Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[CH:5]=1.I[CH3:22]>CN(C=O)C.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][CH3:22])[CH2:18][CH2:19]2)[CH:5]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
0.6 g sodium hydride (60%) were added to a cooled solution (−7° C.) of 2.55 g 4-fluoro-2-(trans-4-hydroxy-cyclohexyloxy)-1-nitro-benzene and iodomethane in 30 ml DMF. The mixture was allowed to warm to rt overnight, diluted with EtOAc and washed with water and brine (3×). The organic phase was dried (MgSO4), passed through a hydrophobic frit and evaporated. The residue was purified by flash column chromatography (silica gel, 100% i-hexane→7:1 i-hexane:EtOAc).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].O=O.[C:8](=[S:10])=[S:9]>C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:8](=[S:10])[S:9][S:9][C:8](=[S:10])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:2]
Reactant: CCNCC
Reactant: S=C=S
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: O=O
Product: CCN(CC)C(=S)SSC(=S)N(CC)CC
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Diethylamine (150 g, 2.05 moles) and manganese acetate catalyst (30 mg, 0.12 mmole) were charged into a 1 liter reactor at room temperature. The reactor was evacuated to 0.6×105 Pa (0.6 bar) and carbon disulfide (87.5 g, 1.15 moles) was dosed in 20 min while increasing the temperature to 60° C. The reactor was pressurized to 3×105 (3 bar) with pure oxygen and the stirring speed was raised to 1400 rpm. Carbon disulfide dosing was started again at a dosing rate of 2 moles per mole oxygen reacted, i.e. 68.5 g (0.90 mole) in 280 min. The reaction was stopped when the oxygen flow fell below 1 ml/min. After removal of the reaction water formed by evaporation, 295 g of tetraethyl thiuram disulfide were obtained (yield: 97.2 wt %) with a purity of 96.7 wt % (as determine d by the H2S titration method).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C(C)=O.[Na].O>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:11])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
4-Methoxyphenylacetyl chloride (76 g, 0.413 mole) was added to a stirred suspension of ethyl acetoacetate, sodium salt (62.8 g, 0.413 mole) in ether (250 ml) over a period of 1.5 hours and the reaction was allowed to sit for 3 days. The reaction mixture was treated with water (100 ml) and extracted with ether. The ether extract was cooled in an ice bath and ammonia gas was bubbled into the solution for 2.5 hours while the reactants were allowed to warm to room temperature. The reaction was washed with water, filtered and the ether fraction was stirred with 3N hydrochloric acid (100 ml) for 16 hours. The ether layer was washed with water, 5% sodium bicarbonate, brine and dried with sodium sulfate. The solvent was removed and the residue was distilled on a kugelrohr apparatus to give the product as a yellow oil (19.7 g, 20%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([C:17]([OH:19])=O)[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23].CN1CCOCC1>ClCCl.C(OCC)C>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH:23][C:17]([C:13]1[N:12]=[C:11]([S:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:16]=[N:15][CH:14]=1)=[O:19]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1cncc(Sc2cccc([N+](=O)[O-])c2)n1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(F)cc1F)c1cncc(Sc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7 g (11 mmol) of a 50% strength solution of propanephosphonic anhydride in dichloromethane are added to a solution of 2.8 g (10 mmol) of 2-(3-nitrophenylthio)-6-pyrazinecarboxylic acid, 3.2 g (25 mmol) of 2,4-difluoroaniline and 3 g (30 mmol) of 4-methylmorpholine in dichloromethane at 0° C. The reaction mixture is heated to room temperature. After 12 hours, the solvent is istilled off under reduced pressure. The residue is taken up in diethyl ether and the solution is extracted with 10% strength, aqueous hydrochloric acid, washed with distilled water and with saturated, aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is purified by chromatography (silica gel, cyclohexane/ethyl acetate 4/1 (v/v)). Yield 1.6 g (40%); light yellow, crystalline solid, mp. 131-135° C.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:18][CH:17]([F:20])[F:16])(=[O:8])=[O:9]
Reactant: OCC(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
With cooling with ice, 2.7 ml of trifluoromethanesulfonic acid anhydride was added to a chloroform (100 mL) solution of 1 mL of 2,2-difluoroethanol and 2.2 mL of triethylamine, and stirred for 30 minutes. The reaction liquid was diluted with chloroform, and washed with aqueous saturated sodium bicarbonate solution and saturated saline water in that order. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [F:1][CH2:2][CH:3](O)[CH2:4][F:5].N1C=CC=CC=1.C(#N)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39]1[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47][C:41]=2[CH:40]=1>>[F:1][CH2:2][CH:3]([N:45]1[CH2:46][CH2:47][C:41]2[CH:40]=[C:39]([O:38][CH3:37])[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]=2[CH2:43][CH2:44]1)[CH2:4][F:5]
Reactant: OC(CF)CF
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(CF)CF)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of 1,3-difluoro-propan-2-ol (0.697 mL, 9.00 mmol) and pyridine (0.910 mL, 11.2 mmol) in acetonitrile (42.3 mL, 810 mmol) was cooled at 0° C. and trifluoromethanesulfonic anhydride (1.59 mL, 9.45 mmol) was added dropwise. The mixture was stirred for 30 minutes and then potassium carbonate (1.24 g, 9.00 mmol) and 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.00 g, 4.50 mmol) were added. The reaction was heated at 50° C. overnight and then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in DCM (75 mL) and washed with water (75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 3-(2-fluoro-1-fluoromethyl-ethyl)-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow amorphous solid (679 mg, 50%). LCMS (m/e) 301 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.67 (s, 1H), 6.83 (s, 1H), 4.75-4.65 (m, 2H), 4.63-4.54 (m, 2H), 3.96 (s, 3H), 3.29-3.11 (m, 1H), 2.99-2.93 (m, 2H), 2.93-2.82 (m, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([Br:16])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([Br:16])=[C:8]([C:12]([F:14])([F:13])[F:15])[CH:9]=1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.40 g, 4.68 mmol) was suspended in MeOH (15 ml); Sodium hydroxide (2.0 M aqueous solution) (14.04 ml, 28.1 mmol) was added and the suspension was stirred at RT overnight. The mixture was concentrated in vacuo and the resulting residue was dissolved in water (100 ml) and then acidifed by the addition of 5.0M HCl(aq). The product was extracted into ethyl acetate (2×75 ml) and the combined organic extracts were washed with water (50 ml), brine (25 ml), dried (MgSO4) and concentrated in vacuo to afford the title product as a yellow solid. 1H-NMR: [400 MHz, DMSO-d6, δH 13.24 (1H, br s, CO2H), 7.74 (1H, s, ArH), 7.17 92H, br s ArNH2). m/z 285.1, 287.1 [M+H]+
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1.FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.[H-].[Na+]>C(OCC)(=O)C.O>[F:26][C:25]([F:28])([F:27])[CH2:24][O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(CO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COCC(F)(F)F)nc1
Yield: 23 %

Procedure:
To an N,N-dimethylformamide solution (10 mL) of methyl 6-(hydroxymethyl)nicotinate (500 mg, 2.99 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (518 μL, 3.59 mmol), sodium hydride (179 mg, 4.49 mmol) was added at 0° C. and the resultant mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain the title compound (171 mg, yield 23%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8](SC)=[C:9](O)[CH:10]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C[S:30]([CH3:32])=O.O>CCCCCC.C(OCC)(=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH:22]([S:30][C:32]1[CH:6]=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:2]=2[Br:1])[CH:10]=[CH:9][C:8]=1[CH3:7])[CH3:28])[CH3:27]
Reactant: CS(C)=O
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2Br)cc1O
Reactant: CCOC(=O)C(C)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)C(C)Sc1cc(Oc2ccc([N+](=O)[O-])cc2Br)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2-Bromo-4-nitrophenoxy)-2-(methylthio)phenol (0.05 mole) potassium carbonate (0.2 mole), ethyl 2-bromopropionate (0.08 mole) and dimethylsulfoxide (200 ml) are charged into a 500 ml glass reaction flask equipped with a mechanical stirrer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into 500 ml of water. The resulting mixture is extracted three times with 100 ml portions of methylene chloride. The extracts are then combined, washed with water and thereafter dried. The dried solution is then stripped of solvent under reduced pressure to leave a residue. The residue is subjected to chromatography using a clay column and hexane/ethyl acetate mixtures as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product ethyl-2-[5-(2-bromo-4-nitrophenoxy)-2-methylthiophenoxy]propionate as the residue.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:61]([O:68][CH2:69][CH2:70][CH2:71][CH2:72]O)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62].N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:72][CH2:71][CH2:70][CH2:69][O:68][Si:61]([C:64]([CH3:65])([CH3:67])[CH3:66])([CH3:62])[CH3:63])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (0.6 g, 1.01 mmol), triphenyl phosphine (0.4 g, 1.52 mmol), and 4-{[tert-butyl(dimethyl)silyl]oxy}-1-butanol (0.31 g, 1.52 mmol, J. Org. Chem. 1986, 51, 3388-3390) in anhydrous dichloromethane (9 mL) at 0° C. under nitrogen atmosphere was slowly added a solution of diisopropyl azodicarboxylate (0.29 mL, 0.3 g, 1.52 mmol) in anhydrous dichloromethane (2 mL) and the mixture was stirred at ambient temperature for 2 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, hexanes/ethyl acetate, 1:1) to provide the title compound as a solid foam (0.39 g). In NMR (DMSO-d6): δ 0.0 (6H, s), 0.78 (3H, d), 08.0 (3H, d), 0.82 (9H, s), 1.22 (1H, dd), 1.4 (1H, quintuplet), 1.55 (2H, quintuplet), 1.7 (2H, quintuplet), 1.8-1.9 (1H, m), 2-35 (1H, t), 2.65-2.80 (3H, m), 2.9 (1H, d), 3.0 (1H, dd), 3.2-3.3 (2H, m), 3.4-3.5 (1H, m), 3.52-3.62 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.9 (2H, t), 4.8 (1H, dt), 5.0 (1H, br s), 5.5 (1H, d), 6.18 (2H, s), 6.77 (2H, d), 7.0-7.1 (3H, m), 7.19 (1H, d), 7.21 (1H, s), 7.3 (1H, d); MS: 801 (M+23); C38H58N2O11SSi.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8]C)=[O:6].COC(OC)[N:16]([CH3:18])C.O.[NH2:22]N>>[C:2]([C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:18][NH:16][N:22]=1)([CH3:12])([CH3:11])[CH3:1]
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: O
Product: COC(=O)c1c[nH]nc1C(C)(C)C

Procedure:
Using ethyl 4,4-dimethyl-3-oxopentanoate (3.4 g), dimethylformamide dimethylacetal (2.8 mL) and hydrazine monohydrate (1.1 mL), and in the same manner as in Example 1(3), a crude product of methyl 3-tert-butyl-1H-pyrazole-4-carboxylate was obtained. This was dissolved in dimethylformamide (15 ml), potassium carbonate (1.2 g) and 2-chloro-5-trifluoromethylpyridine (1.7 g) were added, and the mixture was stirred at room temperature overnight. In the same manner as in Example 1(4), the title object compound (2.8 g, 43%) was obtained as a white solid.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]([CH2:16][CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:11][OH:12])[CH2:6][OH:7]
Reactant: CC(=O)NC(CC=Cc1ccccc1)(COC(C)=O)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(CO)(CO)CC=Cc1ccccc1
Yield: 66.2 %

Procedure:
2-Acetamido-1,3-diacetoxy-2-(3-phenyl-2-propenyl)propane (170 mg) was dissolved in 6 ml of methanol and 6 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 3 hours. After the reaction, the solvent was distilled away and the residue was purified by silica gel column chromatography (methanol:chloroform=1:30-1:6) to give 70 mg of 2-amino-2-(3-phenyl-2-propenyl)-1,3-propanediol as pale brown crystals.
Reaction SMILES: [NH3:1].O=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C1(C)C=CC=CC=1>[NH2:1]/[C:3](/[C:11]([F:14])([F:13])[F:12])=[C:4](/[F:10])\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)C(=O)C(F)(F)F
Reactant: N
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(F)=C(\N)C(F)(F)F

Procedure:
Ammonia is introduced with stirring into a solution of 7.5 g of ethyl 3-oxo-2,4,4,4-tetrafluorobutyrate in 20 ml of toluene at 75° C. up to saturation. Then the reaction mixture is heated using a water separator for 5 hours, during which ethyl 3-amino-2,4,4,4-tetrafluorocrotonate is formed as an intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5](I)[CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14](B(O)O)[C:15]([F:18])=[N:16][CH:17]=1>[F-].[K+].C(#N)C.O>[Br:11][C:12]1[CH:13]=[C:14]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[CH:7][C:6]=2[NH2:9])[C:15]([F:18])=[N:16][CH:17]=1
Reactant: COc1cc(I)c(N)cn1
Reactant: OB(O)c1cc(Br)cnc1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(-c2cc(Br)cnc2F)c(N)cn1
Temperature: 95 °C
Yield: 70.6 %

Procedure:
A mixture of 6-methoxy-4-iodopyridin-3-amine (9.5 g, 38 mmol), 5-bromo-2-fluoropyridin-3-ylboronic acid (16.7 g, 76 mmol), and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.5 g, 2 mmol) in 1N aqueous potassium fluoride (95 mL) and acetonitrile (200 mL) was heated at 95° C. for 16 h. The cooled reaction mixture was diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layer was dried over sodium sulfate, filtered, and evaporated to afford a residue which was purified by flash chromotagraphy (silica, 120 g column, ISCO, 0-40% ethyl acetate in hexanes) to afford the title compound as a yellow/orange solid (8.0 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH2:10][C:11]([O:13]C)=[O:12])=[C:4]([O:15][CH3:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:15][CH3:16])=[C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: COC(=O)CNc1cc(I)c(Cl)cc1OC
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+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1NCC(=O)O
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A mixture of methyl 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetate (5.0 g, 14.08 mmol), 2,5-dichlorophenylboronic acid (4.03 g, 21.12 mmol), Pd(PPh3)4 (1.626 g, 1.04 mmol), Na2CO3 (4.477 g, 42.24 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was stirred at reflux under argon for 6 h. Then reaction mixture was allowed to cool to room temperature, quenched with water and acidified with HCl (10% in water) to adjust the pH to 3-4. The mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50% petroleum ether/ethyl acetate) to afford the desired product (3 g, 59% yield) as an off-white solid. ESI-MS m/z: 360.2 [M−H]−.
Reaction SMILES: OS(O)(=O)=O.[Na+].C([C:9](CC)([C:13]([C:15]([O-:17])=[O:16])=O)[C:10]([O-:12])=O)C.[Na+].[N:21]1([CH2:27][CH2:28][NH:29][NH2:30])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[CH2:31](OCC)[CH3:32]>CCO>[CH2:31]([O:17][C:15]([C:13]1[CH:9]=[C:10]([OH:12])[N:29]([CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:30]=1)=[O:16])[CH3:32]
Reactant: CCOCC
Reactant: NNCCN1CCOCC1
Reactant: CCC(CC)(C(=O)[O-])C(=O)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)n(CCN2CCOCC2)n1

Procedure:
H2SO4 (conc., 0.98 g, 10 mmol) was added dropwise into a suspension of diethyloxalacetate sodium salt (10 mmol) in 100 mL anhydrous ethyl ether. Na2SO4 was filtered off after the addition. Excess acid was removed by 30 ml KHCO3 (sat.) to give diethyl oxacetate. 2-(N-morpholinyl)ethylhydrazine (1.45 g, 10 mmol) in 2 ml EtOH was added, and the mixture was refluxed for 45 min. The solvent was removed under vacuum to yield 2.1 g of the crude pyrazole-based compound A.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([OH:44])=O)([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:64][S:61]([CH:58]6[CH2:60][CH2:59]6)(=[O:63])=[O:62])=[O:44])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)c3ccc(OC)c(C)c3n2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)c3ccc(OC)c(C)c3n2)cc1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
The acid (130) (70 mg, 0.111 mmol) was dissolved in DCM (2 ml). EDAC (26 mg, 0.133 mmol) was added and the mixture was stirred at room temperature over night. Cyclopropanesulfonic acid amide (15 mg, 0.122 mmol) and DBU (35 μl, 0.233 mmol) was added and the reaction mixture was stirred at room temperature over night. 5% Citric acid was added to the reaction mixture, and the mixture was extracted with brine, dried over Na2SO4 and purified by column chromatography (DCM/MeOH 20:1) to give the title compound (29 mg, 36%). MS (M+H)=733
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.CCO.O1CCOCC1>[C:7]1([CH2:6][NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](N)CO
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@@H](CO)NCc1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of (2S)-2-amino-1-propanol (5.01 g, 66.70 mmol) in toluene (130 mL) was added benzaldehyde (7.08 mL, 70.05 mmol). The flask was fitted with a Dean-Stark trap, and the solution was heated at 150° C. for 2 h. The solution was then cooled to room temperature and concentrated in vacuo. To a 0° C. solution of the residue in EtOH (130 mL) was added NaBH4 (6.31 g, 166.8 mmol) and sufficient 4 N HCl in dioxane to adjust the pH to ca. 2. The mixture was stirred overnight and then concentrated in vacuo. The residue was partitioned between 1 N aq. HCl (200 mL) and DCM (100 mL). The aqueous phase was washed with a fresh portion of DCM (100 mL), and then adjusted to pH>13 with 6 N aq. NaOH. The aqueous phase was extracted with DCM (2×150 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide (2S)-2-[(phenylmethyl)amino]-1-propanol (10.52 g, 95%) as a colorless oil. LCMS: (M+H)+: 166.1.