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of ethyl 2-methyl-2-(2-methyl-1H-indol-1-yl)propanoate (1.2 g, 4.9 mmol) in anhydrous tetrahydrofuran (10 mL) was added lithium aluminum hydride (1 g, 24.5 mmol) dissolved in anhydrous tetrahydrofuran (5 mL) dropwise between −10° C. and 0° C. After the addition, the mixture was stirred below 0° C. for 1 hour, and then allowed to stir for 3 hours at room temperature. The reaction mixture was cooled down to 0° C., quenched by 10 mL water, and then 10 mL 4N sodium hydroxide. The resulting white precipitate was filtered off, washed with acetic ester. The filtrate was dried by anhydrous sodium sulphate. The solvent was removed to afford the crude product an purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 20:1→10:1→5:1) to give 2-methyl-2-(2-methyl-1H-indol-1-yl)propan-1-ol (780 mg, 79%) as a light green oil. LCMS (M+H+) m/z: calcd. 202.14. found 202.9.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:44][C@H:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]([NH2:48])=[O:47])(=[O:43])=[O:42])=[CH:37][CH:36]=1.[CH3:55][O:56][C:57](=[O:66])[C:58]1[CH:63]=[CH:62][C:61]([CH2:64]O)=[CH:60][CH:59]=1>O1CCCC1>[CH3:55][O:56][C:57](=[O:66])[C:58]1[CH:63]=[CH:62][C:61]([CH2:64][N:44]([C@@H:45]([C:46](=[O:47])[NH2:48])[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[S:41]([C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)(=[O:42])=[O:43])=[CH:60][CH:59]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: NC(=O)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN([C@@H](C(N)=O)c2ccccc2)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (48 mmg, 0.2 mmol) in 0.7 mL of tetrahydrofuran is added diisopropyl azodicarboxylate (0.04 mL, 0.2 mmol) and the reaction stirred for 30 min. To the reaction is added 0.4 mL of tetrahydrofuran, (R)-2-(4-chloro-benzenesulfonylamino)-2-phenyl-acetamide (32 mg, 0.2 mmol), and methyl-4-hydroxymethylbenzoate (73 mg, 0.2 mmol). The reaction is allowed to warm to room temperature and stirred overnight. The solvent is removed and the resultant residue purified by silica gel chromatography to provide the title compound. C13 NMR (100 MHz, CDCl3) 49.9, 52.3, 64.4, 127.9, 129.0, 129.2, 129.4, 129.5, 130.1, 133.5, 139.7, 142.5, 167.0, 171.0. MS 473.1 m/z (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[C].[Pd].C(O)(C)C>[C:1]([O:5][C:6](=[O:7])[NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN=Cc1ccc(-c2ccccn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NNCc1ccc(-c2ccccn2)cc1
Temperature: 5 °C
Yield: 83.9 %

Procedure:
N-(tert-Butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine (20 g, 67.3 mmol), isopropyl alcohol (80 ml) and palladium-carbon (1 g) were charged in a 300 ml four-necked flask and hydrogen was added at 50° C. under atmospheric pressure. Hydrogen was continuously added for 8 hr under the same conditions. The reaction mixture was filtered to remove the catalyst. After 90% of isopropyl alcohol in the obtained filtrate was evaporated by concentration, the same volume of heptane was added. The mixture was cooled with stirring and crystals were precipitated at around 40° C. The mixture was further cooled to 5° C. with stirring and the precipitated crystals were collected by filtration and dried to give 16.91 g of tert-butyl3-[4-(pyridin-2-yl)benzyl]carbazate as white crystals. The yield was 84.0% of N-(tert-butoxycarbonyl)-N′-[4-5 (pyridin-2-yl )phenylmethylidene]hydrazine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([CH2:27]OC)OC>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>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:3]=[C:2]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][C:24]=3[CH3:27])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=2)[CH2:12][CH2:13]1
Reactant: COCCOC
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
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: [Na+]
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A mixture of 200 mg (0.666 mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in the previous step), 136 mg (0.999 mmol) and 77.0 mg (0.0666 mmol) of tetrakis(triphenylphosphine)palladium (0) under Ar was added 4.0 mL of degassed dimethoxyethane (DME) and 400 μL (0.799 mmol) of 2.0 M aq Na2CO3. The mixture was heated with stirring under Ar at 80° C. for 14 h. The cooled (RT) mixture was concentrated and chromatographed on a 10-g silica SPE column with 1-5% MeOH in dichloromethane-hexane (1:1). The product fractions were treated with 80 mg of decolorizing carbon, filtered, concentrated, and then rechromatographed on a similar column with 1-3% EtOH-dichloromethane to afford 265 mg of the title compound as a yellow resin (75% purity by 1H-NMR as a mixture with triphenylphosphine) that was used in the following reaction without further purification: Mass spectrum (ESI, m/z): Calcd. for C11H21N3O3, 312.2 (M+H), found 312.2.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:19])([F:20])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnccn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M82) (0.36 g, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (163 mg, 58%).