Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH:19]([C:23]([NH2:25])=[O:24])[CH2:20][CH2:21][CH3:22])=[O:17])[CH2:12][C:13](=[O:15])[OH:14])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].ClC1C=C(Cl)C(Cl)=CC=1[O:35][C:36](=O)[C@H:37]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[NH:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40].Cl.N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC.C(OC(N[C@H](C(N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC)=O)CC1C2C(=CC=CC=2)NC=1)=O)(C)(C)C>>[CH2:42]([O:41][C:39]([NH:38][C@H:37]([C:36]([NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH:19]([C:23]([NH2:25])=[O:24])[CH2:20][CH2:21][CH3:22])=[O:17])[CH2:12][C:13](=[O:14])[OH:15])=[O:9])[CH2:4][CH2:5][S:6][CH3:7])=[O:35])[CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)=[O:40])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Oc1cc(Cl)c(Cl)cc1Cl)OCc1ccccc1
Reactant: CCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CCSC)C(N)=O
Agent: CSCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: Cl
Product: CCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(N)=O

Procedure:
When equivalent quantities of L-methionyl-L-aspartyl-DL-norvaline amide hydrochloride and N-benzyloxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester are substituted for the L-methionyl-L-aspartyl-D-alanine amide hydrochloride and the N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester of Example 6, and the procedure detailed therein substantially repeated, there is obtained N-benzyloxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-DL-norvaline amide. This compound is represented by the following formula.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].[CH:15]1(O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH:22]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH2:22][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OC1CCCCC1
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: Clc1ccc(Nc2nccs2)cc1OCC1CCCCC1
Reaction time: 1 h
Yield: 5 %

Procedure:
Following the procedure general for O-alkylation, Method C, 2-chloro-5-(thiazol-2-ylamino)phenol (70 mg, 0.31 mmol), 1-cyclohexanol (34 μM, 0.32 mmol), Ph3P (84 mg, 0.32 mmol) were suspended in THF (0.1 mL). The reaction flask was lowered into a sonication bath and sonicated for several minutes giving a clear and highly viscous solution. While sonication, DEAD (0.063 mL, 0.32 mmol) was added slowly. The reaction mixture was stirred for 1 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 5% yield (5 mg).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([C:17]([CH:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[OH:20])=[CH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:19](=[O:20])[C:17]([C:11]1[CH:12]=[CH:13][C:14]([CH3:1])=[CH:15][CH:16]=1)=[CH2:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(c1ccccc1)C(O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To oxalyl chloride (1.01 g) in dichloromethane (10 ml) at -70° C. was added dimethylsulphoxide (1.23 g) in dichloromethane (6 ml). To the resulting mixture was dropwise added a solution of α-(1-phenylethenyl)-2,4-dichlorobenzenemethanol (2.07 g) in dichloromethane (6 ml). Triethylamine (2.17 g) was added to the reaction mixture and the resulting mixture was stirred for an additional 20 minutes and then allowed to warm to room temperature. The reaction mixture was washed with water and the organic phase separated and concentrated under reduced pressure. The resulting residue was redissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulphate. The solvent removed under reduced pressure to yield 1-(2,4-dichlorophenyl)-2-(4-methylphenyl)propen-1-one (δ (CDCl3), 5.92 (1H,s) 6.16 (1H,s) and 7.1-7.3 (10H,m) p.p.m.) as an oil having the formula: ##STR19##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([Si:16]([CH3:27])([CH3:26])[O:17][CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH:22]=O)([CH3:15])([CH3:14])[CH3:13].C[O-].[Na+]>CO>[C:12]([Si:16]([CH3:26])([CH3:27])[O:17][CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[CH2:21]/[CH:22]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(CC=O)CCO[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C/C=C1\C(=O)Nc2cc(Cl)ccc21)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the mixture of 6-chlorooxindole (3.3 g, 20 mmol) (Crescent) and 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentanal (6.5 g, 26.6 mmol) in methanol (150 mL) was added a methanolic solution (25%, Aldrich) of sodium methoxide (10 g, 46 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 min. The solvent was removed, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography (25-33% EtOAc in hexanes) to give E/Z-3-[5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentylidene]-6-chloro-1,3-dihydro-indol-2-one as a off white solid (Yield 3.6 g, 46%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].[CH3:7][N:8]([CH3:11])C=O.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1>O.CCOC(C)=O.CCCCCC>[Br:12][C:13]1[CH:18]=[C:17]([S:1][CH2:2][CH2:3][OH:4])[CH:16]=[N:15][CH:14]=1.[Br:19][C:17]1[CH:18]=[C:13]([S:1][CH2:2][CH2:7][NH:8][CH3:11])[CH:14]=[N:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: OCCS
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CNCCSc1cncc(Br)c1
Product: OCCSc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2-mercaptoethanol (3.30 g, 42.21 mmol), sodium hydroxide (1.69 g, 42.21 mmol) and N,N-dimethylformamide (50 mL) was stirred at ambient temperature for 4 h. The resulting solution was cooled to 0-5° C. and 3,5-dibromopyridine (8.00 g, 33.77 mmol) was added in one portion. The mixture was stirred at 0-5° C. for 20 min, warmed to ambient temperature and further stirred for 1 h. TLC analysis on silica gel eluting with EtOAc-hexane (3:1) indicated an incomplete reaction. Therefore, the mixture was heated at 75° C. (oil bath temperature) for 17 h. After cooling to ambient temperature, the mixture was poured into water (250 mL) and extracted with ether (3×75 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated (rotary evaporator) to a light-yellow oil. The oil was vacuum distilled using a short-path distillation apparatus to afford 4.55 g (57.5%) of a light-yellow oil, bp 138-140° C. at 0.35 mm Hg.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
A homogeneous mixture of 3-acetyl-6-chloropyridine (5 mL) (which can be prepared in a similar manner by the methods disclosed in Lee, C-H. et al., J. Med. Chem. (2001), Vol. 44, pp. 2133-2138) in N,N-dimethylformamide dimethylacetal (15 mL) was refluxed for 4 h. After cooling the reaction mixture to ambient temperature, it was diluted with hexanes (100 mL), sonicated for 30 seconds and the solid formed was isolated by filtration. The resulting solid was then washed with hexanes (3×25 mL), dried and analyzed to afford 3-(3-(dimethylamino)prop-2-en-1-onyl)-6-chloropyridine; LCMS: purity: 92%; MS (m/e): 212 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH2:9][CH3:10])=[CH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[C:6]([CH2:9][CH3:10])[N:5]=1
Reactant: CCc1ccc(C#N)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1ccc(C#N)c(Cl)n1
Yield: 49 %

Procedure:
A mixture of 3-cyano-6-ethyl-2(1H)-pyridone (36.2 g, 0.24 mol) and phosphorus oxychloride (250 ml) was heated under reflux for 2 hours. The reaction solution was concentrated under a reduced pressure, and the resulting residue was mixed with toluene and concentrated under a reduced pressure. The thus obtained residue was diluted with chloroform and washed with 1 N sodium hydroxide aqueous solution. The aqueous layer was extracted with chloroform, and the chloroform layers were combined and dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-3-cyano-6-ethylpyridine (19.6 g, 49%) as an oily material.
Reaction SMILES: [C:1]([O:4][CH:5]([C:30]1[S:31][CH:32]=[C:33]([C:35]([NH:37][CH:38]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:39][CH:40]([CH3:44])[C:41]([OH:43])=[O:42])=[O:36])[N:34]=1)[CH2:6][CH:7]([N:11]([C:20](=[O:29])[CH:21]([N:26]=[N+]=[N-])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][O:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].FC1C([O:59][C:60](=O)[CH2:61][N:62]([CH3:64])[CH3:63])=C(F)C(F)=C(F)C=1F>CCOC(C)=O.[Pd]>[C:1]([O:4][CH:5]([C:30]1[S:31][CH:32]=[C:33]([C:35]([NH:37][CH:38]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:39][CH:40]([CH3:44])[C:41]([OH:43])=[O:42])=[O:36])[N:34]=1)[CH2:6][CH:7]([N:11]([C:20](=[O:29])[CH:21]([NH:26][C:60](=[O:59])[CH2:61][N:62]([CH3:64])[CH3:63])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][O:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CN(C)CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCC(C)C(N=[N+]=[N-])C(=O)N(COC(=O)CC(C)C)C(CC(OC(C)=O)c1nc(C(=O)NC(Cc2ccccc2)CC(C)C(=O)O)cs1)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)C(NC(=O)CN(C)C)C(=O)N(COC(=O)CC(C)C)C(CC(OC(C)=O)c1nc(C(=O)NC(Cc2ccccc2)CC(C)C(=O)O)cs1)C(C)C
Reaction time: 26 h
Yield: 47.8 %

Procedure:
Pd/C (10 wt %, 8.7 μg) and azide 8 (18.0 mg, 0.0247 mmol) were added to a 0.20 M solution of 18 (0.0988 mmol) in 0.40 mL of EtOAc (filtered through activated alumina). The reaction mixture was stirred under a hydrogen atmosphere for 26 h and then filtered through a plug of Celite with washing of the filter pad with EtOAc. The filtrate was concentrated, and a 1:1 mixture of deoxygenated H2O/dioxane (4.0 mL) was added. The mixture was stirred for 20 h at rt and concentrated. Reverse-phase HPFC (20:80 to 100:0 MeCN:H2O) followed by lyophilization afforded 9.3 mg (48%) of 6 as an amorphous solid. [α]D23=−2.0 (c=0.6, MeOH). IR: 1226, 1496, 1542, 1741, 2964 cm−1. 1H NMR (500 MHz, MeOD): δ 0.81 (d, 3H, J=6.5 Hz), 0.87 (d, 3H, J=6.5 Hz), 0.89 (d, 3H, J=7.0 Hz), 0.92 (t, 3H, J=7.5 Hz), 0.98 (d, 3H, J=6.5 Hz), 1.06 (d, 3H, J=6.5 Hz), 1.12-1.21 (m, 1H), 1.17 (d, 3H, J=7.0 Hz), 1.58-1.70 (m, 2H), 1.77-1.91 (m, 2H), 1.92-2.05 (m, 3H), 2.06-2.17 (m, 2H), 2.16 (s, 3H), 2.35 (s, 6H), 2.46-2.57 (m, 2H), 2.92 (d, 2H, J=5.5 Hz), 3.11 (q, 2H, J=16.2 Hz), 4.28-4.50 (br s, 1H), 4.32-4.38 (m, 1H), 4.70 (d, 1H, J=8.5 Hz), 5.46 (d, 1H, J=12.0 Hz), 5.87 (d, 1H, J=11.0 Hz), 6.05 (d, 1H, J=12.0 Hz), 7.12-7.18 (m, 1H), 7.19-7.26 (m, 4H), 8.09 (s, 1H). 13C NMR (125 MHz, MeOD) δ 11.1, 16.6, 19.0, 20.3, 20.8, 20.9, 22.9, 25.5, 26.2, 26.9, 32.4, 35.9, 37.6, 39.1, 39.7, 42.1, 44.5, 45.8, 51.2, 55.2, 62.7, 70.8, 125.6, 127.5, 129.4, 130.6, 139.7, 150.9, 162.7, 170.8, 171.7, 172.0, 173.3, 176.5, 181.8. HRMS (FAB) calcd for C40H62N5O9S (M+H): 788.4268. Found: 788.4256.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=O)[CH3:2].[CH:11]1([C:14]([NH:16][NH2:17])=[O:15])[CH2:13][CH2:12]1>C(O)C>[Cl:10][C:7]1[N:6]=[CH:5][C:4]([C:1](=[N:17][NH:16][C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:15])[CH3:2])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: NNC(=O)C1CC1
Solvent: CCO
Product: CC(=NNC(=O)C1CC1)c1ccc(Cl)nc1

Procedure:
Following the general method of procedure 53 and making non-critical variations, except the product was purified by recrystallization from absolute ethanol rather than by chromatography, 5.25 gm (0.0337 mole) of 3-acetyl-6-chloropyridine and 3.40 gm (0.034 mole) of cyclopropanecarboxylic acid hydrazide yield 6.52 gm (81%) of the title compound having a melting point of 218.1° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].O>CN(C=O)C>[Si:30]([O:20][CH2:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)=[CH:12][CH:13]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CCCO)cc2)nc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]-n-propanol (1.17 g, 4.3 mmol) in DMF (10 mL) were added imidazole (580 mg, 8.5 mmol) and t-butylchlorodimethylsilane (640 mg, 4.2 mmol), and the resulting solution was stirred for 13 hours at room temperature. Water was added to the reaction mixture, and extracted with diethyl ether, and the diethyl ether layer was washed with water and then brine. The diethyl ether layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.14 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13](O)=O)[O:12][C:7]=2[CH:6]=1.Cl.[CH2:30]([NH2:32])[CH3:31].[O:33]1CCOC[CH2:34]1>>[CH2:30]([NH:32][C:34]([CH2:13][C:11]1([CH3:16])[C:10](=[O:17])[N:9]([CH3:18])[C:8]2[CH:19]=[CH:20][C:5]([O:4][C:3]3[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:2]=3[Cl:1])=[CH:6][C:7]=2[O:12]1)=[O:33])[CH3:31]
Reactant: C1COCCO1
Reactant: CCN
Reactant: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Agent: Cl
Product: CCNC(=O)CC1(C)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O

Procedure:
An acid chloride (0.4 g) prepared in the same manner as in Example 6 from 7-(2-chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylic acid (Compound 23) was dissolved in dioxane (5 ml), and ethylamine hydrochloride (0.1 g) was added thereto, followed by heating under reflux for 3 hours. The solvent was then evaporated under a reduced pressure, and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=2/1) to give 0.3 g of the title compound (colorless crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7]2.[C:22]1([S:28]([N:31]=C=O)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClCCl>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])[CH:5]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7]2
Reactant: O=C(c1ccccc1)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(c1ccccc1)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-2-benzoyl-1,4-dihydroquinolin-4-one (0.57 g, 1.8 mmol) and benzenesulfonyl isocyanate (0.26 mL, 2.0 mmol) in acetonitrile (9 mL) and heat at reflux for 18 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a residue. Chromatograph the residue on a column of silica gel eluting with dichloromethane to obtain a solid. Recrystallize the solid from ethyl acetate/hexane to give the title compound; mp, 186°-187° C. Rf =0.37 TLC/silica gel/dichloromethane. Elem. Anal. Calcd. for C22H14Cl2 N2O3S: C, 57.77; H, 3.09; N, 6.13. Found: C, 57.76; H, 3.22; N, 5.91.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>P(=O)(O)(O)O>[CH2:9]([C:8]([C:7](=[O:13])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4])[CH2:10][CH2:11][CH3:12]
Reactant: O=CC(=O)O
Reactant: CCCCCC(C)=O
Agent: O=P(O)(O)O
Product: CCCCC(=CC(=O)O)C(C)=O

Procedure:
Prepared from glyoxylic acid (15.2 g, 0.17 mol), 2-heptanone (34.2 g, 0.3 mol) and orthophosphoric acid (30 ml). 1H n.m.r. δ (CDCl3) 0.91, t J 7.2 Hz, 3H, CH3; 1.38, m, 4H, CH2; 2.39, s, 3H, CH3; 2.77, t J 7.2 Hz, 2H, CH2; 6.49, s, CH.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[N:25]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[C:13]2[N:14]=[C:15]([NH:18][C@@H:19]([CH3:24])[C:20]([OH:23])([CH3:22])[CH3:21])[N:16]=[CH:17][C:12]=2[CH:11]=1)=[O:9].[CH2:34]([OH:37])[CH2:35]O.[F-:38].[F-].[F-].B>C(Cl)Cl.O>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[N:25]1[C:13]2[N:14]=[C:15]([NH:18][CH:19]([CH3:24])[C:20]([CH3:22])([OH:23])[CH3:21])[N:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:8]1([C:3]2[CH:2]=[CH:7][C:6]([F:38])=[CH:5][CH:4]=2)[O:37][CH2:34][CH2:35][O:9]1
Reactant: OCCO
Reactant: [F-]
Reactant: C[C@H](Nc1ncc2cc(C(=O)c3ccccc3Cl)n(-c3c(F)cccc3F)c2n1)C(C)(C)O
Agent: B
Solvent: ClCCl
Solvent: O
Product: CC(Nc1ncc2cc(C3(c4ccc(F)cc4)OCCO3)n(-c3c(F)cccc3F)c2n1)C(C)(C)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-(2-chlorophenyl)-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone, 8, (0.17 g, 0.36 mmol) and ethylene glycol (0.045 ml, 0.726 mmol) in CH2Cl2 (2 ml) is added borane trifluoride etherate (0.02 ml, 0.15 mmol) and the mixture is stirred for 17 hours at room temperature. Additional borane trifluoride etherate (0.01 ml) is added as needed to drive the reaction to completion. The reaction mixture is diluted with H2O and extracted with EtOAc the combined organic phases are washed with additional H2O, aqueous NH4Cl solution, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified over silica (50% EtOAc/hexanes, then 80% EtOAc/hexanes) to afford 68 mg of the desired product as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 7.43-6.92 (m, 7H), 6.47 (s, 1H), 8.0 Hz, 1H), 3.98-3.84 (m, 6H), 1.22-1.15 (m, 9H); HRMS calcd for C26H25F3N4O3 (M+H)+ 499.1957, found 499.1946.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([NH2:18])=O)=[C:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:12]=2[C:27]#[N:28])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].COC(OC)[N:32]([CH3:34])C.[NH2:37]N>C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:13]2[C:12]([C:27]#[N:28])=[C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=3)[S:15][C:14]=2[C:16]2[NH:18][CH:34]=[N:32][N:37]=2)=[CH:25][CH:24]=1
Reactant: CC(=O)Nc1cc(-c2sc(C(N)=O)c(Cc3ccc(Cl)cc3)c2C#N)ccn1
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(Cc3ccc(Cl)cc3)c2C#N)ccn1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To a solution of 5-[2-(acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxamide (0.030 g, 0.073 mmol) in toluene (0.75 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.0970 mL, 0.730 mmol), and the mixture was stirred at 100° C. for 90 minutes. The mixture was concentrated and the residue was dissolved in acetic acid (0.75 mL). Hydrazine (0.0114 mL, 0.365 mmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was concentrated and the residue was treated with water. The precipitate was collected, washed with water and dried in a vacuum oven to yield the title compound (0.016 g, 48%). LCMS: (FA) ES+, 435. 1H NMR (400 MHz, d6-DMSO) δ: 10.76 (s, 1H), 8.77 (s, 1H), 8.54-8.46 (m, 2H), 7.50-7.47 (m, 1H), 7.37-7.26 (m, 4H), 4.63 (s, 2H), 2.12 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:10]=1.O>C1COCC1>[Cl:8][C:9]1[N:14]=[C:13]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:20])[F:21])[N:10]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)COCc1cc(OCC2CC2)nc(Cl)n1
Reaction time: 0.08 h

Procedure:
Sodium hydride (19.0 mg, 0.46 mmol) was added to a solution of cyclopropylmethanol (0.037 mL, 0.46 mmol) in dry THF (1 mL) at room temperature. The mixture was stirred for 5 minutes and then a solution of 2,4-dichloro-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidine (120 mg, 0.46 mmol) in dry THF (1 mL) was added. The reaction was stirred at room temperature for 2.5 hours. Water was added and the mixture was extracted with ethylacetate. The organic phase was washed with water, brine, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with mixtures of 0% to 10% ethyl acetate in heptanes to afford the title compound as a solid, 40 mg, (29%) as yellow solid.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)=[N:6]1)(C)(C)C.NC1N=CN=C2NN=C(C3C=C(O)C=CC=3)C=12>C(O)=O.Cl>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)[CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)n1nc(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc21
Agent: Cl
Agent: Nc1ncnc2[nH]nc(-c3cccc(O)c3)c12
Solvent: O=CO
Product: Nc1ncnc2[nH]nc(-c3cccc(OCc4ccccc4)c3)c12

Procedure:
1-tert-butyl-3-(3-(benzyloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (19 mg, 0.052 mmol) was dissolved in a solution of formic acid (1 mL) and conc. HCl (0.1 mL) and heated to reflux for 30 min. Reaction yielded a mixture of ZK136 and 3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol (ZK138). Reaction was concentrated in vacuo and the products purified by RP-HPLC (MeCN:H2O:0.1% TFA). ZK136: ESI-MS (M+H)+ m/z calcd 318.1, found 318.3. ZK138: ESI-MS (M+H)+ m/z calcd 228.1, found 228.3.