Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[C:5]([CH3:16])([CH3:15])[C:4]1=[O:17])[CH3:2]>CO.O1CCCC1>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:15])([CH3:16])[C:4](=[O:17])[N:3]2[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCN1C(=O)C(C)(C)c2ccc([N+](=O)[O-])cc21
Solvent: C1CCOC1
Solvent: CO
Product: CCN1C(=O)C(C)(C)c2ccc(N)cc21

Procedure:
To a solution of 1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (5.9 g, 25.19 mmol) in methanol/tetrahydrofuran (THF) palladium on charcoal (10%) was added and the mixture hydrogenated at room temperature. After filtration and evaporation of the solvents 5.05 g (98%) 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one was isolated as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][CH2:34][CH2:35][OH:36]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:33]([CH2:34][CH2:35][OH:36])[CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[O:25])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCNCc1ccccn1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][NH2:12])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:13][N:14]1[CH:19]=[C:18]([CH2:20]Cl)[C:17]([C:22](OC)=[O:23])=[C:16]([Cl:26])[C:15]1=[O:27]>CC#N>[Cl:26][C:16]1[C:15](=[O:27])[N:14]([CH3:13])[CH:19]=[C:18]2[CH2:20][N:12]([CH2:11][CH2:10][C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)[C:22](=[O:23])[C:17]=12
Reactant: COC(=O)c1c(CCl)cn(C)c(=O)c1Cl
Reactant: NCCc1cn2ccccc2n1
Solvent: CC#N
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1cn3ccccc3n1)C2
Temperature: 100 °C
Yield: 48 %

Procedure:
TEA (5 ml, 36 mmol) was added to a suspension of 2-(imidazo[1,2-a]pyridine-2-yl)ethanamine (1.934 g, 12 mmol) and 1-methyl-2-oxo-1,2-dihydro-3-chloro-4-methoxycarbonyl-5-chloromethyl-pyridine (3 g, 12 mmol, see compound (6) of Example b1)) in MeCN (5 ml). The reaction was heated in a CEM microwave at about 100° C. for about 40 min. The solvent was removed and the resulting mixture was deposited onto silica gel, loaded onto a silica gel column and eluted with DCM/MeOH (50:1) to give 2.9 g of crude product. The crude product was washed with water, dried to afford the title compound (2 g, 5.76 mmol, 48.1% yield).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH:25]1([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26]1.O>CN1C(=O)CCC1>[CH:25]1([CH2:29][NH:30][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: NCC1CCC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCC3CCC3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.5 g, 1.314 mmol) and (cyclobutylmethyl)amine (0.24 g) in NMP (5 ml) was stirred at ambient temperature for 18 h. Water (50 ml) was then added, and the resulting precipitate was collected by filtration and dried, giving the title compound as a cream solid (0.434 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH2:34]O)[CH:12]=2)[N:7]=1>ClCCl>[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH2:34][Cl:3])[CH:12]=2)[N:7]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CO)ccc2n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CCl)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
218 μl of thionyl chloride are added dropwise to 622 mg of [2-amino-6-(2-hydroxymethyl-5-fluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 50 ml of dichloromethane, and the mixture is stirred at 25° C. for 2 h. The mixture is evaporated to dryness in vacuo, the residue is taken up in 10 ml of toluene, and the operation is repeated. The residue is employed in the subsequent reactions without further treatment.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:33][N:32]=4)=[O:24])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(F)cn1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cn1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Yield: 502.6 %

Procedure:
Stir mixture of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid (0.767 g, 0.0.21 m mol), C-(5-fluoro-pyridin-2yl)-methylamine (0.041 g, 0.25 mmol), and EDC (0.063 g, 0.33 mmol) in dry CH2Cl2 (15 mL) under N2 and add DMAP (0.061 g, 0.50 mmol.). Stir the resulting mixture at ambient temperature for 72 h Dilute the reaction mixture to 50 mL with CH2Cl2, wash with H2O, 1N NaOH, and brine sequentially. Dry the organic layer (MgSO4), filter and evaporate to give 0.189 g of crude product. Chromatograph on the ISCO using a 12 g column and eluting with Hexane-EtOAc (0-100%) to gives the title compound 0.60 g as a foam:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22](Cl)=[O:23]>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:23]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 88.1 %

Procedure:
To a solution of 4-fluoro-3-nitro-phenylamine (3.0 g, 20 mmol) in dichloromethane (60 mL) was added pyridine (3.2 g, 40.0 mmol). The solution was cooled to 0° C. and 3,5-dichlorobenzoyl chloride (4.0 g, 20.0 mmol) was added. The ice bath was removed and the reaction was allowed to warm to room temperature over 18 h. The reaction was poured into water and a precipitate formed. The solid was collected and washed with excess water. This solid was than dried under vacuum at 50° C. for 18h. This solid was taken up in ethyl acetate. The ethyl acetate was washed with 5% HCl, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (5.8 g, 92%).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:25]3[CH2:27][CH2:26]3)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: OB(O)C1CC1
Reactant: CC(C)(CO)NC(=O)c1nn(-c2ccc(Br)cn2)c2c1C[C@@H]1C[C@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(C3CC3)cn2)c2c1C[C@@H]1C[C@H]21
Temperature: 100 °C
Yield: 28.4 %

Procedure:
To a mixture of (1aS,5aS)-2-(5-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.020 g, 0.051 mmol), cyclopropylboronic acid (6.59 mg, 0.077 mmol) and potassium phosphate (0.033 g, 0.153 mmol) in toluene/H2O (1.5 mL/0.050 mL) under nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (5.91 mg, 5.11 μmol) was added. The reaction was heated at 100° C. for 30 min in a heavy walled sealed tube under microwave irradiation. Additional cyclopropylboronic acid (6.59 mg, 0.077 mmol) was added and the reaction was heated at 100° C. for 2 more hours. The mixture was purified by HPLC to give the titled compound (5.1 mg) as a white solid. LCMS m/z=353.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19]1(C)[CH:24]=CC=[CH:21][CH:20]=1.CC(O)C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:15]([C:12]([CH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])([CH2:24][CH:19]=[CH:20][CH3:21])[CH:13]=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(C=O)CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccccc1
Agent: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC=CCC(C=O)(CCCC)CS(=O)(=O)c1ccc(C)cc1

Procedure:
Advantageously, the conversion of 18a to 47 and the conversion of 47 to 31 can be carried out sequentially or simultaneously in a single reaction vessel or in a single reaction mixture without isolation. To further advantage, the preparation of the acetal 18 from aldehyde 19, the conversion of 18 to the corresponding enol ether intermediate, and the conversion of the enol ether intermediate to 31 can all be carried out in a single reaction vessel or reaction mixture. For example, 2-(((4-methylphenyl)sulfonyl)methyl)hexanal can be heated in a solvent such as toluene in the presence of 3-buten-2-ol and p-toluenesulfonic acid with removal of water (e.g., with a Dean-Stark trap) to produce 2-butyl-2-(((4-methylphenyl)sulfonyl)methyl)hex-4-enal.
Reaction SMILES: [I-].C[N+]1(C)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>O.CO>[C:11]([N:15]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C[N+]1(C)CCC(=O)CC1
Reactant: CC(C)(C)N
Agent: [I-]
Solvent: O
Solvent: CO
Product: CC(C)(C)N1CCC(=O)CC1
Yield: 4.6 %

Procedure:
A suspension of 64.5 g (253 mmol) of 1,1-dimethyl-4-oxo-piperidinium iodide in 50 mL of water and 90 mL (860 mmol) of tert-butylamine was stirred for 15 min when 1.0 mL of 40% Triton B in MeOH was added. The mixture was refluxed for 2 hr under N2, and then it was extracted with Et2O (4×100 mL). The aqueous phase was basified with 20 g of NaOH in 20 mL of water, and then it was extracted further with Et2O (4×100 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residual oil was shaken with 1.5 L of petroleum ether, which was decanted and concentrated. The residue was distilled under vacuum to provide 1.8 g of 1-tert-butyl-piperid-4-one.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([SH:10])=[CH:5][C:3]=1[NH2:4].[C:11](=O)([O-])[O-].[K+].[K+].IC>O>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10][CH3:11])=[CH:5][C:3]=1[NH2:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)c(N)cc1S
Agent: [K+]
Solvent: O
Solvent: CI
Product: CSc1cc(N)c(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
9.2 g of 2-fluoro-4-methyl-5-mercaptoaniline disclosed in WO2006/043635 was dissolved in 70 mL of water, and 9.7 g of potassium carbonate and 8.3 g of iodomethane were added under cooling with ice, followed by stirring at room temperature for 2 hours. The formed crystals were collected by filtration and washed with water to obtain 10.0 g of 2-fluoro-4-methyl-5-methylthioaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[N:45][CH:44]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:42](=[O:49])[C:43]5[CH:48]=[CH:47][CH:46]=[N:45][CH:44]=5)[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N(C(=O)c1cccnc1)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 29.4 %

Procedure:
The title compound was prepared according to the procedure as described in Example 3 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol), triethylamine (228 μL, 1.6 mmol) and nicotinoyl chloride hydrochloride (146 mg, 0.2 mmol) in CHCl3 (10 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (35 mg, 28.9%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=1)[C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[CH3:15][C:4]1[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][N:38]=[C:30]([F:29])[CH:31]=2)[S:19][CH:20]=1
Reactant: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(N)n1
Reactant: O=C(O)c1ccnc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccnc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-amine (11-5, 200 mg, 0.60 mmol) in CH2Cl2 (2.0 mL) was added triethylamine (0.20 mL, 1.9 mmol) followed by 2-fluoroisonicotinic acid (107.7 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243.9 mg, 1.27 mmol) and hydroxybenzotriazole (172.0 mg, 1.27 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give N-{4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-yl}-2-fluoroisonicotinamide (19, 68.4 mg) as yellow solids in 25% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1 H), 8.47-8.50 (m, 2 H), 8.36-8.41 (m, 2 H), 7.96 (s, 1 H), 7.80 (s, 1 H), 7.41 (s, 2 H), 7.33 (s, 1 H), 2.13 (s, 6 H); ESI-MS: m/z 438.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1C.[Cl:22][C:23]([Cl:33])=[CH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[CH:24]=[C:23]([Cl:22])[Cl:33])=[O:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1C=C(Cl)Cl
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Solvent: Cc1ccccn1
Solvent: Cc1ccccc1
Product: CC(C)C(C(=O)OCc1ccccc1C=C(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
2.8 g (0.012 mole) of 2-(4-chlorophenyl)-isovaleryl chloride in 50 ml of absolute toluene are introduced into 1.2 g (0.013 mole) of -picoline and 3.2 g (0.015 mole) of 2-(2,2-dichlorovinyl)-benzaldehyde in a conical flask at room temperature, while stirring. After 30 minutes, the mixture is filtered under suction over silica gel, and washing is carried out with toluene.
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][OH:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].Cl.C(O[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=N)C.C(N(CC)CC)C>O>[CH3:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C@H:3]2[O:4][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:1][C@@H:2]2[CH2:15][OH:16])=[CH:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: CCOC(=N)c1ccccc1
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1

Procedure:
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) (about 10 g, 0.04077 moles) is reacted at about 0° C. in a reaction vessel with 2,2-dichloro-ethanimidic acid ethyl ester hydrochloride (Compound IV hydrochloride wherein R2 is dichloromethyl and R4 is ethyl) (about 8.6 g, 0.0448 moles) in 1,2-dichloromethane (about 250 mL) containing triethylamine (about 4.1 g, 0.04077 moles). Next, water (about 125 mL) is added. The resulting solids are filtered, then dried to yield (4R,5R)-2-(Dichloromethyl)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is dichloromethyl).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]1([NH:13][NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:7]1([NH:13][N:14]=[C:15]([Cl:2])[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSc1ccc(C(=O)NNc2ccccc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(C(Cl)=NNc2ccccc2)cc1
Yield: 44.9 %

Procedure:
A mixture consisting of 14.2 g. (0.068 mole) phosphorus pentachloride, 100 ml. carbon tetrachloride, and 16.78 g. (0.065 mole) p-(methylthio)benzoic acid 2-phenylhydrazide (prepared in Part A above) was reacted at 25°C. until evolution of gas ceased. The reaction mixture was then heated to the reflux temperature and a clear solution resulted. The solution was chilled in ice and a suspension of 20.7 g. (0.22 mole) phenol in 50 ml. carbon tetrachloride was added. After removing the carbon tetrachloride by evaporation on a rotary evaporator at 31°C. the resulting suspension of product in triphenylphosphate was filtered. The filter cake was washed with technical hexane ((Skellysolve B, a mixture of isomeric hexanes having a boiling range between 146° and 156° Fahrenheit), and then was washed with diethyl ether. Crystallization from 75 ml. ethyl acetate gave 8.10 g. (44.9% yield) of p-(methylthio)-benzoyl chloride phenylhydrazone having a melting point of 138.5° to 142.5°C. Recrystallization from a mixture of ethyl acetate and the Skellysolve B gave the compound with the same melting point.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9]O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[Na].C([O:24]S([O-])(=O)=O)CCCCCCCCCCC.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O>[CH3:9][CH:8]([OH:24])[CH2:7][O:6][C:1]([C:2]([CH3:4])=[CH2:3])=[O:5]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: C=C(C)C(=O)OCCCO
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Product: C=C(C)C(=O)OCC(C)O
Reaction time: 12 h

Procedure:
A 150 mL media bottle equipped with a stir bar was charged with 2.532 g (17.5 mmol) of hydroxypropyl methacrylate (HPMA) monomer, 52.73 mg (0.266 mmol) of ethylene glycol dimethacrylate(EGDM) crosslinker, 107.6 mg (0.3730 mmol) sodium-dodecylsulfate (SDS), and 118 mL of nitrogen degassed Milli-Q H2O. The bottle was closed and stirred to form a clear solution. In a separate vial, 83 mg of K2S2O8 was dissolved into 2 mL of Milli-Q H2O and added to the media bottle while stirring. The media bottle with clear solution was transferred into a 40° C. water bath and held at constant temperature for 12 hours. The resulting suspension of hydrogel nanoparticles had an opalescent blue color. The particles were analyzed by laser light scattering and found to have an average particle size of 21.3 nm and a size range from 14 nm to 41 nm. The suspension had approximately 1% solid polymer by mass. To date, the suspension of hydrogel nanoparticles resisted flocculation or aggregation for two years at room temperature.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4]([NH:7][C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][O:10][C:11](=[O:13])[CH3:12])=[N:3]1.[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[C:22]([CH:29]=O)=[CH:21]1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:6](=[CH:29][C:22]2[C:23]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:20][CH:21]=2)[S:5][C:4]([NH:7][C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][O:10][C:11](=[O:13])[CH3:12])=[N:3]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(=O)OC[C@H](NC1=NC(=O)CS1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)OC[C@H](NC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1)c1ccccc1
Temperature: 150 °C
Yield: 145.3 %

Procedure:
To a suspension of acetic acid 2-[4-oxo-4,5-dihydro-thiazol-2-ylamino]-2-(R)-phenyl-ethyl ester (400 mg, 1.43 mmol) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (77.3 mg, 0.53 mmol) in toluene (5 mL) in a microwave tube was added benzoic acid (17.64 mg, 0.144 mmol) and piperidine (14.5 uL, 0.144 mmol) at room temperature. The microwave tube was sealed and heated to 150° C. in a closed microwave for 1 h. Then, the mixture was cooled to room temperature and diluted with toluene. The solids were collected by filtration and washed with toluene and dichloromethane. After drying in air, 313 mg (53.6% yield) of acetic acid 2-[4-oxo-5-(1H-pyrrolo[2,3,b]pyridine-3-ylmethylene)-4,5-dihydro-thiazol-2-ylamino]-2-(R)-phenyl-ethyl ester was isolated as a white solid: mp 243.7-246.8° C.; HRES(+) m/e calcd for C21H18N4O3S (M+H)+ 407.1173. found 407.1172.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:31][CH2:30][N:11]2[C:12](=[O:29])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][C:14]=3[C:25]([F:28])([F:27])[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:31][CH2:30][N:11]2[C:12](=[O:29])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=3[C:25]([F:27])([F:28])[F:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(C#C[Si](C)(C)C)cc3C(F)(F)F)[C@@H]2C1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 0.08 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-trimethylsilylethynyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one, prepared according to procedures described in Example 29 with substitution of tributyl(trimethylsilylethynyl)tin for 2-(tributylstannyl)furan (44 mg, 0.1 mmol in MeOH (1.0 mL) was added potassium carbonate (13 mg, 0.1 mmol). The reaction was stirred for 5 min and then quenched with brine. The reaction was extracted with EtOAc (2×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a pale yellow oil. The oil was purified by radial chromatography (silica gel, 30% EtOAc in hexanes) to give 27 mg of the desired-product as a pale yellow oil. MS (ESI) 381 (M+H).