Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([C:37]1[CH:38]=[N:39][C:40]2[C:45]([C:46]=1[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=1)=[CH:44][C:43]([S:56]([C:59]1[CH:60]=[C:61]([CH:65]=[CH:66][CH:67]=1)[C:62](O)=[O:63])(=[O:58])=[O:57])=[CH:42][C:41]=2[CH3:68])(=[O:36])[NH2:35].[NH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76]2([CH2:81][CH2:82][CH2:83][CH2:84][N:85]([CH2:93][C@H:94]([O:107][Si:108]([C:111]([CH3:114])([CH3:113])[CH3:112])([CH3:110])[CH3:109])[C:95]3[CH:104]=[CH:103][C:102]([OH:105])=[C:101]4[C:96]=3[CH:97]=[CH:98][C:99](=[O:106])[NH:100]4)[C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])[S:80][CH2:79][CH2:78][S:77]2)=[CH:72][CH:71]=1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[Si:108]([O:107][C@H:94]([C:95]1[CH:104]=[CH:103][C:102]([OH:105])=[C:101]2[C:96]=1[CH:97]=[CH:98][C:99](=[O:106])[NH:100]2)[CH2:93][N:85]([CH2:84][CH2:83][CH2:82][CH2:81][C:76]1([C:73]2[CH:74]=[CH:75][C:70]([NH:69][C:62](=[O:63])[C:61]3[CH:65]=[CH:66][CH:67]=[C:59]([S:56]([C:43]4[CH:44]=[C:45]5[C:40](=[C:41]([CH3:68])[CH:42]=4)[N:39]=[CH:38][C:37]([C:34](=[O:36])[NH2:35])=[C:46]5[NH:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=4)(=[O:57])=[O:58])[CH:60]=3)=[CH:71][CH:72]=2)[S:80][CH2:79][CH2:78][S:77]1)[C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])([C:111]([CH3:114])([CH3:113])[CH3:112])([CH3:110])[CH3:109]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)O)c4)cc23)c1
Reactant: CC(C)(C)OC(=O)N(CCCCC1(c2ccc(N)cc2)SCCS1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C6(CCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(O)c8[nH]c(=O)ccc78)C(=O)OC(C)(C)C)SCCS6)cc5)c4)cc23)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
DMAP (20 mg), HATU (110 mg, 0.29 mmol) and DIEA (0.15 mL, 0.87 mmol) were added to a stirring mixture of 3-[[3-carbamoyl-4-[(3-methoxyphenyl)amino]-8-methylquinolin-6-yl]sulfonyl]benzoic acid (144 mg, 0.29 mmol) and Intermediate 105 (0.18 g, 0.35 mmol) in NMP (3 mL). The reaction mixture was stirred overnight in an 80° C. oil bath and then purified by reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1% TFA) to provide, after concentration, the title compound as a dark yellow solid (90 mg, 27%). ES/MS calcd. for C60H71N6O10S3Si+ 1159.4. Found m/z=1159.6 (M+H)+.
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:22](OC)(=O)[CH2:23]CCCCCC/C=C\CCCCCCCC>>[CH3:22][CH2:23][CH2:18][CH2:17][CH2:16]/[CH:15]=[CH:14]\[CH2:13]/[CH:12]=[CH:11]\[CH2:10]/[CH:9]=[CH:8]\[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCCC(=O)O

Procedure:
Methyl ester of DGLA is recovered preferably by extracting the above-mentioned treated solution with an organic solvent such as hexane, an ether such as ethyl ether, or an ester such as ethyl acetate. Next, the resulting extract is dried on, for example, anhydrous sodium sulfate, and the solvent is distilled off preferably under reduced pressure to obtain a mixture comprising fatty acid esters. This mixture contains, in addition to the desired fatty acid HGLA methyl ester, other fatty acid methyl esters, such as methyl parmitate, methyl stearate, methyl oleate and the like. To isolate methyl ester of DGLA from the mixture of these fatty acid methyl esters, column chromatography, low temperature crystallization, the urea-inclusion method, the liquid/liquid countercurrent chromatography method, and the like can be used alone or in combination.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:12](O)([CH3:15])([CH3:14])[CH3:13].[I-].ClC1C=CC=C[N+]=1C.C(N(CCCC)CCCC)CCC>ClCCl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([O:10][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
A mixture of 3,6-dichloropyridazine-4-carboxylic acid (5.79 g, 30 mmol), tert-butanol (2.45 g, 33 mmol), 2-chloro-1-methylpyridinium iodide (6.12 g, 24 mmol), and tributylamine (8.9 g, 48 mmol) in dichloromethane (52 mL) was stirred at refluxing under N2 for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using a silica gel cartridge (330 g) which was pretreated with 1% Et3N in hexanes for 10 min at 10 mL/min, eluting with a gradient of EtOAc (0-50%) in hexanes to afford 6.1 g (81%) of the title compound as a white solid. HPLC/MS (Method B): retention time=2.95 min, [M+H]+=249.1.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Br[CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([O:23][CH3:24])=[CH:12][CH:11]=2>CN(C)C=O>[CH3:24][O:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:25])[N:8]([CH3:26])[C:7]([CH2:6][O:2][CH3:1])=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CO
Reactant: COc1ccc2c(=O)n(C)c(CBr)c(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1c(-c2ccccc2)c2cc(OC)ccc2c(=O)n1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methanol (0.057 mL, 1.40 mmol) in 2 mL of dimethylformamide was added sodium hydride (45 mg, 60% dispersion in mineral oil, 1.11 mmol). After 10 minutes, 3-(bromomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one was added (100 mg, 0.279 mmol). After 30 minutes, the reaction mixture was cooled to 0° C., and quenched with 1 mL of saturated NaHCO3 solution. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography through SiO2 (50% EtOAc/hexane) to provide the titled product as a white solid. 1H-NMR (500 MHz, CDCl3) δ 8.43 (d, J=9.0 Hz, 1H), 7.44-7.50 (m, 3H), 7.29-7.31 (m, 2H), 6.91 (dd, J=9.0, 2.5 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 4.18 (s, 2H), 3.75, (s, 3H), 3.69 (s, 3H), 3.24 (s, 3H) ppm. ESI+ MS: 310.23 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH:11]=[CH:12][CH:13]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[I:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(3-iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 533.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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>[CH3:27][C:16]1[CH:15]=[C:14]([O:13][CH:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 70 °C
Yield: 61.7 %

Procedure:
Ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (200 mg, 0.46 mmol) was dissolved in dry THF (3 mL), and treated with 4-(trifluoromethyl)benzeneboronic acid (104 mg, 0.55 mmol), Pd(PPh3)4 (53 mg, 0.046 mmol) and sodium carbonate (146 mg, 1.38 mmol) in water (2 mL). The mixture was then heated at 70° C. for 3 hours, cooled to rt and partitioned between EtOAc and water. The layers were separated and the organic layer washed with brine, dried (Na2SO4) and concentrated to give a brown oil. Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with petroleum ether 40-60° C.:EtOAc (19:1) afforded the title compound as a colourless gum (142 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC[C@H]1CC[C@H](CO[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC[C@H]1CC[C@H](CO)CC1

Procedure:
In 10 ml of dry tetrahydrofuran was dissolved 1.05 g of N-t-butoxycarbonyl-2-(trans-4-t-butyldimethylsilyloxymethylcyclohexyl)ethylamine, and 8.48 ml of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution) were added dropwise thereto with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight. To the reaction mixture were added 150 ml of ethyl acetate, and the mixture was washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (2:1) as an eluting solvent to obtain 471 mg of the desired compound as a colorless crystalline solid.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[BrH:10].N([O-])=O.[Na+]>O.C(OCC)C>[Br:10][C@@H:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)C[C@H](Br)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
To a 500 mL round bottom flask was added L-aspartic acid ((S)-aspartic acid, 25 g, 188 mmol) and 245 mL of 5 N HBr. The reaction was cooled in an ice bath to 0-50° C., followed by the dropwise addition of sodium nitrite (20.7 g, 301 mmol) in 75 mL of water over five hours. The temperature was maintained below 50° C. during the addition. After the addition was complete, the reaction was allowed to stir for 12 hours at 23-25° C. The reaction was diluted with diethyl ether (120 mL). The aqueous layer was removed and the organic phase was washed with 1 N HCl (100 mL). The combined aqueous phases were washed with EtOAc (100 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to leave the product as a slightly yellow solid. The solid was recrystallized from EtOAc (˜100 mL) and hexanes (˜10 mL) to obtain the product (19.03 g, 97 mmol, 51%) as a white crystalline solid.
Reaction SMILES: O.[C:2]([NH:12][NH2:13])(=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][NH2:10])=[O:8]>CC(=O)C>[CH:2](=[N:10][NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:12][N:13]=[CH:5][CH2:6][CH3:7])=[O:11])[CH2:3][CH3:4]
Reactant: NNC(=O)CCCCC(=O)NN
Solvent: O
Solvent: CC(C)=O
Product: CCC=NNC(=O)CCCCC(=O)NN=CCC

Procedure:
In a stainless steel flask equipped with an agitator, 54.6 grams of water were added, the agitator was turned on, then 25 grams of adipic acid dihydrazide were added. The mixture was agitated for at least 10 minutes until a stable dispersion was formed. 16.4 grams of 2-propanone were then added under mixing. A clear solution formed after a few minutes. Mixing was continued for at least another hour until reaction product precipitated and formed a stable dispersion. 4 grams of AQUAFLOW NLS-200 (rheology additive) were added to the dispersion under agitation.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:31]([CH:40]=[O:41])=[CH:32][C:33]3[NH:37][CH:36]=[N:35][C:34]=3[C:38]=2[F:39])=[C:25]([Cl:42])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:31]([C:40](=[O:41])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:32][C:33]3[NH:37][CH:36]=[N:35][C:34]=3[C:38]=2[F:39])=[C:25]([Cl:42])[CH:24]=1
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CS(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CS(=O)(=O)CC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
To a solution of methyl sulfone (65 mg, 0.68 mmol) in THF (1.5 mL) is added a solution of n-BuLi (0.27 mL, 0.68 mmol, 2.5 M solution in hexane) at −78° C. After stirring for 5 minutes, HMPA (0.1 mL) is added. After stirring for additional 10 minutes, a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (26 mg, 0.069 mmol) in THF (1 mL) is added. The resulting solution is stirred for 1.5 hours at −78° C. The reaction is quenched with saturated aqueous NH4Cl, warmed to room temperature, and diluted with EtOAc. The organic layer is washed with water, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (3% MeOH in CH2Cl2) to give the crude desired product (31 mg, 96%) which is used directly without further purification: MS APCI (+) m/z 462, 464 (M+, Br pattern) detected.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]=[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:6]=[N:7][OH:8].Br.[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29]Br)[CH2:23]1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][O:8][N:7]=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH2:3][CH:2]([CH3:15])[CH3:1])[CH2:23]1)=[O:21])[CH3:18]
Reactant: CC(C)CC=C(C=NO)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=CC(=CCC(C)C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.6 %

Procedure:
A mixture of the above oxime (2.0 g, 10 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (3.4 g, 10 mmol), potassium carbonate (4.7 g, 34 mmol) and acetone (25 ml) was stirred at room temperature for 4 days. The mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The residue was purified by column chromatography on silica gel (75 g, cyclohexane/ethyl acetate, gradient 3/1 to 2/1) to give 1.3 g of (R)-1-(2-(((5-methyl-2-phenyl-2-hexen-1-ylidene)-amino)oxy)ethyl)-3- piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [OH-].[Na+].S(O[CH2:8][C:9]([NH2:12])([CH3:11])[CH3:10])(O)(=O)=O.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O>[CH3:10][C:9]([NH2:12])([CH3:11])[CH2:8][S:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(N)COS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)CSc1ccccc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
In 5 ml of water was dissolved 0.20 g (5 mmol) of sodium hydroxide, followed by adding thereto 0.85 g (5 mmol) of 2-amino-2-methylpropyl hydrogensulfate and 0.66 g (6 mmol) of thiophenol, and the resulting mixture was stirred at 80° C. for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and acidified with 6N hydrochloric acid. The aqueous layer was washed with ethyl acetate and made basic with an aqueous sodium hydroxide solution, and the desired compound was extracted three times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 0.52 g of 2-methyl-1-phenylthio-2-propylamine was obtained (yield: 57%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2([OH:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:28][OH:29]>C(O)C.O>[C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2([OH:21])[CH2:19][CH2:18][C:17](=[N:28][OH:29])[CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Yield: 93 %

Procedure:
To a solution of 2.00 g of 1-[2-(phenylmethyl)phenyl]-4-oxocyclohexanol of Example 4 in 100 ml of 95% ethanol is added a solution of 1.2 g of sodium acetate in 10 ml of H2O and a solution of 1.0 g of hydroxylamine hydrochloride in 4 ml of H2O and the mixture is refluxed for 90 minutes. The solvents are removed under reduced pressure and the product is crystallized from ethanol-H2O (20 ml-100 ml) and dried (P2O5 --40°) in vacuo to provide 1.96 g of 1-[2-(phenylmethyl)phenyl]-4-oxocyclohexanol oxime, m.p. 137°-138° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:36])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]#[CH:27])[N:24]=3)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].[N:37]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)=[N+:38]=[N-:39].CC(O)(C)C>S([O-])([O-])(=O)=O.[Cu+2].[Cu].O>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:36])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[N:39]=[N:38][N:37]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[CH:27]=4)[N:24]=3)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: C#Cc1cnc2c(n1)c(C(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C1CC1)cn2COCC[Si](C)(C)C
Reactant: [N-]=[N+]=NC1CCCC1
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-c3cn(C4CCCC4)nn3)cnc21
Temperature: 125 °C
Yield: 68.8 %

Procedure:
A microwave vial was charged with 2-ethynyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol), azidocyclopentane (32.9 mg, 0.3 mmol), t-BuOH (0.6 mL), and H2O (0.6 mL). To this sticky mixture was added 1.0 M aqueous copper (II) sulfate (39.5 μL, 0.04 mmol) and copper powder (10.0 mg, 0.16 mmol). The vial was sealed and the heterogeneous reaction mixture was heated in a microwave reactor at 125° C. for 5 min. The reaction mixture was cooled to room temperature and filtered, rinsing with EtOAc. The filtrate was washed with water, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/hexanes) to afford 85 mg (70%) of 2-(1-cyclopentyl-1H-[1,2,3]triazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as an off-white foamy solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7](=[O:16])[C:6]=2[CH:17]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:16]=[C:7]1[C:6]2[CH:17]=[C:2]([O:1][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=[CH:4][C:5]=2[O:15][C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8]1
Reactant: O=C1CC2(CCCCC2)Oc2ccc(O)cc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)C(=O)CC1(CCCCC1)O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
A mixture of 6-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 14) (0.878 g, 3.78 mmol), ethyl bromoacetate (0.69 g, 4.13 mmol), anhydrous potassium carbonate (0.78 g, 5.65 mmol) and dry N,N-dimethylformamide (DMF) (7.5 ml) is stirred at room temperature for 4 hours under nitrogen gas. DMF is removed by distillation under reduced pressure and the residue is extracted with diethyl ether. The ether layer is separated and washed successively with water, dilute sodium hydroxide and saturated brine, dried and distilled to remove ether. The residue is recrystallized from cyclohexane to obtain the title compound as a crystalline solid (1.11 g, yield 92.5%, m.p=72°-73° C.). ##STR10##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](OCC)=O)=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[NH2:23])[S:7][C:6]=2[CH:24]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[C:10]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)=[N:23][C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[NH:15][C:8]=3[S:7][C:6]=2[CH:24]=1
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(Br)ccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4cc(Br)ccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 6-bromo-2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate (3.8 g), 1-methylpiperazine (16 ml), anisole (85 ml) and titanium tetrachloride (3.0 ml), 3-bromo-8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.16 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[N:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[N+]=[N-].C[O-].[Na+].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:10]=[C:9]2[C:6]([CH:7]=[C:14]([C:15]([OH:17])=[O:16])[NH:11]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: N#Cc1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 11.6 %

Procedure:
A solution of 4-cyanobenzaldehyde (1.27 g, 9.69 mmol) and ethyl azidoacetate (5 g, 38.76 mmol) in methanol (6 ml) was added dropwise over 0.16 h to a stirred solution of sodium methoxide (2.143 g, 39.7 mmol) in methanol (24 ml) at −8° C. The reaction was stirred with ice cooling for a further 3 h before being poured into ice/water (500 ml). The precipitate was filtered, washed with water and dried in vacuo. A sample of the residue (0.55 g) was dissolved in xylene (15 ml) and added dropwise to refluxing xylene (35 ml) over 0.75 h. After a further 1.5 h reflux the mixture was cooled and the precipitate filtered, washed with a small amount of xylene and dried in vacuo. The residue was dissolved in aqueous methanol (20 ml, 1:1) and sodium hydroxide (1 equivalent) added. The mixture was stirred at room temperature for 18 h, concentrated to half volume and poured into water (50 ml). The resultant solution was washed with ethyl acetate (50 ml) and the aqueous layer acidified with 2N HCl. The precipitate was filtered, washed with water and dried in vacuo to afford the title compound as a pale yellow solid (0.209 g, 11%).