Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>C(O)C>[CH2:13]([NH:16][C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])[CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: C=CCNc1c(OCC)c(=O)c1=O
Yield: 99.7 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.2 g, 31 mmol) in ethanol (80 mL) was treated at room temperature with allylamine (2.3 mL, 31 mmol), which was dissolved in ethanol (40 mL), over a 2 hour period. The reaction mixture was concentrated in vacuo to afford crude 1-(2-propenylamino)-2-ethoxy-3,4-dioxo-1-cyclobutene as a light yellow solid (5.6 g). The crude intermediate was dissolved in anhydrous dimethylformamide (50 mL) and added dropwise to a suspension of 60% sodium hydride (1.5 g, 37 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen. The anion was quenched with t-butyl bromoacetate (6.0 mL, 37 mmol) and the reaction mixture was stirred for 1.5 hours, poured into water (500 mL), extracted with ethyl acetate (2×200 mL), and dried (MgSO4) to yield N-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)-N-(2-propenyl)glycine 1,1-dimethylethyl ester. Purification was achieved by flash chromatography (10 cm diameter, elution with 20% ethyl acetate in petroleum ether) affording a yellow oil (4.56 g, 50%); 1H NMR (CDCl3, 300 MHz): δ 5.88-5.72 (m, 1H), 5.35-5.22 (m, 2H), 4.80-4.68 (m, 2H), 4.35, 4.08 (d, J=7 Hz, 2H), 4.28, 3.95 (s, 2H), 1.48 (s, 9H), 1.45 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[C:27]#[C:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1.O>C(Cl)Cl>[Br:5][CH2:1][C:27]#[C:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1ccc(C#CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#CCBr)cc1
Reaction time: 13 h
Yield: 109.2 %

Procedure:
1.7 g of carbon tetrabromide and 1.15 g of triphenylphosphine were added to 10 ml of a solution of 0.70 g of ethyl 4-(3-hydroxy-1-propynyl)benzoate in methylene chloride at room temperature. The obtained mixture was stirred at that temperature for 13 hours, followed by the addition thereto of 20 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 5% diethyl ether/n-hexane) to give 1.0 g of the title compound as a pale-yellow oil. 1H-NMR (400 MHz, CDCl3) δ(ppm); 1.38(t, J=7.2 Hz, 3H), 4.17(s, 2H), 4.36(q, J=7.2 Hz, 2H), 7.50(d, J=8.4 Hz, 2H), 7.99(d, J=8.4 Hz, 2H)
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][C:28](=[O:30])[O:27][N:26]=2)=[C:21]([O:31][CH3:32])[CH:20]=1)C1C=CC=CC=1.I[Si](C)(C)C.CO.C(=O)(O)[O-].[Na+]>ClCCl>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][C:28](=[O:30])[O:27][N:26]=2)=[C:21]([O:31][CH3:32])[CH:20]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1-c1noc(=O)[nH]1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCO)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 39.9 %

Procedure:
118 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one were dissolved in 14 mL of dichloromethane by heating and allowing to cool down to room temperature. To the resulting solution was added 144 μL of iodotrimethylsilane. The resulting mixture was stirred at room temperature for 6.5 h and 6 mL of methanol were added followed by a saturated aqueous solution of sodium bicarbonate. The mixture was stirred for 1 h, filtered and concentrated under reduced pressure. Dichloromethane/water were added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane 90/methanol 10) to give 40 mg of 3-{4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:28](Cl)(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[C:28]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCC=CCCCCCCCC(O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCC=CCCCCCCCC(=O)Cl
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
Starting from tert-butyl 3-hydroxy-11-eicosenoate (11 g) and 9-octadecenoyl chloride (15 g), tert-butyl 3-(9-octadecenoyloxy)-11-eicosenoate (14 g) was obtained as an oil according to a similar manner to that of Preparation A-2(4).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[CH2:7]([C:1]1[CH:6]=[CH:5][C:4]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To a solution of 1-phenyloctane (5.86 g, 30.8 mmol) in CHCl3 (50 mL) was added chlorosulfonic acid (17 mL, 29.8 g, 256 mmol) and the mixture was stirred at rt for 20 h. The mixture was poured on ice (200 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The yellow oily residue (ca 80% yield) was used without further purification in the next reaction; 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7 Hz), 1.27-1.32 (m, 10H), 1.64-1.66 (m, 2H), 2.72 (t, 2H, J=8 Hz), 7.42 (d, 2H, J=8 Hz), 7.93 (d, 2H, J=8 Hz).
Reaction SMILES: C(Br)C.[Mg].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]#[CH:11].[Cl:12][CH2:13][C:14]([C:16]1([Cl:19])[CH2:18][CH2:17]1)=[O:15].[Cl-].[NH4+]>C(OCC)C>[Cl:12][CH2:13][C:14]([C:16]1([Cl:19])[CH2:18][CH2:17]1)([OH:15])[C:11]#[C:10][C:6]1[S:5][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCl)C1(Cl)CC1
Reactant: C#Cc1cccs1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Product: OC(C#Cc1cccs1)(CCl)C1(Cl)CC1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
22.2 g (0.203 mole) of ethyl bromide are slowly added to 4.9 g (0.203 mole) of magnesium turnings in 100 ml of diethyl ether. After completion of the addition, the reaction mixture is heated under reflux for 30 minutes and then cooled to room temperature, and a solution of 20 g (0.185 mole) of 2-thienylethine in 50 ml of diethyl ether is subsequently added dropwise with stirring. The mixture is heated under reflux for 1 hour and again cooled to room temperature. 28.3 g (0.185 mole) of 1-chloro-cyclopropyl chloromethyl ketone are added dropwise with stirring and the mixture is then heated under reflux for a further 2 hours. After cooling to room temperature, the reaction mixture is poured into a saturated aqueous ammonium chloride solution and the mixture is extracted three times with diethyl ether. The combined organic phases are washed once with water, dried over sodium sulphate and concentrated under reduced pressure. 47.0 g (97% of theory) of 1-chloro-2-(1-chlorocyclopropyl)-4-(thiophen-2-yl)-but-3-in-2-ol are obtained in this way in the form of an oil which is reacted further without additional purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:39][NH2:40])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:39][NH:40][C:24](=[O:26])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(OC)c(Br)c1
Yield: 53.9 %

Procedure:
A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.0 g, 2.478 mmol) and 1-[3-bromo-4-(methyloxy)phenyl]methanamine (0.581 g, 2.69 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.781 ml, 5.6 mmol) was stirred in dichloromethane (45 mL) at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, followed by saturated NaCl. The organic layer was dried over Na2SO4 and then evaporated to dryness which gave, initially, a glassy gum, but which then appeared to crystallize. The residue was taken up in a small amount of MeOH and sonicated for a while. A crystalline white solid formed and was collected and dried to afforded N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (804 mg, 53.9%) as a white solid. LC-MS m/z 601.3 (M+H)+, 0.77 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H].CC(C)=O>C(O)C.[C].[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[CH:10]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In ethanol (250 mL) was dissolved 100 g (F.W. 201.57, 496 mmol) of 2-chloro-4-nitrobenzoic acid (1) and after replacing with argon, a 10% palladium carbon catalyst (4.0+1.5 g) was added thereto. After replacing with hydrogen, the mixture was stirred at room temperature for 72 hours. The formed crystal was dissolved with acetone and filtered to remove the catalyst. The solvent was distilled under reduced pressure to quantitatively obtain 88 g of the target 4-amino-2-chlorobenzoic acid (2).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:7][CH:6]=1)=O.[NH2:23][OH:24]>N1C=CC=CC=1.CCO>[F:1][C:2]([F:22])([F:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:7][CH:6]=1)=[N:23][OH:24]
Reactant: NO
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)C(F)(F)F)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
tert-Butyl 1-(4-(2,2,2-trifluoroacetyl)phenyl)ethylcarbamate (1.02 g, 3.21 mmol) was mixed with NH2OH*HCl (223 mg, 3.21 mmol) in pyridine (25 ml) and EtOH (12 ml). The mixture was stirred at 80° C. for 16 hours and then evaporated. The residue was dissolved in EtOAc (60 ml), washed with H2O (2*40 ml), dried over MgSO4, filtered and evaporated. The product was purified by flash chromatography using CH2Cl2/MeOH (20:0→20:1) as eluent to give 640 mg (60%) of the title compound as pale solids.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:19]=[C:18]([NH:20][C:21](=[O:26])C(C)(C)C)[C:17]([CH2:27][CH2:28]C(OCC)=O)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:19]=[C:18]2[C:17]([CH2:27][CH2:28][C:21](=[O:26])[NH:20]2)=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(OCCCCOCc2ccccc2)nc1NC(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1CCc2ccc(OCCCCOCc3ccccc3)nc2N1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To a solution of intermediate 9 (1.76 g, 3.9 mmol) in 1,4-dioxane (14 mL) was added 3N HCl (7.1 mL) and the mixture was then heated to reflux for 3 h. The mixture was cooled to rt and then anhydrous K2CO3 was slowly added to neutralize the reaction mixture to pH=8, then extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel column (elution with PE/EtOAc=4:1-1:1) to give 7-(4-(benzyloxy)butoxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (intermediate 10) (671 mg, 54%) as an oil.
Reaction SMILES: CC(C)([O-])C.[K+].O.Cl.[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:25]([C:37]#[N:38])=[C:24](SC2C=CC=CC=2)[N:23]=1.O>COCCOC>[NH2:21][C:22]1[N:23]=[C:24]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=2)[C:25]([C:37]#[N:38])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:27]=1[C:28]#[N:29]
Reactant: CNC(=O)c1cc(CO)ccn1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1cc(COc2nc(N)c(C#N)c(-c3ccc(F)cc3)c2C#N)ccn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.62 g (14.44 mmol) of potassium tert-butoxide were suspended in 10 ml of 1,2-dimethoxyethane. After addition of 1.44 g (8.66 mmol) of 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide hydrochloride monohydrate (Example 40A) and 1.00 g (2.89 mmol) of 2-amino-4-[4-fluorophenyl]-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 38A), the mixture was stirred at 60° C. for 2 h and at RT overnight. 30 ml of water were added to the reaction mixture. The precipitate was filtered off and washed with water.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[C:14]([NH:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)(=[O:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:24][C:20]1[CH:19]=[C:18]([NH:17][C:14](=[O:16])[CH3:15])[CH:23]=[CH:22][CH:21]=1)([O-:3])=[O:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a mixture of 3,4-dinitrofluorobenzene (1.0 g, 5.4 mmol, 1.0 eq.) and 3-acetamidophenol (0.8 g, 5.4 mmol, 1.0 eq.) in 10 mL of anhydrous DMF, K2CO3 (0.7 g, 5.4 mmol, 1.0 eq) was added. The reaction mixture was heated to 120° C. and stirred for 16 h. The mixture was cooled to RT and EtOAc was added (100 mL). After washing with H2O (100 mL), the organic layer was dried (MgSO4), filtered and concentrated. The resulting crude material was purified by column chromatography (20-100% EtOAc in hexanes) to obtain pure N-[3-(3,4-dinitro-phenoxy)-phenyl]-acetamide.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[C:4]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)=[N:5][CH:6]=[CH:7][CH:8]=4)[CH2:23][CH2:22]3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Product: COc1cc(-c2ncccc2CN2CCCN(Cc3cccnc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC

Procedure:
3-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (311 mg) and homopiperazine (53 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH:15][CH3:16]>C(O)(=O)C>[CH3:14][N:15]([CH3:16])[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNC
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CC(=O)O
Product: CN(C)c1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 62.5 °C
Yield: 91 %

Procedure:
2-Chloro-5-nitro benzoic acid (2 g, 10 mmol) was added to 40% dimethylamine aq. solution (20 ml) at room temperature and then heated at 60-65° C. for 3 hr. The reaction mixture was chilled to 0° C. and acidified with dilute acetic acid. The mixture was then extracted with ethyl acetate, and the organic layer washed with water, then brine and dried. Evaporation of the solvent yielded 2-dimethylamino-5-nitro-benzoic acid (2.1 g, 91%), as a solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9]>C(O)C.C[O-].[Na+]>[N+:8]([CH2:11][C:4]1([OH:7])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1)([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCSCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCSCC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 42.7 %

Procedure:
Under a nitrogen atmosphere sodium methoxide (1.03 mL of 25 wt % in methanol, 4.51 mmol) was added dropwise to a solution of tetrahydro-4H-thiopyran-4-one (10.48 g, 90.20 mol) and nitromethane (7.33 mL, 135.3 mmol) in ethanol (6 mL). The reaction mixture was stirred at ambient temperature for 5 days and then concentrated under reduced pressure. The residue was partitioned between chloroform (400 mL) and water (60 mL). The aqueous was extracted with chloroform (5×100 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by HPFC eluting with a gradient of 3-35% ethyl acetate in hexanes to provide 10.23 g of 4-(nitromethyl)tetrahydro-2H-thiopyran-4-ol.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:32][O:33][C:34](=[O:39])[C:35]([NH2:38])([CH3:37])[CH3:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH3:32][O:33][C:34](=[O:39])[C:35]([NH:38][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:30])([CH3:37])[CH3:36]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)O)c(C)c2)cc1C)CC
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)NC(C)(C)C(=O)OC)c(C)c2)cc1C)CC
Yield: 77.4 %

Procedure:
4-{1-Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (437 mg, 1.07 mmol), α-aminoisobutyric acid methyl ester hydrochloride (247 mg, 1.61 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (309 mg, 1.61 mmol), 1-hydroxybenzotriazole hydrate (218 mg, 1.61 mmol) and triethylamine (597 μL, 4.28 mmol) are reacted and purified analogous to Example 1J to give the title compound (419 mg, 77%).
Reaction SMILES: CS[C:3]([N:10]1[CH2:14][CH:13]([CH2:15][CH3:16])[CH:12]=[N:11]1)=[N:4][CH2:5][C:6]([F:9])([F:8])[F:7].[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>C(#N)C>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([N:27]=[C:3]([N:10]2[CH2:14][CH:13]([CH2:15][CH3:16])[CH:12]=[N:11]2)[NH:4][CH2:5][C:6]([F:7])([F:8])[F:9])(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: CCC1C=NN(C(=NCC(F)(F)F)SC)C1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Solvent: CC#N
Product: CCC1C=NN(C(=NS(=O)(=O)c2cccc(Cl)c2)NCC(F)(F)F)C1
Yield: 0.1 %

Procedure:
0.57 g (1 mol equiv.) 4-Ethyl-N-(2,2,2-trifluoro-ethyl)-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 3.0 g (6.8 mol equiv.) 3-chloro-benzenesulfonamide were added to 20 mL acetonitrile. The reaction mixture was refluxed for 72 hours, and volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:PA=1:1) afforded 0.36 g (38%) 3-chloro-N-[(4-ethyl-4,5-dihydro-pyrazol-1-yl)-(2,2,2-trifluoro-ethylamino)-methylene]-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.00 (t, J=7.5 Hz, 3H), 1.51-1.74 (m, 2H), 3.16-3.27 (m, 1H), 3.87 (dd, J=11.2, 7.5 Hz, 1H), 4.03-4.14 (m, 2H), 4.28 (t, J=11.2 Hz, 1H), 7.03 (d, J=1.5 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.46-7.50 (m, 1H), 7.79-7.84 (m, 1H), 7.91-7.94 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36](N(CC)CC)[CH3:37]>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH:36]=[CH2:37])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCCO
Product: C=Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Yield: 84.5 %

Procedure:
N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.421 g, 0.781 mmol), potassium vinyl trifluoroborate (0.262 g, 1.953 mmol), PdCl2(dppf)2 (0.057 g, 0.078 mmol), and triethylamine (1.089 ml, 7.81 mmol) in n-propanol (7.81 ml) were heated at 100° C. in a screw-top vial overnight. The reaction mixture was filtered through celite and the celite rinsed with EtOAc. The combined organic portions were washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude mixture was placed on silica gel and chromatography (0 to 80% DCM/EtOAc, gradient) to obtain the title compound (350 mg, 84%). 1H NMR (400 MHz, DMSO-d6) d ppm 10.88 (s, 1H), 8.56 (d, J=5.31 Hz, 1H), 7.67 (ddd, J=14.28, 8.15, 6.13 Hz, 1H), 7.43 (t, J=7.60 Hz, 2H), 7.31 (t, J=7.69 Hz, 1H), 7.22 (t, J=9.25 Hz, 2H), 6.74 (m, 2H), 6.44 (dd, J=17.58, 1.65 Hz, 1H), 5.75 (dd, J=10.62, 2.01 Hz, 1H), 1.43 (m, 9H); MS (ESI): 531 [M+H]+.