Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][OH:23])([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:24]>[Pd].CO>[ClH:24].[OH:23][CH2:22][C:11]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cccc(NC2(CO)CCN(Cc3ccccc3)CC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cccc(NC2(CO)CCNCC2)c1
Reaction time: 24 h

Procedure:
A mixture of 1-benzyl-4-hydroxymethyl-4-(3-methylphenylamino)piperidine (0.2 g, 0.64 mmol) and 10% palladium on charcoal (0.4 g) in a mixture of methanol (15 mL) and methanol saturated with anhydrous hydrochloride gas (10 mL) was shaken in a Parr hydrogenator at 60 psi for 24 h. The resultant mixture was filtered through a plug of Celite, and the filtrate was concentrated to provide the title compound.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[C:7]([F:18])[CH:6]=1>CO.S([O-])([O-])(=O)=O.[Ag+2]>[CH3:3][O:4][C:5]1[C:10]([I:1])=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[C:7]([F:18])[CH:6]=1
Reactant: II
Reactant: COc1ccc(-c2ccccc2C)c(F)c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1cc(F)c(-c2ccccc2C)cc1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of silver sulfate (0.34 g, 1.11 mmol), iodine (0.28 g, 1.11 mmol) in MeOH (10 ml) at room temperature, a solution of 2-fluoro-2′-methylbiphenyl-4-yl methyl ether from above (0.24 g, 1.11 mmol) in MeOH (5 ml) was added dropwise. The mixture was stirred at room temperature for 4 h until the color turned to light yellow. The solid was filtered off and the filtrate was concentrated. The residue was purified via flash column using hexane as the eluant to give the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:8]=2[C:7]=1[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:5].C(N(CC)CC)C.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][C:36]2[N:39]([CH2:52][CH2:53][CH:54]=O)[N:40]=[C:41]([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=3)[C:35]=2[CH2:34]1)(=[O:32])=[O:31].C([O-])(O)=O.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:2][O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:8]=2[C:7]=1[CH:16]1[CH2:21][CH2:20][N:19]([CH2:54][CH2:53][CH2:52][N:39]2[C:36]3[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][C:35]=3[C:41]([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:50])([F:49])[F:51])=[CH:44][CH:43]=3)=[N:40]2)[CH2:18][CH2:17]1)=[O:5]
Reactant: COC(=O)c1sc2cc(F)ccc2c1C1CCNCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1sc2cc(F)ccc2c1C1CCN(CCCn2nc(-c3ccc(C(F)(F)F)cc3)c3c2CCN(S(C)(=O)=O)C3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a stirred solution of 410 mg (1.25 mmol) of 6-fluoro-3-piperidin-4-yl-benzo[b]thiophene-2-carboxylic acid methyl ester hydrochloride salt in 10 mL of dichloromethane and 0.18 mL (1.25 mmol) of triethylamine was added 500 mg of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (1.25 mmol) and 2 g of NaHCO3. The mixture was stirred for 4 h before the portion wise addition of 792 mg (3.73 mmol) sodium triacetoxyborohydride. The reaction was stirred at room temperature for 3 h before quenching with 20 mL of water. The aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (silica, 0-5% MeOH/CH2Cl2) to afford 650 mg (77%) of a white solid. MS (electrospray): exact mass calculated for C32H34F4N4O4S2: 678.20; m/z found, 679.2 [M+H]+. 1H NMR (CDCl3, 400 MHz): 7.74 and 7.66 (A and B of AB quartet, J=8.22 Hz, 4H), 7.50 (dd, J=8.41, 2.54 Hz 1H), 7.14 (t, J=8.22 Hz, 1H), 4.56 (s, 2H), 4.17 (m, 3H), 3.91 (s, 3H), 3.70 (t, J=5.67 Hz, 2H), 3.03 (br m, 2H), 3.00 (t, J=5.67 Hz, 2H), 2.90 (s, 3H), 2.40 (br m, 4H), 2.13 (br m, 4H), 1.76 (br d, J=11.15 Hz, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:17]#[N:18].C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:17]#[N:18])[CH:12]=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: Brc1cncc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cncc(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
3-(Benzyloxy)-5-bromopyridine (5.38 g, 20.4 mmol, Harrowven et al. Tetrahedron, 2001, 57, 4447-4454) in DMF (33 mL) was stirred with copper cyanide (2.9 g, 32.6 mmol) at 160° C. for 7 hours. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate was added and the formed suspension was stirred at 50° C. for 15 minutes. After filtration the liquid phases were separated. The precipitate was triturated with 10% DMF in ethyl acetate (500 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) at 50° C. and filtration and phase separation were performed. The treatment of the precipitate with saturated aqueous sodium hydrogen carbonate solution and 10% DMF in ethyl acetate was repeated two times and the combined organic phases washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 0 to 65%) to yield 3.13 g 5-(benzyloxy)pyridine-3-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:28])=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:28][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nn2c(-c3ccc(F)c(N(C)S(C)(=O)=O)c3)ccnc2c1C#N
Yield: 55.7 %

Procedure:
A mixture of 0.041 g (0.33 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.1 g (0.33 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 66 mg of N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 55%).
Reaction SMILES: CC[O:3][C:4]([C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[C:17]([NH2:19])=[O:18])=[O:7])=[O:5]>O>[CH3:16][O:15][C:11]1[C:10]([C:17]([NH2:19])=[O:18])=[C:9]([NH:8][C:6]([C:4]([OH:5])=[O:3])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)Nc1cccc(OC)c1C(N)=O
Solvent: O
Product: COc1cccc(NC(=O)C(=O)O)c1C(N)=O
Yield: 59.6 %

Procedure:
2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (1.33 g, 0.005 mole) is stirred in 50 ml water, and 5.0 ml of N NaOh is slowly added, giving a solution. After 1/2 hour the solution is filtered, and the filtrate is acidified to pH 2 with N HCl, giving 0.71 g of the title compound, m.p. 214°-215° C., after crystallization from ethanol.
Reaction SMILES: C(O[C:6](=[O:34])[NH:7][C@@H:8]([CH3:33])[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[O:32])[NH:18][C@@H:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Br:31])=[CH:26][CH:27]=3)[N:22]=2)[CH3:20])[NH:12]1)=[O:10])(C)(C)C.Cl.O1CCOCC1.[OH:42][C@@H:43]([C@@H:47]([O:49][CH3:50])[CH3:48])C(O)=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[Br:31][C:25]1[CH:24]=[C:23]2[C:28]([CH:29]=[CH:30][C:21]([C@H:19]([NH:18][C:17]([C@@H:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:8]([NH:7][C:6](=[O:34])[C@@H:43]([OH:42])[C@@H:47]([O:49][CH3:50])[CH3:48])[CH3:33])[NH:12]3)=[O:32])[CH3:20])=[N:22]2)=[CH:27][CH:26]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: CO[C@@H](C)[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: CO[C@@H](C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
A solution of ((S)-2-{(S)-3-[(R)-1-(7-bromo-quinolin-2-yl)-ethylcarbamoyl]-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (838 mg, 1.44 mmol) in dichloromethane (20 mL) was treated with hydrogen chloride in 1,4-dioxane (4 M, 1.44 mL, 5.76 mmol) and stirred for 2 h at room temperature. The solution was evaporated to dryness. The residue was dissolved in dichloromethane (20 mL) and (2S,3S)-2-hydroxy-3-methoxy-butyric acid (193 mg, 1.44 mmol) was added followed by N,N-diisopropylethylamine (1.0 mL, 5.76 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (819 mg, 2.16 mmol). The solution was stirred at room temperature for 20 h and then evaporated to dryness. The residue was purified by silica gel chromatography eluting with a gradient of acetone/ethyl acetate 1:9 to 1:1 to yield the title compound (243 mg, 31%) as a white gum. 1H NMR (300 MHz, CDCl3) δ 1.14 (d, J=6.2 Hz, 3H), 1.33-1.50 (m, 6H), 1.58 (d, J=6.7 Hz, 3H), 2.20-2.30 (m, 1H), 2.66-2.79 (m, 1H), 3.26-3.63 (m, 3H), 3.37 (s, 3H), 3.90 (d, J=11.8 Hz, 1H), 4.20 (d, J=5.1 Hz, 1H), 4.46-4.56 (m, 1H), 5.20-5.31 (m, 1H), 5.36-5.49 (m, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.61-7.70 (m, 2H), 8.15 (d, J=8.5 Hz, 1H), 8.41 (s, 1H). LCMS (m/z) 550.0, 552.0 [M+H], Tr=2.05 min.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=O)[OH:5])[OH:3].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=O)=[CH:16][CH:17]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:3][C@@H:2]2[C:1](=[O:9])[O:10][C:6](=[O:8])[C@H:4]2[O:5][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)=[O:20])=[O:20])=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)O[C@@H]2C(=O)OC(=O)[C@H]2OC(=O)c2ccc(C)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a 300 ml reaction vessel equipped with a stirrer, thermometer, condenser and a dropping funnel, 30 g of D-tartaric acid, 70 g of toluene, 0.12 g of ferric chloride and 59.9 g of p-toluic acid were supplied, and the mixture was heated to 90° C. While keeping this temperature, 83.7 g of thionyl chloride was added from the dropping funnel for 6 hours and the resulting mixture was aged at 105°-110° C. for another 1 hour to carry out the reaction. The reaction mixture was then cooled to room temperature and the precipitated crystals were collected by filtration, followed by drying to obtain 67.2 g of O,O'-di-p-toluoyl-D-tartaric anhydride in the form of pale yellow crystals (purity: 100%, yield: 91.3%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[CH3:15][N:16]([CH2:27][CH2:28][CH2:29][CH2:30]Br)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C>CN(C)C=O>[CH3:15][N:16]([CH2:27][CH2:28][CH2:29][CH2:30][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CN(CCCCBr)S(=O)(=O)c1ccc(F)cc1
Reactant: COc1cccc2c1CC(CN)CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC(CNCCCCN(C)S(=O)(=O)c1ccc(F)cc1)CC2

Procedure:
The compound is prepared from 1 g of 2-aminomethyl-8-methoxytetralin (5.2 mmol), 1.7 g of N-methyl-N-(4-bromobutyl)-4-fluorophenylsulphonamide (5.2 mmol) and 0.73 ml of triethylamine (5.2 mmol) in 20 ml of dimethylformamide analagously to the working directions of Example 47.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CS(C)=O>[N+:12]([C:10]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[S:15][C:4]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: COC(=O)CS
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C

Procedure:
24.8 g (126.7 mmol) of 2,4-dinitrobenzaldehyde, 13.4 g (126.7 mmol) of methyl mercaptoacetate and 35.3 ml (253.3 mmol) of triethylamine in 74.5 ml of DMSO are heated at 80° C. for 1 h. The reaction solution is poured into 250 ml of ice-water. The resulting precipitate is filtered off with suction, washed with water and dried at 50° C. under reduced pressure overnight. This gives 16.1 g (53.6% of theory) of the title compound.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C[Si]([C:13]#[N:14])(C)C.N12CCCN=C1CCCCC2>C1COCC1>[C:13]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N:1]=1)#[N:14]
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
To a suspension of 4-picoline N-oxide (13.64 g, 0.124 mole) in 82 ml of THF, under an inert atmosphere, was added trimethylsilyl cyanide (20.1 ml, 0.15 mole) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.4 ml, 0.028 mole). After stirring at 25° C. for 12 hours, the reaction mixture was heated to reflux. After 4.5 hours, the solvent was removed under reduced pressure and the crude sample was eluted with methylene chloride through a pad of Florisil®. The solvent was removed under reduced pressure to provide (8.7 g, 60%) of 2-cyano-4-methyl pyridine, a white crystalline solid: mp 88-89° C. Anal. Calc'd. for C7H6N2: C, 71.17; H, 5.12; N, 23.71. Found: C, 70.17; H, 5.12; N, 23.44.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].CC(C)([O-])C.[Na+:30].CC(C)=O>C(C(C)=O)C(C)C.CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:30]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: CC(=O)CC(C)C
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of esomeprazole (4.7 g, 13.6 mmol; 2.3% sulfone, 2.3% R-enantiomer) in methyl isobutyl ketone (30 mL) and methanol (2.1 mL) was cooled to 15° C. Sodium tert-butoxide (1.33 g, 13.8 mmol) was added in 5 min and the mixture stirred for 15 min. To the resulting solution, acetone (30 mL) was added slowly over 15 min and a solid started to crystallize. The mixture was heated to 25° C. and methyl tert-butyl ether (7.5 mL) was added dropwise. The slurry was stirred overnight. The solid was collected by filtration, rinsed with acetone (2×5 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 3.2 g (65%). Sulfone content: 0.26%. R-enantiomer content: 0.01%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:14]1[O:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=1)([O-])=O>CS(C)=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[O:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Oc1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.7 %

Procedure:
To a solution of 4-fluorophenol (2.39 g, 21.3 mmol) in dimethylsulfoxide (20 mL) was added sodium hydride (785 mg, 19.6-23.6 mmol, 60-72% in oil), and the solution was stirred at room temperature for 20 minutes. Next, a solution of 5-nitro-furan-2-carbaldehyde (3 g, 21.3 mmol) in dimethylsulfoxide (10 mL) was added dropwise, the solution was then stirred for 2 hours at room temperature. The reaction mixture was poured into brine, and the mixture was extracted with ethyl acetate. The fractionated organic layer was dried over anhydrous magnesium sulfate, then concentrated, and the title compound (4.3 g, 20.8 mmol, 98%) was obtained.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:11]([NH:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][SH:20])(=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15]>>[C:1]([NH:4][C@@H:5]([CH2:6][S:7][S:20][CH2:19][C@H:18]([NH:17][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:21]([OH:23])=[O:22])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CCCCC(=O)N[C@@H](CS)C(=O)O
Product: CCCCC(=O)N[C@@H](CSSC[C@H](NC(C)=O)C(=O)O)C(=O)O

Procedure:
This material was prepared as in Example 18, starting from N-acetylcysteine and N-pentanoylcysteine.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O>[N+:22]([C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:24])=[O:23]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.3 %

Procedure:
Pyrrolidine ((983 μl, 12.0 mmol, commercially available product) was added at 0° C. to a N,N-dimethylformamide (DMF; 4 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.02 g, 4.89 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for 4.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=5/1). Thus, 1-[2-nitro-4-(trifluoromethyl)phenyl]pyrrolidine (1.26 g, 99.3%) was yielded as an orange-colored solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3O[C:13](=O)[C:14]4[C:20]([F:21])=[CH:19][C:18]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[CH:17][C:15]=4[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)(O)O.[NH2:34][NH:35][C:36]([NH2:38])=[NH:37]>N1C=CC=CC=1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:34]4[N:35]=[C:36]([NH2:38])[N:37]=[C:13]4[C:14]4[C:20]([F:21])=[CH:19][C:18]([N:22]5[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]5)=[CH:17][C:15]=4[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN1CCN(c2cc(F)c3c(=O)oc(Cc4ccc5c(c4)OCO5)nc3c2)CC1
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: O
Solvent: c1ccncc1
Product: CN1CCN(c2cc(F)c3c(c2)nc(Cc2ccc4c(c2)OCO4)n2nc(N)nc32)CC1
Temperature: 180 °C
Yield: 46 %

Procedure:
To a suspension of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (0.15 g, 0.35 mmol) in a mixture of tetrahydrofuran (10 mL), methanol (1 mL) and water (2 mL), was added lithium hydroxide (0.15 g, 3.49 mmol). The reaction was stirred at room temperature overnight then the solvent was evaporated. The residue was diluted with water and 2 N HCl solution was added until pH 7. The solid precipitated was filtered and washed with water to obtain the 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid crude. 2-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid was suspended in acetic anhydride (3 mL) and the reaction mixture was heated under microwave condition at 130° C. for 10 minutes. The solvent was evaporated to obtain the 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one crude. To a solution of 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one in dry pyridine (3 mL) was added aminoguanidine hydrogencarbonate (0.05 g, 0.39 mmol) and the mixture was heated under microwave condition at 180° C. for 15 minutes. The reaction was cooled at room temperature and diluted with water to induce the precipitation of a brown solid which was washed with a mixture MeOH/H2O 8/2, to afford the title compound (0.07 g, 46% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9](O)=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20].CC1C(=O)NC(=O)C=1C.S(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([Cl:32])=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20]
Reactant: O=S(Cl)Cl
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)O)c(Cl)cc2F)C1=O
Agent: CC1=C(C)C(=O)NC1=O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(c2cc(C(=O)Cl)c(Cl)cc2F)C1=O

Procedure:
A mixture of 6 g of N-(2-fluoro-5-carboxy-4-chlorophenyl)-2,3-dimethylmaleic acid imide, 0.5 ml of dimethylmaleinimide, 2 ml of thionyl chloride and 50 ml of toluene is heated under reflux for 4 hours. After cooling, the whole is concentrated by evaporation in vacuo. 6 g of N-(2-fluoro-5-chlorocarbonyl-4-chlorophenyl)-2,3-dimethylmaleic acid imide having a melting point of 123°-124° are obtained.
Reaction SMILES: ICI.[CH3:4][C:5]1([CH3:29])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]2[CH:10]=[C:9]([C:17]([C:19]3[CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:23][CH:24]=3)=[CH2:18])[CH:8]=[CH:7][C:6]1=2.[CH2:30]([Zn]CC)C.CCCCCCC>ClCCl>[CH3:4][C:5]1([CH3:29])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]2[CH:10]=[C:9]([C:17]3([C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:25]([O:27][CH3:28])=[O:26])[CH2:30][CH2:18]3)[CH:8]=[CH:7][C:6]1=2
Reactant: C=C(c1cccc(C(=O)OC)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC[Zn]CC
Solvent: CCCCCCC
Solvent: ICI
Solvent: ClCCl
Product: COC(=O)c1cccc(C2(c3ccc4c(c3)C(C)(C)CCC4(C)C)CC2)c1
Reaction time: 15 h

Procedure:
Diiodomethane (1.1 ml, 13.7 mmol) is added dropwise, at 60° C., to a mixture of methyl 3-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (2.2 g, 6.3 mmol) and a 1M solution of diethylzinc in heptane (13 ml, 13 mmol) in dichloromethane (50 ml). The heating is continued for 15 h. The solution is extracted with ethyl acetate. After separation of the phases by settling, the organic phase is washed with 1N HCl solution and then with water, dried over anhydrous magnesium sulphate and concentrated.