Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O:3][CH2:4][CH3:5].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9](S(O)(=O)=O)=[CH:8][CH:7]=1>CO>[CH2:9]([C:10]([CH2:11][CH2:6][CH3:16])=[CH:9][CH2:8][CH2:7]/[CH:16]=[CH:6]/[CH2:7][CH2:8][CH2:5][CH2:4][OH:3])[CH2:10][CH3:11]
Reactant: CCOCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCC(=CCC/C=C/CCCCO)CCC

Procedure:
0.6 g of diethyl 6-propyl-2,5-nonadienylphosphonate was dissolved in 10 ml. of tetrahydofuran, and an equivalent amount of n-butyl lithium was added at -60° C. in an atmosphere of argon. To this solution was further added 0.56g of 4-butyl iodide-1-tetrahydropyranyl ether. The temperature of the reaction system was gradually elevated to room temperature. The reaction mixture was poured into ice water, and extracted with ether. Concentration of the solvent gave a pale yellow viscous oily substance. The oily product was dissolved in 20 ml. of ether, and reduced with 0.2 g of lithium aluminum hydride to afford 0.5g of 10-propyl-trans-5,9-tridecadiene-1-tetrahydropyranyl ether in a yield of 80%. This ether was treated with a catalytic amount of p-toluenesulfonic acid in methanol to split off the protective group. Thus, there was obtained pure 10-propyl-trans-5,9-tridecadienol in a quantitative yield. The properties of this product were as follows:
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([S:12]SC#N)#[N:11]>>[C:1]1([CH:7]([S:12][C:10]#[N:11])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: N#CSSC#N
Product: N#CSC(C=O)c1ccccc1

Procedure:
In synthesis of 5-phenylthiazole derivatives, the intermediate α-bromo-α-phenylacetaldehyde is first synthesized by allowing phenylacetaldehyde to react with bromine according to the method as disclosed in Helv. Chim. Acta. Vol. 30, pp.2058 (1945). As the next step, according to the method disclosed in J. Amer. Chem. Soc. Vol. 71, pp.4007 (1949), α-bromo-α-phenylacetaldehyde is allowed to react respectively with thioformaldehyde, thioacetamide, thiourea and ethylthiocarbamate at room temperature in methanol as a reaction solvent to obtain 5-phenylthiazole (m.p. 45°-46° C.), 2-methyl-5-phenylthiazole (m.p. 74°-76° C.), 2-amino-5-phenylthiazole (m.p. 206°-208° C.) and 2-hydroxy-5-phenylthiazole (m.p. 202°-204° C.). On the other hand, according to the method as described in U.S. Pat. No. 2,603,646 (1952), phenylacetaldehyde is allowed to react with thiocyanogen to obtain α-phenyl-α-thiocyanoacetaldehyde, which is then allowed to react with ammonium dithiocarbamate in the presence of an acid catalyst such as dilute sulfuric acid to obtain 2-mercapto-5-phenylthiazole (m.p. 207°-209° C.).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:11]=[C:10]([CH2:12][O:13][N:14]=[C:15]([C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:8][CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.O.CCOC(C)=O>[CH3:27][N:26]1[C:22]([C:15](=[N:14][O:13][CH2:12][C:10]2[N:11]=[C:6]([CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:23][N:24]=[N:25]1
Reactant: Cn1nnnc1C(=NOCc1cccc(C2OCCO2)n1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nnnc1C(=NOCc1cccc(C=O)n1)c1ccccc1
Temperature: 100 °C
Yield: 106.9 %

Procedure:
To a solution of N-{[6-(1,3-dioxolan-2-yl)pyridin-2-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (3.3 g, 9 mmol, 1 eq.) in 75 ml of DMSO and 15 ml of water was added p-TSA (1.79 g, 9.45 mmol, 1.05 eq.). The reaction was heated to 100° C. for 1.5 hrs. After cooling to room temperature, the mixture was diluted with 400 ml of EtOAc, washed with sat. aqueous NaHCO3, followed by water (×2). The organic layer was separated, dried over MgSO4 and concentrated to give 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridine-2-carbaldehyde (3.1 g, 96% yield) as a viscous yellow oil.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.[N:8]1([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]2[C:40]3[C:47]4[CH2:48][CH2:49][NH:50][CH2:51][C:46]=4[S:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH:34]=[CH:35][C:36]=1[Cl:37].CCN=C=NCCCN(C)C>C(Cl)Cl.O>[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]2[C:40]3[C:47]4[CH2:48][CH2:49][N:50]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:11]5[CH2:10][CH2:9][N:8]([C:14]([N:16]6[CH2:17][CH2:18][CH2:19][CH2:20]6)=[O:15])[CH2:13][CH2:12]5)[CH2:51][C:46]=4[S:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Reactant: O=C(O)/C=C/CBr
Reactant: O=C(N1CCCC1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/CN1CCN(C(=O)N2CCCC2)CC1)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.7 %

Procedure:
(2E)-4-Bromobut-2-enoic acid (106 mg, 0.64 mmol) and piperazin-1-yl(pyrrolidin-1-yl)methanone (125 mg, 0.68 mmol) were dissolved in DCM (5.0 mL), and DIPEA (111 mg, 0.85 mmol) was added. The mixture was stirred at rt for 2 h. Subsequently, the compound from Example 15A (150 mg, 0.43 mmol), DIPEA (55 mg, 0.43 mmol) and EDCI (82 mg, 0.43 mmol) were added. The reaction was stirred at 50° C. overnight. Then, water was added, and the mixture was extracted three times with DCM. The combined organic layers were dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to yield 25 mg (10%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O:15][C:16]1[C:17](=O)[C:18](=O)[C:19]=1[O:20]CCCC)CCC.[NH3:27]>C(O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]2[C:19](=[O:20])[C:16](=[O:15])[C:17]=2[NH2:27])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: N
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CC(=O)c1ccc(Nc2c(N)c(=O)c2=O)cc1
Yield: 52.1 %

Procedure:
Ex-102A: To a solution of 2.7 g (20 mmol) of 4′-aminoacetophenone in 90 mL of ethanol, 4.5 g (20 mmol) of 3,4-dibutoxy-3-cyclobutene-1,2-dione (Aldrich) was added. The mixture was then heated to reflux overnight. A light yellow precipitate formed. To the reaction mixture, 20 mL (40 mmol) of ammonia (2.0 M in ethanol) was added, and the resultant mixture was stirred at room temperature for 2 hr. The light yellow solid was filtered and washed with ethanol to give 2.4 g (52%) of 3-(4-acetyl-phenylamino)-4-amino-cyclobut-3-ene-1,2-dione. 1H-NMR (DMSO-d6) δ 9.99 (br, 1H), 7.90 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H), 4.31 (br, 2H), 2.48 (s, 3H). HMRS (EI) calcd. for C12H10N2O3: 230.0691; found: 230.0691.
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:17]C)=[CH:5][CH:4]=1.C1C=CC2C(=O)C3C(=C(O)C=CC=3O)C(=O)C=2C=1.[BH4-].[Na+]>COCCOCCOC.CO>[C:3]1(=[O:2])[C:16]2[C:7](=[CH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6](=[O:17])[CH:5]=[CH:4]1
Reactant: COc1ccc(OC)c2cc3ccccc3cc12
Agent: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOCCOC
Product: O=C1C=CC(=O)c2cc3ccccc3cc21
Yield: 95 %

Procedure:
Although the preparation of 1,4-dimethoxyanthracene (1) has been reported (Criswell, et al., J. Org. Chem. 1974, 39, 770-774) by using methylation of quinizarin (3) followed by sequential reduction of the diketo function with sodium borohydride in diglyme, the difficulty in the reduction steps prompted us to investigate an easier method in the preparation of 1. Reduction of 3 with sodium borohydride in MeOH followed by quenching with HCl gave a 95% yield of 1,4-anthraquinone (4) (Scheme 2). Reduction of the quinone moiety of 4 with aqueous sodium hydrosulfite in 1,4-dioxane provided 1,4-dihydroxyanthracene (5). Methylation of 5 with sodium hydride in DMF at room temperature gave excellent yield of 1.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[C:27]5[CH3:33])=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:34][CH3:35])[CH2:7][CH2:6]1)=[O:4].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.[I-].[K+]>CN(C=O)C>[CH3:35][O:34][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:6][CH2:7]1)[N:20]=[CH:19][N:18]=[C:17]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH3:33]
Reactant: C1CCNC1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)CCl)CC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)CN2CCCC2)CC1
Temperature: 80 °C

Procedure:
A mixture of 7-{[1-(chloroacetyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline (0.118 g), pyrrolidine (0.059 ml), potassium iodide (0.01 g) and DMF (3 ml) was stirred and heated to 80° C. for 40 minutes. The mixture was cooled to ambient temperature, the solvent was removed by evaporation under vacuum and the residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with dichloromethane and ending dichloromethane/methanol saturated with ammonia (3.5M) (94/6). Evaporation of the solvents gave a foam which was triturated under ether/pentane (70/30) to give a solid which was collected by filtration and dried under vacuum to give 6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]methoxy}quinazoline (0.096 g).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:7])[NH:5][CH:6]=1.CCN(C(C)C)C(C)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CN(C1C=CN=CC=1)C>[I:1][C:2]1[N:3]=[C:4]([CH3:7])[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1nc(I)c[nH]1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1cc(I)nc1C
Temperature: 0 °C
Yield: 94.3 %

Procedure:
In general, modifications were made from the procedure given in J. Org. Chem., 1999, 64, 23, 8608-8615. A solution of commercially available 4-iodo-2-methyl-1H-imidazole (520 mg, 2.5 mmol) in THF (8.3 mL), containing DIEA (1.07 mL, 6.25 mmol) and DMAP (150 mg, 1.30 mmol), was cooled in a ice bath at 0° C. A solution of ethyl chloroformate (678 mg, 6.25 mmol) in THF (2.5 mL) was slowly added over a period of 20 min to the reaction mixture. The reaction mixture was heated at 50° C. for 48 h and the solvent was removed under reduced pressure. The residue was dissolved in DCM and the organic layer was washed with brine, water, dried over MgSO4, filtered and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH: 97/3 as eluent) to afford 660 mg of ethyl 4-iodo-2-methyl-1H-imidazole-1-carboxylate (Yield: 94%) as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OC(C)(C)C)=O)[CH2:8][C@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 1.5 h

Procedure:
Preparation (3R, 3aR, 6S, 6aS)-tert-Butyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)carboxylate (35). Ethanol (20 mL) was added dropwise to a mixture of 10% palladium on charcoal (50 mg) and anti-(33) (578 mg, 1.33 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1.5 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol then the solvents removed in vacuo from the filtrate to obtain (3R, 3aR, 6S, 6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate which was used without further purification.
Reaction SMILES: O.[SH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.O.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19](CBr)=[CH:18][CH:17]=1.[CH3:26]N(C=O)C>>[F:25][C:14]([F:13])([F:24])[O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:22][CH:23]=1)[CH2:26][S:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: CN(C)C=O
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: O
Product: FC(F)(F)Oc1cccc(CSc2ncnc3nc[nH]c23)c1

Procedure:
After stirring a mixture of 30 mmol of 6-mercaptopurine monohydrate (5.12 g) and 30 mmol of water-free K2CO3 (4.12 g) in 25 mL of dry DMF for 5 minutes, 30 mmol of 4-trifluormethoxybenzylbromide (6.48 g) was added. After stirring for 4 h, 200 mL of H2O was added. The obtained solid was filtered and washed with EtOAc and CH2Cl2, followed by drying under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([Cl:23])[CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+]>>[Cl:23][C:4]1[CH:3]=[C:2]([NH:1][CH3:24])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]1
Reactant: C[C@H]1CN(Cc2ccc(N)cc2Cl)CCN1C(=O)OC(C)(C)C
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(Cl)c1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(4-amino-2-chlorophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D104) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. overnight prior to, and for 24 h after addition of sodium borohydride. (3 eq.). MS (ES): MH+ 354/356.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([Br:11])[CH:7]=[C:8]([CH3:10])[CH3:9]>>[Br-:11].[CH3:9][C:8]([CH3:10])=[CH:7][CH2:6][S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)=CCBr
Reactant: C1CCSC1
Product: CC(C)=CC[S+]1CCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of prenyl bromide (2.9 g in 10 mL dry tetrahydrofuran) at 0° C. was added 1.8 mL tetrahydrothiophene and the mixture allowed to warm to room temperature. After 22 hours, the mixture was concentrated in vacuo and the remaining starting materials removed by azeotrope with toluene to give the crude title compound as a white solid (2.2 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[CH3:14])(=[O:4])=[O:3].O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[CH3:14])[NH2:11])(=[O:3])=[O:4]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(N)cc1S(C)(=O)=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
2-Methylsulfonyl-1-methyl-4-nitrobenzene (500 mg, 2.3 mmol) was dissolved in absolute ethanol (15 mL). Stannous chloride (2.6 g, 11.6 mmol) was added and the reaction mixture was stirred at 75° C. for 4 hours. The mixture was poured into water (50 mL), pH was adjusted with a saturated solution of sodium carbonate to basic reaction, followed by addition of ethyl acetate (150 mL). The organic phase was extracted with water (2×50 mL), dried (MgSO4) and concentrated in vacuo to give 0.36 g of 3-methylsulfonyl-4-methylaniline as an oil.
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:18][CH2:17][CH2:16][C:15]([F:20])([F:19])[CH2:14][CH2:13]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[ClH:4].[F:19][C:15]1([F:20])[CH2:16][CH2:17][CH2:18][NH:12][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(F)(F)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: FC1(F)CCCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (3.9 mL) was added to methanol (90 mL) at 0° C. and stirred for 20 minutes before addition of 4,4-difluoro-azepane-1-carboxylic acid tert-butyl ester as a solution in methanol (10 mL). After 30 minutes, HCl in dioxane (4 N, 40 mL) was added cautiously and the mixture was stirred at room temperature for 3 hours. The solution was concentrated, triturated with ether, filtered and dried under vacuum overnight to afford the title compound as an off-white solid (2.1 g). 1H NMR (400 MHz, DMSO): δ 9.5 (s, 2H), 3.2-3.1 (m, 4H), 2.5-2.4 (m, 2H), 2.3-2.2 (m, 2H), 1.9-1.8 (m, 2H).
Reaction SMILES: [C:1]([S:20](F)(=[O:22])=[O:21])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[O-]S([O-])=O.[Na+:28].[Na+].O>O1CCOCC1>[C:1]([S:20]([O:22][Na:28])=[O:21])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [Na+]
Agent: O=S([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=S(O[Na])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Fluorochemical sulfinates can be prepared by deiodosulfination of the corresponding iodides following the general procedure of Hu et al. in J. Org. Chem., Vol. 56, No. 8, 1991, page 2803. The fluorochemical sulfinates C4F9SO2Na and C6F13SO2Na were prepared by reduction of the corresponding sulfonyl fluorides C4F9SO2F and C6F13SO2F with Na2SO3 in a one to one mixture of water and dioxane. See also, U.S. Pat. No. 5,285,002, supra. The purity of these fluorochemical sulfinates, as determined by 19F NMR analysis, was about 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([CH3:11])[CH:3]=1.Cl.[N:13]1([CH2:19][CH:20]([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:21][C:22]#[N:23])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C1COCC1>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([C:27]2[CH:26]=[N:25][N:24]([CH:20]([CH2:21][C:22]#[N:23])[CH2:19][N:13]3[CH2:18][CH2:17][N:16]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[CH3:11])=[O:10])[CH2:15][CH2:14]3)[CH:28]=2)=[N:34][CH:33]=1
Reactant: Cc1cc(F)ccc1N=C=O
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1NC(=O)N1CCN(CC(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reaction time: 1 h

Procedure:
4-Fluoro-1-isocyanato-2-methylbenzene (10 mg, 0.068 mmol) was added to a solution of 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (20 mg, 0.034 mmol; from Example 12, Step 2) and triethylamine (28 uL, 0.20 mmol) in THF (0.39 mL). The reaction was stirred for one hour, then solvent was removed in vacuo. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in a solution of methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product as the free base (11 mg, 67%). 1H NMR (400 MHz, d6-dmso): δ 12.12 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.61 (d, 1H), 7.11 (dd, 1H), 7.02 (dd, 1H), 6.98 (d, 1H), 6.92 (dt, 1H), 5.01 (tt, 1H), 3.42-3.29 (m, 4H), 3.26-3.19 (m, 2H), 2.86 (dd, 1H), 2.81 (dd, 1H), 2.54-2.46 (m, 2H), 2.43-2.34 (m, 2H), 2.11 (s, 3H); LCMS (M+H)+: 488.3.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[I:21]I.S(S([O-])=O)([O-])(=O)=O.[K+].[K+]>C(Cl)Cl.C1COCC1>[C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[I:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)c1ccncc1
Reactant: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccncc1I
Temperature: -69 °C
Reaction time: 14 h

Procedure:
Into a 4-necked RBF equipped with an overhead stirrer and a J-Kem internal temperature probe was placed N-phenylisonicotinamide (35.1 g, 0.18 mol) and anhydrous THF (700 ml). All material appeared to go into solution. This mixture was cooled to −69° C. in a dry ice/IPA bath. To this was slowly added nBuLi (156 ml of a 2.5 M in Hexanes) in two portions. While adding the first equivalent of nBuLi, an exotherm was observed raising the temperature to approx. −41° C. The orange reaction mixture was slightly heterogeneous. This was allowed to slowly warm to 12° C. over 2 h. This mixture was re-cooled to −70° C. At this point, a THF solution (175 ml) of iodine (47.2 g, 0.19 mol) was added. This was allowed to warm and stirred at room temperature for 14 h. To this solution was added 150 ml of a saturated solution of potassium meta-bisulfite and diluted with CH2Cl2. The two layers were separated and the organic layer was extracted with brine. The two layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a black oil. This material was purified by SiO2 column chromatography using 40% ethyl acetate/Hexane as eluent. Concentration gave 38.6 g (67% th) of an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][CH:23]=1>>[OH:20][C:14]1[CH:13]=[CH:12][C:11]([N:10]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][C:15]=1[C:16]([NH:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][CH:23]=1)=[O:17]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc4cn[nH]c4c3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride and 6-aminoindazole were reacted together as described in Preparation 7. The product was crystallized in aqueous pyridine, m.p. 279°, λmax (methanol)=350 nm.