Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]([C@@H:18]1[O:20][CH2:19]1)=[O:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[F:13][C:11]1[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=[C:2]([NH:1][CH2:19][C@@H:18]([OH:20])[C:16]([O:15][CH3:14])=[O:17])[CH:12]=1
Reactant: COC(=O)[C@H]1CO1
Reactant: Cn1c(=O)oc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C
Temperature: 90 °C
Yield: 99.6 %

Procedure:
A mixture of 6-amino-4-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (Step 7, 0.630 g, 3.46 mmol), methyl (2R)-glycidate (0.353 g, 3.46 mmol) and lithium trifluoromethanesulfonate (0.540 g, 3.46 mmol) in acetonitrile (10 ml) is stirred and heated at 90° C. overnight. The reaction mixture is diluted with ethyl acetate, washed with water and saline, dried (MgSO4), and evaporated under reduced pressure. Final purification by flash column chromatography (50% ethyl acetate/hexane) gives pure product as a white solid (0.98 g, 60%); MS for C12H13FN2O5 m/z 285 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([OH:17])[CH2:14][N:13]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])(=O)=O)=CC=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]([N:13]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:12]2[CH2:11][N:35]2[C:34](=[O:36])[C:33]3=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]3[C:31]2=[O:41])=[O:19])=[CH:27][CH:26]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol p-toluenesulfonate (24 g: 55.1 mmole) in dimethylformamide (200 ml), potassium phthalimide (15.3 g) is added. The mixture is stirred at 80° C. for 4 hours. The reaction mixture is diluted with ethyl acetate, successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxy-2-phthalimidomethylpyrrolidine (18.1 g). Yield: 80%. NMR δ(CDCl3) ppm: 1.9 to 2.2(m, 2H), 3.4 to 4.05(m, 5H), 3.80(s, 3H), 4.3 to 4.6(m, 2H), 4.8 to 5.1(m, 2H), 6.83(d, J=8.2 Hz, 2H), 7.25(d, J=8.2 Hz, 2H), 7.6 to 7.9(m, 4H). IR ν (CHCl3) cm-1 : 3458, 1773, 1712.
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([CH2:33][CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](O)=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:83][OH:84]>C(Cl)Cl>[O:49]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20]([CH2:33][CH2:34][C:35]([CH3:40])([CH3:41])[CH2:36][C:37]([NH:83][OH:84])=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)NO)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
A solution of 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethylpentanoic acid (35 mg, 0.050 mmol) in DCM (2 mL) was treated with HATU (28.6 mg, 0.075 mmol), N,N-diisopropylethylamine (0.026 mL, 0.150 mmol), and hydroxylamine (1.8 mg, 0.055 mmol). The reaction mixture was stirred at rt for 16 h. The mixture was concentrated and the crude product was purified by prep HPLC (Method 10) to afford 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-N-hydroxy-3,3-dimethylpentanamide (1.9 mg, 5% yield). LC/MS m/e 714.5 (M+H)+, 2.23 min (ionization peak, no UV) (method 3). 1H NMR (500 MHz, DMSO-d6) δ 10.29 (2, 1H), 5.20 (d, J=5.5 Hz, 1H), 4.69 (s, 1H), 4.55 (s, 1H), 3.14-3.01 (m, 4H), 2.98-2.84 (m, 4H), 2.65-2.55 (m, 3H), 2.50-2.44 (m, J=5.9 Hz, 1H), 2.40-2.31 (m, J=5.1 Hz, 1H), 1.97-0.76 (m, 28H), 1.65 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.94 (s, 9H), 0.87 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>[CH2:13]([O:11][C:1](=[O:12])[CH:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)C(CO)c1ccccc1
Reactant: CCCCCCCCO
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)C(CO)c1ccccc1
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a mixture of 49.9 g (300 mmol) of tropic acid and 5.00 g of montmorillonite K10 in 200 ml of toluene is added dropwise at 110° C. 104 g (800 mmol) of 1-octanol. The reaction mixture is stirred for 8 hours, and then toluene/water are removed by azeotropical distillation. The catalyst residue is filtered off and the filtrate is evaporated to dryness to afford 60.4 g (72%) of 3-hydroxy-2-phenyl-propionic acid octyl ester.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([I:1])[CH:3]=1)=[O:22]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Iodo-4-methylaniline (2.42 g, 10.4 mmol) was dissolved in DCM (20.00 mL) and triethylamine (TEA) (1.70 mL, 12.2 mmol) was added and the resulting mixture was cooled to 0° C. To the mixture was added dropwise 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1.60 mL, 10.5 mmol) and the resulting mixture was stirred at 0° C. for 45 minutes and at 25° C. for 16 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water sat. Na2CO3, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The reaction product was used in the next reaction without purification. 1H NMR (CDCl3): δ □ 8.98 (d, 1H), 7.78 (s, 1H), 7.72 (m, 2H), 7.55 (m, 2H), 7.23 (d, 1H), 2.42 (s, 3H). MS (EI) m/z=424 (M+H).
Reaction SMILES: [I:1]Cl.[C:3]1([CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4].O.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[I:1][C:8]1[CH:9]=[CH:10][C:3]([OH:4])=[CH:5][C:6]=1[OH:7]
Reactant: Oc1cccc(O)c1
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Oc1ccc(I)c(O)c1
Yield: 50 %

Procedure:
A solution of iodine monochloride (8.2 g, 50.5 mmol) in dry diethyl ether (100 mL) was added drop-wise over 45 minutes to a cold solution (0° C.) of resorcinol (5.5 g, 49.9 mmol) in dry ether (50 mL). After stirring at room temperature for one hour 100 mL of water and 1.0 g of sodium sulfite was added. The organic phase was separated and the aqueous phase was washed with 100 mL of ether, the combine ether phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified using flash chromatography over silica gel using a mixture of CH2Cl2:MeOH (100:1) to provide the title compound in 50% yield. 1HNMR (300 MHz, CDCl3) δ 4.95 (s, 1H), 6.23 (m, 1H), 6.55 (m, 1H), 7.43 (m, 1H). MS (CDI) m/z 237 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:11]([CH:15]=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)[CH3:17])([O:13][CH3:14])=[O:12]>>[C:11]([CH:15]=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)[CH3:26])=[CH:20][CH:19]=1)[CH3:17])([O:13][CH3:14])=[O:12]
Reactant: Cc1nc(C(O)CN)cs1
Reactant: COC(=O)C=C(C)c1ccc(CC(C)=O)cc1
Product: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C)n2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with 1-[4-(2-carbomethoxy-1-methylethenyl)phenyl]propan-2-one followed by purification of the base on a silica gel column using toluene/methanol=19:1 as eluant.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1>CS(C)=O>[CH:6]1([CH2:9][NH:10][CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH2:8][CH2:7]1
Reactant: NCC1CC1
Reactant: C=CC(=O)O
Solvent: CS(C)=O
Product: O=C(O)CCNCC1CC1

Procedure:
The above resin bound acrylic acid (50 mg) was treated with 300 μmol cyclopropylmethyl amine (21.3 mg) in 300 μL DMSO for 72 hours at 25° C. The excess reagent was filtered off and the resin was washed with 3×1 mL DMSO and 3×1 mL DMF.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([N:13]1[C:12](=[O:22])[C:11]2([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:24][CH2:23]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
8-(tert-Butoxycarbonyl)-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (1.441 g) was dissolved in N,N-dimethylformamide (28 ml), added with sodium hydride (60%, in oil, 521 mg) and stirred at room temperature for 1.5 hours. The reaction mixture was added with benzyl bromide (1.81 ml) with ice cooling and further stirred at room temperature for 1 hour. The reaction mixture was added with water (50 ml) and extracted twice with dichloromethane (70 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=5:1 →4:1) to obtain 1.710 g of the title compound. Yield: 94%.
Reaction SMILES: [N:1]1([NH:14]C(=O)OC(C)(C)C)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.Cl>C(O)C.C(OCC)C>[N:1]1([NH2:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)Nn1cnc2cnc3ccccc3c21
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Nn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A solution of tert-butyl N-(1H-imidazo[4,5-c]quinolin-1-yl)carbamate (6.74 g, 23.7 mmol) in 40 mL of ethanol was treated with 40 mL of HCl (40 mL, 119 mmol, 3 M in ethanol) and heated to reflux. After 1 h, the reaction mixture was cooled to ambient temperature, diluted with 80 mL of diethyl ether, and cooled in an ice water bath which precipitated a tan solid. The HCl salt of the product was collected by vacuum filtration and rinsed with diethyl ether until the filtrate ran clear. The dried HCl salt was dissolved in 75 mL of water and made basic by addition of 50% NaOH solution until the pH of the water was 12–13. The free base of the product precipitated out and was triturated in the basic water for 30 min while being cooled in an ice water bath. The solid was collected by vacuum filtration and dried under vacuum to give 2.86 g of 1H-imidazo[4,5-c]quinolin-1-amine as a tan granular solid.
Reaction SMILES: [CH:1]([B:5]([O:10][CH:11]([CH3:13])[CH3:12])OC(C)C)([CH2:3][CH3:4])[CH3:2].[C:14]([Li])#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl.[B]>C(OCC)C>[CH:1]([B:5]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[O:10][CH:11]([CH3:12])[CH3:13])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)B(OC(C)C)OC(C)C
Reactant: [Li]C#CCCCCCC
Agent: Cl
Agent: [B]
Solvent: CCOCC
Product: CCCCCCC#CB(OC(C)C)C(C)CC

Procedure:
sec-Butyl(1-octynyl)isopropoxyborane was prepared following the method of Example 12 with sec-butyldiisopropoxyborane (10.79 g, 58 mmol) in ethyl ether (58 mL) and added to a solution of 1-octynyllithium (64 mmol in 64 mL, THF) and quenched with HCl in ethyl ether (18.82 mL, 64 mmol). Yield: 10.1 g (74%), bp 68°-70° C. (0.1 mm Hg); n20D 1.4366; proton NMR (CDCl3) δ4.60 (septet, J=18 Hz, 1H), 2.23 (triplet, 2H), 1.17 (d, J=18 Hz, 6H), 0.87 (m, 9H); boron NMR (CDCl3) δ+41.6 ppm(s); mass spectrum (chemical ionization, isobutee) m/e 237 (M+H, 15%); IR (thin film) 2183, 1324 cm1. Anal. Calcd. for C15H29BO: C, 76.77; H, 12.38; B, 4.58. Found: C, 76.30; H, 12.39; B, 4.63.
Reaction SMILES: N[C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[O:5].COC1C=CC=CC=1OC.COC1C=C(C=CC=1OC)C(O)=O>>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[C:4]([C:3]1[CH:2]=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=[O:5]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: COc1ccc(C(=O)O)cc1OC
Solvent: COc1ccccc1OC
Product: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC

Procedure:
A process for the preparation of 2-amino-4,5,3',4'-tetramethoxybenzophenone of formula: comprising, in a first stage, acylating 1,2-dimethoxybenzene using 3,4-dimethoxybenzoic acid in the presence of polyphosphoric acid to provide 3,3',4,4'-tetramethoxybenzophenone of formula: ##STR10## in a second stage, nitrating the 3,3',4,4'-tetramethoxybenzophenone of formula II using nitric acid in the presence of acetic acid to 2-nitro-4,5,3',4'-tetramethoxybenzophenone of formula: ##STR11## and, in a third stage, reducing the 2-nitro-4,5,3',4'-tetramethoxybenzophenone of formula III to the 2-amino-4,5,3',4'-tetramethoxybenzophenone of formula I.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH3:14]>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: N
Product: NC(=O)c1ccc([N+](=O)[O-])cc1Cl
Yield: 90 %

Procedure:
Thereafter, 2-chloro-4-nitrobenzoyl chloride (450 g, 2.1 m) was added dropwise to a stirred 28% ammonia solution (2,000 ml) at below room temperature between 9° and 16° C. The precipitated reaction mixture was washed with water and 30% methanol and then vacuum-dried to yield 2-chloro-4-nitrobenzamide (379 g, 90%, mp 168°-170° C.).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][N:15]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCOCCCc1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCOCCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 94.7 %

Procedure:
A mixture of methyl thiosalicylate (7.4 g, 43.8 mmol), tert-butyl 3-[3-[2-cyano-4-pyridyl]propoxy]propanoate (14.0 g, 48.2 mmol), triethylamine (7.1 g, 70.2 mmol) and toluene (37 ml) was refluxed under nitrogen atmosphere for 24 hrs. The reaction mixture was concentrated under reduced pressure, subjected to a column chromatography and eluted with ethyl acetate-hexane (3:2, v/v) to give the titled compound (17.7 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[SH:8].[Cl:15][C:16]1[N:21]=[C:20](S(C)(=O)=O)[N:19]=[C:18]([NH:26][C:27]2[NH:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[CH:17]=1>C(O)(C)(C)C.CCOC(C)=O>[CH3:32][C:29]1[CH:28]=[C:27]([NH:26][C:18]2[CH:17]=[C:16]([Cl:15])[N:21]=[C:20]([S:8][C:7]3[CH:6]=[CH:5][C:4]([NH:9][C:10]([CH:12]4[CH2:13][CH2:14]4)=[O:11])=[CH:3][C:2]=3[F:1])[N:19]=2)[NH:31][N:30]=1
Reactant: O=C(Nc1ccc(S)c(F)c1)C1CC1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3F)n2)[nH]n1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A solution of N-(3-fluoro-4-mercaptophenyl)cyclopropane-carboxamide (1.0 g, 4.8 mmol) and 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (1.4 g, 4.8 mmol) in t-butanol (10 ml) was heated 70° C. for 18 h. Reaction mixture cooled to room temperature then diluted with EtOAc (60 ml), washed with sat. NaHCO3 solution (30 ml), brine (30 ml), dried (MgSO4), filtered and concentrated in vacuo. Crude product was purified by flash chromatography on silica (EtOAc/Petrol 20 to 60%) to give the title compound as white solid (800 mg, 40%). ES+ 419.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[N:13]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:21]([F:26])([F:25])C([O-])=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:21]([F:26])[F:25])[N:13]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1cc(-c2cccc(C=O)n2)ccc1Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cccc(C=C(F)F)n2)ccc1Cl
Temperature: 120 °C

Procedure:
To a solution of methyl 2-chloro-5-(6-formylpyridin-2-yl)benzoate (Preparation 39, 302 mg, 1.10 mmol) in DMF (5.5 mL) was added sodium chlorodifluoroacetate (250 mg, 1.64 mmol) and triphenylphosphine (435 mg, 1.64 mmol) and heated to 120° C. for 40 minutes followed by cooling to room temperature for 2 hours. The reaction was concentrated in vacuo and partitioned between water and EtOAc. The aqueous layer was washed with EtOAc (2×10 mL) and the organic layers combined, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-20% EtOAc in heptanes to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([CH2:9]O)[CH:5]=1)([O-:3])=[O:2].O=S(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][CH2:9][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(CO)n[nH]1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CCl)n[nH]1

Procedure:
(5-Nitro-1H-pyrazol-3-yl)methanol (524 mg, 3.66 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 3-(chloromethyl)-5-nitro-1H-pyrazole. Then following General Procedure A, the title compound (515 mg, 49%) was prepared from 2-amino-4-chlorobenzenethiol (161 mg, 1.01 mmol), crude 3-(chloromethyl)-5-nitro-1H-pyrazole, K2CO3 (468 mg, 3.39 mmol) in DMF (3 ml).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](C2C=CC(O)=CC=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl[C:25]1[CH:26]=[CH:27][C:28]([N+:35]([O-:37])=[O:36])=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[N+:35]([C:28]1[CH:27]=[CH:26][C:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=2)=[CH:30][C:29]=1[C:31]([F:34])([F:33])[F:32])([O-:37])=[O:36]
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(C(F)(F)F)C(F)(F)F)cc2)cc1C(F)(F)F
Yield: 95.9 %

Procedure:
16.0 g (47.6 mmol) of 2,2-bis(4-hydroxyphenyl)hexafluoropropane, 26.9 g (119 mmol) of 5-chloro-2-nitrobenzotrifluoride and 20.2 g (190 mmol) of sodium carbonate were reacted at 150° C. for 4 hours in 100 ml of dimethylformamide. After the reaction, the product was injected into 250 ml of iced water and extracted with ethyl acetate. The organic layer was washed with water and dried on anhydrous sodium sulfate. After filtration, the solvent was distilled off to recover a crude product, which was then purified by silica gel column chromatography (eluent: toluene/hexane=1/1) and then treated by activated carbon to obtain 32.6 g (yield: 95.9%) of 2,2-bis[(4-(4-nitro-3-trifluoromethylphenoxy)phenyl]hexafluoropropane.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH2:19][C:20]1[CH:24]=[C:23]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[NH:22][N:21]=1>O1CCCC1>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:23]1[NH:22][N:21]=[C:20]([NH:19][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:24]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1cc(-c2ccco2)[nH]n1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1cc(-c2ccco2)[nH]n1

Procedure:
The named compound is prepared by substituting 3-amino-5-(2-furyl)-pyrazole for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.10 gms.) is reacted with 0.1480 gms. of 3-amino-5-(2-furyl)-pyrazole by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [O:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:8][C:9]([S:12](/[N:14]=[CH:6]/[C:5]1[O:1][CH:2]=[N:3][CH:4]=1)=[O:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1cnco1
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1cnco1
Temperature: 65 °C
Yield: 58.7 %

Procedure:
Oxazole-5-carbaldehyde (1.0 g, 10.30 mmol), 2-methylpropane-2-sulfinamide (2.247 g, 18.54 mmol; CASRN 146374-27-8), and tetraethoxytitanium (8.460 g, 37.09 mmol) were stirred in THF (15 mL) and heated to 65° C. for 12 h under nitrogen. The reaction was cooled and poured onto water. The solids were filtered off and the filtrate was extracted with EtOAc. The layers were separated and the organic layer was dried (MgSO4), filtered and concentrated. The resulting residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20 to 25% EtOAc) to afford 1.211 g (58.7%) of (E)-2-methyl-N-(oxazol-5-ylmethylene)propane-2-sulfinamide (20).