Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[OH:21])[C:15]([OH:17])=[O:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>O1CCCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15]([OH:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2cc(C(=O)O)ccc2O)C=C(C(C)(C)C)C1=O
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2cc(C(=O)O)ccc2O)cc(C(C)(C)C)c1O
Yield: 63.6 %

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-4-hydroxybenzoic acid, 0.05 g of 5% palaldium on charcoal catalyst, 250 ml of ethanol and 50 ml of tetrahydrofuran was placed on a Paar apparatus. Hydrogen uptake was complete in about 10 minutes. The reaction mixture was filtered to remove catalyst. The filtrate was evaporated to give a tan solid which was recrystallized from a mixture of 40 ml of ethanol and 15 ml of water to give 3.2 g of reddish tan granular 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-4-hydroxybenzoic acid, m.p. 254.5°-255° C. (dec). Analysis: Calculated for C21H27NO4 : % C, 70.6; % H, 7.6; % N, 3.9; Found: % C, 71.0; % H, 7.6; % N, 4.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22](C2C=NC=CC=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:27]=3)[CH2:22][NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccc(-c3ccccc3)cc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-6-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared. The product was purified by LC 2000 chromatography, eluting with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:13]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]=2[NH2:1])=[O:15])=[CH:19][CH:18]=1
Reactant: Nc1c(C(=O)O)cnn1-c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Nc1c(C(=O)Nc2ccc(Cl)cc2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
A suspension of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (500 mg, 2.46 mmol) in thionyl chloride (2.0 mL) is stirred at room temperature for about 15 min before it becomes a clear solution. After removal of the solvent, the crude acid chloride is taken in anhydrous DCM (5.0 mL), and transferred dropwise to a solution of 4-chloroaniline (376.7 mg, 2.95 mmol) and TEA (1.03 mL, 7.38 mmol) in anhydrous DCM (5.0 mL) at 0° C. The reaction mixture is allowed to warm up to room temperature in an hour and lots of precipitate is generated. After filtration, the precipitate is washed with water, followed by small amount of DCM, and air-dried to provide crude 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (4-chloro-phenyl)-amide (506.2 mg, 66% yield) as a white solid product; HPLC-MS calculated for C16H13ClN4O (M+H+) 313.1. Found: 313.0.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14](C2CCCCC2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41][CH2:42][CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[C:32]1([CH2:41][CH2:42][CH:43]2[CH2:44][CH2:45][N:46]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:47][CH2:48]2)[C:31]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Reactant: c1ccc2cc(CCC3CCNCC3)ccc2c1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCc3cccc4ccccc34)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 4-(2-napthylethyl)piperidine (from EXAMPLE 162, Step C) using procedures analogous to those described in EXAMPLE 1, Steps J and K. For the title compound: 1H NMR (500 MHz, CD3OD) a 1.103.80 (m, 33H), 7.10-7.60 (m, 9H), 7.68 (d, J=7.7, 1H), 7.83 (d, J=8.0, 1H), 7.99 (d, J=8.5, 1H); ESI-MS 539 (M+H); HPLC A: 2.83 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1)(=[O:42])[CH3:41]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(O)cc4)cc3)c2cc1OC
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(OC(C)=O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
N-(4-Hydroxyphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (47 mg) was dissolved in methylene chloride (6 ml), after the addition of triethylamine (2 ml), acetic anhydride (0.5 ml) was added, and the admixture was stirred at room temperature for 15 hours. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 35 mg of the title compound (yield: 68%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]#[CH:23])=[N:11][CH:10]=1.[N+:35]([CH2:38][CH3:39])([O-])=[O:36].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(#N)C.C1(C)C=CC=CC=1>[F:30][C:29]([F:32])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]2[O:36][N:35]=[C:38]([CH3:39])[CH:23]=2)=[N:11][CH:10]=1
Reactant: C#Cc1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: CC[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(-c3ccccc3C)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.8 %

Procedure:
To a solution of 55 mg (0.12 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-ethynyl-N-methyl-4-o-tolyl-nicotinamide (Example 63), 0.026 ml (0.35 mmol) nitroethane and 1 mg (0.01 mmol) 4-N,N-dimethylaminopyridine in 0.5 ml acetonitrile a solution of 77 mg (0.35 mmol) di-tert-butyl dicarbonate in 0.1 ml toluene was added, and the mixture was stirred at room temperature over night. Another portion of 0.026 ml (0.35 mmol) nitroethane and 77 mg (0.35 mmol) di-tert-butyl dicarbonate were added, and stirring was continued for 24 h. Quenching with water was followed by extraction with two portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 21 mg (34%) of the title compound as a light yellow amorphous mass.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.[N+](C=C(SC)SC)([O-])=O.[N+:20]([CH:23]=[C:24](SC)[NH:25][CH2:26]CSCC1C=CON=1)([O-:22])=[O:21].CN>>[N+:20]([CH:23]=[C:24]([NH:25][CH3:26])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)([O-:22])=[O:21]
Reactant: NCCSCc1ccon1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccon1
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole (from the dihydrobromide (3.8 g)) with 1-nitro-2,2-bis-methylthioethylene (2.0 g) by the procedure of Example 4(i) and treatment of the resultant 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene with methylamine according to the procedure of Example 3(ii) gives 1-nitro-2-methylamino-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11]>CCO.CCOC(C)=O.[Pt]>[Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc(N)c1Cl

Procedure:
A mixture of 2-chloro-3-nitrotoluene (1.0 g, 5.8 mmol) and 5% platinum-on-carbon (0.1 g) in 25 ml of EtOH was reacted overnight at room temperature and 60 psi. The reaction mixture was filtered and the filtrate concentrated in vacuo to provide an oil. This oil was dissolved in EtOAc, washed with H2O, dried over Na2SO4, filtered and then concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].O[C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16]>>[CH3:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[C@H:5]1[NH:17][C:15](=[O:16])[CH:14]([CH3:18])[O:6]1
Reactant: C[C@H](O)C(N)=O
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1[C@H]1NC(=O)C(C)O1

Procedure:
prepared by reaction of 2,6-dimethoxybenzaldehyde with (S)-(−)-2-hydroxypropionamide; LC-MS: tR=0.45 min; [M+H]+=238.28.
Reaction SMILES: [O:1]=[C:2]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[S:25][C:26]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)[CH:30]=[CH:29][C:27]=3[N:28]=2)[CH2:20][CH2:19]1)[C@@H:3]([NH:10]C(=O)OC(C)(C)C)[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.Cl.Cl.C(OCC)C>O1CCOCC1>[NH2:10][C@@H:3]([CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[C:2]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[S:25][C:26]3[CH:32]=[C:31]([C:33]4[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=4)[CH:30]=[CH:29][C:27]=3[N:28]=2)[CH2:22][CH2:23]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(-c4ccc(C(F)(F)F)cc4)cc3s2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(-c4ccc(C(F)(F)F)cc4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The (S)-tert-butyl 1-oxo-3-(thiophen-2-yl)-1-(4-(6-(4-(trifluoromethyl)phenyl)benzo[d]thiazol-2-yl)piperazin-1-yl)propan-2-ylcarbamate (96 mg) was dissolved in dry 1,4-dioxane (3 mL) and then HCl (4N in 1,4-dioxane, 1 mL) was added. The resulting mixture was stirred at room temperature overnight, then concentrated and chromatographed (93.5:6:0.5 DCM:MeOH:NH4OH) to yield a clear oil, which was added to 1N HCl/diethyl ether. The resulting white precipitate was collected by filtration to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:3]=[CH:4][C:5]=1[F:15])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(Nc1cc(Br)ccc1F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Temperature: 60 °C
Yield: 84.3 %

Procedure:
To an oven-dried flask under N2 was added N-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroacetamide (750 mg, 2.62 mmol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (230 mg, 0.33 mmol), copper(I) iodide (38 mg, 0.20 mmol), and trimethylsilylacetylene (640 mg, 6.53 mmol). Next, triethylamine (2.64 g, 26 mmol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.67 g, 84%) as an off white solid. ESIMS (M−H)−=302.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:15])[NH:12]C(=O)N[C:9]2=[O:14])=[CH:4][CH:3]=1.[OH-:16].[Na+].Cl>O>[NH2:12][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:15])[C:9]([OH:16])=[O:14]
Reactant: CC1(c2ccc(Br)cc2)NC(=O)NC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(N)(C(=O)O)c1ccc(Br)cc1
Temperature: 145 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of 5-(4-bromo-phenyl)-5-methyl-imidazolidine-2,4-dione (4.0 g, 14.9 mmol) and 3 N NaOH (50 mL) was heated in a sealed tube at 145° C. for two days, then diluted with water (100 mL) The solution was adjusted to pH=4 with 6 N HCl carefully and subsequently stirred at room temperature for 2 hours. The precipitate was filtered off, washed with water. The collected white solid was dried under vacuum to give the product (2.5 g, 65%). m/z 243.7, 245.7 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:21][N:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]2[C:29]3[C:12]1=[N:13][NH:14][C:15]=3[N:16]=[C:17](SC)[N:18]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=O)C=1.ClCCl.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50][NH2:51]>CS(C)=O>[CH2:1]([NH:8][C:9]([CH:11]1[C:12]2[C:29]3[C:15]([NH:14][N:13]=2)=[N:16][C:17]([NH:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46])=[N:18][C:19]=3[N:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc2c3c(n[nH]c3n1)C(C(=O)NCc1ccccc1)CN2Cc1ccccc1
Reactant: CN(C)CCCN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)CCCNc1nc2c3c(n[nH]c3n1)C(C(=O)NCc1ccccc1)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,5-dibenzyl-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene-3carboxamide (0.065 g, 0.15 mmol), 3-chloroperbenzoic acid (0.057 g, 0.33 mmol), and dichloromethane (3 mL) were placed in a screw top 2-dram vial and shaken at room temperature for 4 hours. The reactions were quenched by addition of sat NaHCO3 (2 mL). The layers were separated and the organic layers was washed with water (2×3 mL). The organic layer was concentrated under reduced pressure in Genevac centrifugal evaporation system. To the vials containing sulfone were placed N1,N1-dimethylpropane-1,3-diamine (0.45 mmol) and DMSO (1 mL). The vials were capped and shaken at 120° C. for 10 hours. The crude product was purified using reverse phase column chromatography using a Maccel AQ C18 column and a gradient of 1-95% ACN/water containing 0.05% trifluoroacetic acied, to yield the desired products in acceptable purities by LC/MS. LC-Mass: m/e 485 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)=[O:4].[CH3:14][C:15]([CH3:18])([NH2:17])[CH3:16]>CC(O)C>[Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:10]=[N:17][C:15]([CH3:18])([CH3:16])[CH3:14])[CH:12]=1)=[O:4]
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(C(=O)CBr)ccc1O
Solvent: CC(C)O
Product: CC(C)(C)N=Cc1cc(C(=O)CBr)ccc1O
Temperature: -3 °C

Procedure:
5-(Bromoacetyl)-2-hydroxybenzaldehyde (109g) is suspended in 2-propanol (920ml) and cooled to -3° C. with stirring. The reaction mixture is treated with 1,1dimethylethanamine (29.24g) and stirred at -3° C. to 0° C. for 30 minutes whereupon precipitation occurs. The reaction mixture is allowed to warm to room temperature, stirred for 90 minutes then cooled to 10° C. and filtered. The solid obtained is washed with ice cold 2-propanol (2×100ml) and dried in vacuo at 55° C for 18 hours providing 89g of 2-bromo-1-[3-[[(1,1-dimethylethyl)imino]methyl]-4-hydroxyphenyl]ethanone.
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=C(C2N(C(C)C)N=NN=2)C(OCC)=O)=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[C:38]([C:44]2[N:45]=[N:46][N:47]([CH:49]([CH3:51])[CH3:50])[N:48]=2)[C:39](OCC)=[O:40])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[C:38]([C:44]2[N:45]=[N:46][N:47]([CH:49]([CH3:51])[CH3:50])[N:48]=2)[CH:39]=[O:40])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)C)n1
Agent: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C(C)C
Product: CC(C)n1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 88 %

Procedure:
The general procedure of Example 21, Steps A, B, C, and D were repeated, except that the ethyl 3,3-bis(4-flurophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoate utilized therein was replaced by ethyl 3,3-bis(4-fluorophenyl)-2-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2-propenoate and there was thereby produced in 88% yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]1([CH2:37][CH2:38][CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3]1[N:4]([CH2:39][CH2:38][CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:5]([CH3:24])[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1
Reactant: BrCCCc1ccccc1
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)=C(C(=O)OC(C)C)C(C)N1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.7 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (4.0 g, 12.0 mmol) in dry dimethylformamide (10 ml) under argon was treated with finely ground potassium carbonate (4.97 g, 36.0 mmoles), 3-phenylpropyl bromide (2.19 ml, 14.4 mmoles) and a catalytic amount of 18-crown-6. The resulting suspension was allowed to stir at room temperature for 72 hours, diluted with ether, filtered and the filtrate washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by flash chromatography (10-15% ethyl acetate in hexanes) to provide the desired product (3.29 g) as a yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][NH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1.C(N(CC)CC)C>ClCCCl>[CH3:15][N:16]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1nccs1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc(S(=O)(=O)N(C)c2nccs2)cc1
Temperature: 100 °C
Yield: 79.2 %

Procedure:
To methyl 4-chlorosulfonylbenzoate (4 g, 17.05 mmol), N-methylthiazol-2-amine (1.95 g, 17.05 mmol), 1,2-dichloroethane (20 mL), and triethylamine (2.38 mL, 17.05 mmol) were added and the reaction was heated at 100° C. in a pressure vessel for 20.5 hours on a heat block. The solvent was evaporated under reduced pressure. The crude compound was dissolved in dichloromethane and filtered. The filtrate was purified by silica gel chromatography utilizing a gradient of 0-30% ethyl acetate in dichloromethane to yield methyl 4-[methyl(thiazol-2-yl)sulfamoyl]benzoate (4.22 g, 79.2%). 1H NMR (400 MHz, DMSO) δ 8.16 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 3.89 (s, 3H), 3.39 (s, 3H). ESI-MS m/z calc. 312.0, found 313.3 (M+1)+; Retention time: 1.52 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (4.00 g; 17.4 mmol) is dissolved in methylene chloride (125 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (6.36 g; 20.9 mmol), diisopropylethylamine (7.27 g; 55.8 mmol), and PyBOP (10.89 g; 20.9 mmol) are added sequentially. The mixture is stirred for 14 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7](=[O:17])[CH:6]=[CH:5]2.[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:17]=[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)[N:8]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cn1c(=O)ccc2cc(Br)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(=O)ccc2cc(C#C[Si](C)(C)C)ccc21
Temperature: 80 °C

Procedure:
Methyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate (0.67 mmol), CuI (0.67 mmol) and PdCl2(PPh3)2 (0.40 mmol) were dissolved in triethylamine (3 mL) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 5 minutes. Ethynyltrimethylsilane (3.5 mmol) was added to the reaction mixture and the tube was sealed and placed into an oil bath pre-heated to 80° C. for 8 h. The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min)=2.759, method [1], MS(ESI) 314.1 (M+H).