Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30](=[O:45])[N:31]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:27]=[C:26]([Cl:46])[CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:46][C:26]1[CH:27]=[C:28]([CH:29]=[C:24]([O:23][CH2:22][CH2:21][NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:25]=1)[C:30]([N:31]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:45]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCN2CCCC2)C2CCCC2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCN1CCCC1)C1CCCC1
Reaction time: 2 h
Yield: 183.8 %

Procedure:
A solution of (2-{3-chloro-5-[cyclopentyl-(3-pyrrolidin-1-yl-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate (0.080 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure to give the title compound (0.075 g) as a colourless gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=2[N:17]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH:16]=1.[C:31]([C:33](=[CH:37][CH:38]1[CH2:40][CH2:39]1)[C:34](O)=[O:35])#[N:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:24][C:22]1[C:23]2[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:7][C:2]=3[F:1])=[CH:16][N:17]([CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:34]([C:33](=[CH:37][CH:38]3[CH2:40][CH2:39]3)[C:31]#[N:32])=[O:35])[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: N#CC(=CC1CC1)C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)cn2CC1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(=CC1CC1)C(=O)N1CCCC1Cn1cc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
To a mixture of 5-(2-fluoro-4-phenoxy-phenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (100 mg, 0.25 mmol, 1.0 eq), 2-cyano-3-cyclopropyl-acrylic acid (42 mg, 0.3 mmol, 1.2 eq) and DIEA (97 mg, 0.75 mmol, 3.0 eq) in 10 ml of DCM was added HATU (145 mg, 0.38 mmol, 1.5 eq). The mixture was stirred for 4 h at RT under N2. LCMS showed the reaction was completed. The reaction mixture was concentrated and purified by Pre-TLC to provide 71 mg (54%) of the title compound. LCMS: m/z 523.2 (M+H)+. 1HNMR (400 MHz, DMSO-d6): δ 0.866˜0.920 (m, 2H), 1.177˜1.194 (m, 2H), 1.569 (m, 1H), 1.721 (m, 2H), 1.883 (m, 2H), 3.200 (m, 2H), 3.511 (m, 1H), 4.360˜4.475 (m, 2H), 6.125 (m, 2H), 6.642˜6.664 (m, 1H), 6.898˜6.920 (m, 1H), 6.977˜7.010 (m, 1H), 7.150˜7.232 (m, 4), 7.371˜7.471 (m, 3H) and 8.131 (m, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:27](Br)=[CH:28][CH2:29][CH3:30].O>CC(=O)CC>[CH:27]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[CH:28][CH2:29][CH3:30]
Reactant: CCCCCCCCOc1ccc(C(=O)OC)c(O)c1
Reactant: CCC=CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCC=COc1cc(OCCCCCCCC)ccc1C(=O)OC
Yield: 89.9 %

Procedure:
To a solution of 22.0 g (78.5 mmol) of the compound (29) and 65.0 g (471 retool) of potassium carbonate mixed in 300 ml of 2-butanone were added 32.0 g (236 mmol) of butenyl bromide and the whole was refluxed for 18 hours. Water was added to the solution and the whole was extracted with ethyl acetate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 23.6 g of methyl 2-butenyloxy-4-octyloxybenzoate as a colorless clear liquid (yield: 89.9%). Then, 20.0 g (59.8 mmol) of the resulting compound was dissolved in 100 ml of methanol. The solution was poured into a solution of 12.0 g (300 mmol) of sodium hydroxide dissolved in 40 ml of water and 400 ml of methanol. The whole was refluxed for another 2 hours. After removal of the solvent by distillation, the resulting white solid was dissolved in water and the solution was rendered acidic by adding hydrochloric acid, whereby white precipitate formed. The precipitate was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 15.3 g of 2-butenyloxy-4-octyloxybenzoic acid (30) (yield: 80.0%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[Na+].O>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccc(F)cc1

Procedure:
10 g (46 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone and 3.74 g (46 mmol) of sodium thiocyanate were stirred in 80 ml ethanol at 50° C. for 2 h. After addition of water the separated solid was isolated by filtration, washed and dried. Yield: 8.96 g.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[C:39]([Cl:40])=[C:38]([CH3:41])[NH:37][C:36]=1[C:42](NC1CCN(C2C=C(C3N=CON=3)C=C(Cl)N=2)CC1)=[O:43].Cl.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([C:71]2[N:76]=[C:75]([S:77][CH3:78])[N:74]=[C:73]([NH2:79])[CH:72]=2)[CH2:67][CH2:66]1>CN(C=O)C>[NH2:79][C:73]1[N:74]=[C:75]([S:77][CH3:78])[N:76]=[C:71]([N:68]2[CH2:69][CH2:70][CH:65]([NH:64][C:42]([C:36]3[NH:37][C:38]([CH3:41])=[C:39]([Cl:40])[C:35]=3[Cl:34])=[O:43])[CH2:66][CH2:67]2)[CH:72]=1
Reactant: CSc1nc(N)cc(N2CCC(N)CC2)n1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(-c4ncon4)cc(Cl)n3)CC2)c(Cl)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(N)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
Diisopropylethylamine (0.21 ml, 1.25 mmol) and HATU (0.239 g, 0.63 mmol) were added to a stirred solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) (0.122 g, 0.63 mmol) in DMF (2 ml). The resultant solution was stirred for 5 minutes, 6-(4-amino-piperidin-1-yl)-2-(methylthio)pyrimidin-4-amine hydrochloride (Intermediate 46) (0.2 g, 0.63 mmol) was added and the mixture was stirred at room temperature for 18 h. The crude mixture was filtered and purified by semi-preparative HPLC eluting with CH3CN/H2O (0.1% TFA) to give the title product (42 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13]CC#N)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.S(=O)(=O)(O)O.C(OCC)(=O)C.[C:29]([OH:32])(=[O:31])[CH3:30]>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:30][C:29]([OH:32])=[O:31])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(=O)O
Reactant: N#CCCOCCc1ccc2sccc2c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CCOCCc1ccc2sccc2c1

Procedure:
In 0.6 mL of acetic acid was dissolved 200 mg of 3-[2-(1-benzothiophen-5-yl)ethoxy]propiononitrile, followed by adding thereto 0.4 mL of water and 0.184 mL of sulfuric acid, and the resulting mixture was stirred at 90 to 100° C. for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene ethyl acetate=3:1) to obtain 140 mg of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][CH2:13][C:14]2[N:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][O:27][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:37]=4[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]5)[C:20]=3[Cl:39])[CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:48][C:49]1[N:57]=[CH:56][CH:55]=[CH:54][C:50]=1[C:51](Cl)=[O:52]>ClCCl>[Cl:39][C:20]1[C:21]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[C:37]=2[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]3)=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[N:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][NH:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[N:7][C:2]([NH:1][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][CH:56]=[N:57][C:49]=2[CH3:48])=[CH:3][CH:4]=1
Reactant: Cc1ncccc1C(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(N)nc4)c3Cl)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(NC(=O)c5cccnc5C)nc4)c3Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a mixture of 2-[(E)-3-(6-aminopyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole (152 mg) and triethylamine (96 mg) in dichloromethane (3 ml) was added 2-methylnicotinoyl chloride hydrochloride (115 mg) under nitrogen in ice water bath and stirred for 1 hour at the same temperature. The reaction solvent was concentrated in vacuo and the residue was dissolved in methanol. To the solution was added 1M sodium hydroxide solution (0.5 ml) and stirred for 30 minutes. The solution was evaporated and partitioned between chloroform and water. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography on silica gel (ethyl acetate) to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[(E)-3-[6-[2-methylnicotinamido]pyridin-3-yl]acryloylaminomethyl]pyrrole (124 mg) as an amorphous powder. NMR (DMSO6, δ): 2.57 (3H, s), 4.26 (3H, s), 4.06-4.17 (1H, m), 4.21-4.33 (1H, m), 5.35-5.47 (2H, m), 6.18-6.25 (2H, m), 6.63 (1H, d, J=16 Hz), 6.85-6.90 (1H, m), 7.24 (1H, d, J=8 Hz), 7.29-7.36 (2H, m), 7.36-7.47 (3H, m), 7.53 (1H, d, J=8 Hz), 7.64 (1H, d, J=8 Hz), 7.73 (1H, d, J=8 Hz), 7.88 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.16-8.31 (3H, m), 8.51-8.57 (2H, m).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[Cl:45][C:46]1[C:51](O)=[CH:50][CH:49]=[CH:48][N:47]=1>C1COCC1>[Cl:45][C:46]1[C:51]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:50][CH:49]=[CH:48][N:47]=1
Reactant: Oc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
To a solution of triphenylphosphine (1.73 g, 6.6 mmol) in THF (26 mL) was added diethyl azodicarboxylate (1.04 mL, 6.6 mmol) at 0° C., and the reaction mixture was stirred for 15 minutes. 1-BOC-2-(S)-azetidinemethanol (1.03 g, 5.5 mmol) and 2-chloro-3-pyridinol (785 mg, 6.0 mmol, Aldrich Chemical Co.) were then added. The reaction mixture was allowed to warm slowly to room temperature and stir overnight. Solvent was removed, and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous K2CO3 and brine, dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate:hexane (1:4 to 1:1) to afford the title compound (611 mg). MS (DCI/NH3) m/z 299 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:16][C:15]=4[CH3:30])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:34][O-:35].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[N:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][C:11]3[C:12]([O:35][CH3:34])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:16][C:15]=4[CH3:30])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3-(4-(1H-pyrazol-1-yl)benzyl)-2,4-dichloro-8-methylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (1.05 g, 2.20 mmol, Intermediate 14: step a) and dry sodium methoxide (0.59 g, 11.02 mmol) in toluene (10 mL) was heated in a sealed tube at 110° C. for 12 hours. The mixture was cooled to room temperature, diluted with DCM, stirred for 30 minutes at room temperature and the resulting suspension filtered through Celite®, rinsing several times with DCM. The solvents were removed under reduced pressure and the residue chromatographed (DCM/10% MeOH in DCM, gradient) to provide the crude product. Recrystallization from MeOH, filtering and drying under reduced pressure overnight provided the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[N:2]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:1]
Reactant: CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)CCCC(=O)Cl
Product: COC(=O)CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 138 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To a stirred suspension of 1-methylamino-2,4-dinitrobenzene (1.00 g, 5.07 mmol) in xylenes (10 mL) was added methyl-5-chloro-5-oxo-valerate (3.50 mL, 25.28 mmol, 5.0 equiv.) at 20° C. The reaction mixture was then heated to reflux, approximately 138° C. Reaction progress was monitored periodically by HPLC Method A. The reaction was complete after stirring for approximately 24 hours at 138° C. The reaction mixture was cooled to 0° C. and hexanes was added (10 mL) to crystallize the product. The resultant slurry was stirred for approximately 1 hour at −10° C. to 0° C. and then filtered. The wet cake was dried at 60° C. under vacuum/N2 sweep overnight to give 1.30 g (79% yield) as an off-while solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.[CH:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([CH:12]([CH3:14])[CH3:13])[CH:16]=1)=[O:7]
Reactant: CC(C)c1cccc(N)c1
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Product: Cc1cc(Br)cc(C(=O)Nc2cccc(C(C)C)c2)c1
Yield: 99 %

Procedure:
In a manner similar to that described in Preparation 41, 3-bromo-5-methylbenzoic acid (400 mg) and 3-isopropylaniline were converted to the title compound (615 mg, 99%).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[Se:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:28])[C:20]1[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:22][SH:23]>>[CH3:17][O:18][C:19](=[O:28])[C:20]1[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:22][S:23][Se:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11](=[O:12])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1OS
Reactant: O=c1c2ccccc2[se]n1-c1ccccc1
Product: COC(=O)c1ccccc1OS[Se]c1ccccc1C(=O)Nc1ccccc1

Procedure:
Prepared similar to example 1 from 5 g (18,2 mmol) of 2-phenyl-1,2-benzisoselenazole-3(2H)-one and 3,1 g (18,4 mmol) of mercaptosalicylic acid methyl ester.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[N+]=[N-])[CH:16]=[CH:17][CH:18]=1>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8]2)[CH:16]=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=Cc1cccc(Cl)c1
Reactant: O=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CSC
Solvent: ClCCl
Product: Clc1cccc(C2OC2c2ccccc2)c1
Yield: 53 %

Procedure:
To a slurry of rhodium (II) acetate (0.001 g) and dichloromethane (4 ml) were added benzaldehyde (0.025 ml) and dimethylsulphide (0.009 ml). The solution of 3-chlorophenyldiazomethane (produced above) was added to this mixture over 24 hours. The solvent was removed in vacuo and the residue chromatographed on silica (Merck grade 60, 230-400 mesh) eluting with dichloromethane:hexane 2:3 to give the title compound as a colourless oil (0.0305 g, 53% yield) δH (CDCl3): 7.55(8H); 7.45(1H), 4.0(2H)ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.[H-].[Na+].CI.[CH3:18]COC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH3:18])[CH:5]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (4 g, 22.6 mmol) was dissolved in DMF (115 ml) and treated with NaH (1 g, 45.2 mmol) and CH3I (2.8 ml, 45.2 mmol). The reaction mixture was stirred at room temperature for 24 hours. EtOAc was added to the mixture and extracted with 5% citric acid (2×10 mL), saturated NaHCO3 (2×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated to yield the desired product.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:20][C:19]3[CH2:18][NH:17][CH2:16][C:15]=3[CH2:14]2)=[N:10][CH:9]=1)=[O:7].FC(F)(F)C([O-])=O.[Br:29][C:30]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:31]=1[C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:14][C:15]3[CH2:16][N:17]([C:32](=[O:33])[C:31]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:30]=4[Br:29])[CH2:18][C:19]=3[CH2:20]2)=[N:10][CH:9]=1)=[O:7]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CC(C)CCNC(=O)c1cnc(N2CC3=C(CNC3)C2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(Br)c(C(=O)N2CC3=C(C2)CN(c2ncc(C(=O)NCCC(C)C)s2)C3)c1

Procedure:
N-(3-Methylbutyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (43.8 mg, 0.1 mmol) was reacted with 2-bromo-5-methoxybenzoic acid after activation with HATU analogously to example 3f. M+H+: 519.15.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+]>CC(C)=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1CBr
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of 2-bromomethyl-benzonitrile (300 mg, 1.53 mmol) and sodium azide (129 mg, 1.99 mmol) in acetone was stirred overnight at rt. The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (6:1) to give the title compound (212 mg, 88%). MS (DCI/NH3) m/z 176 (M+18)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.69 (s, 2H) 7.58 (td, J=7.67, 1.23 Hz, 1H) 7.66 (d, J=7.67 Hz, 1H) 7.76 (td, J=7.67, 1.23 Hz, 1H) 7.91 (dd, J=7.67, 1.53 Hz, 1H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1>CCOCC>[Br:1][CH:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:14]([C:10]1([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:13][CH2:12][CH2:11]1)=[O:23]
Reactant: BrBr
Reactant: O=C(CCc1ccccc1)C1(c2ccc(Cl)cc2)CCC1
Solvent: CCOCC
Product: O=C(C(Br)Cc1ccccc1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.52 ml) was added dropwise over 20 minutes at ambient temperature to a stirred solution of 1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one (3 g) in ether (50 ml). After the addition was complete and the bromine colour had dissipated, the mixture was stirred at ambient temperature for a further 1 hour then it was washed with water (30 ml), saturated aqueous sodium hydrogen carbonate solution (2×30 ml) and water (30 ml), dried (MgSO4), and the solvent removed in vacuo to give 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one as an oil which was used without purification.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([NH:15][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of tert-butyl 4-oxopiperidin-1-carboxylate (5.01 g) and p-toluidine (2.69 g) dissolved in tetrahydrofuran (50 mL) were added sodium triacetoxyborohydride (7.99 g) and then acetic acid (3.0 mL). The reaction solution was stirred for 2 days. The reaction solution was poured into saturated aqueous sodium bicarbonate solution, and it was extracted with ethyl acetate. The extract was washed in turn with water and saturated aqueous sodium chloride solution, and dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was purified by chromatography (silica gel, 20% ethyl acetate/hexane) to give the title compound (6.49 g).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[CH3:24][N:25]1C=CN=C1>[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].[Cu]I>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:24]#[N:25])=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Reactant: Cn1ccnc1
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Cu]I
Agent: [K+]
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(C#N)sc2n1
Temperature: 160 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (100 mg, 0.232 mmol) in 1-methylimidazole (1.5 mL, 18.82 mmol) was added potassium ferrocyanide (17.06 mg, 0.046 mmol) and copper(I) iodide (4.41 mg, 0.023 mmol) and the reaction stirred at 160° C. for 16 h. The reaction mixture was then cooled to RT before directly purifying on silica, eluting with a gradient of 0-20% 2M NH3 in MeOH in DCM. Further purification by MDAP (acidic conditions), afforded the title compound (25.1 mg). LCMS (A) m/z: 378 [M+1]+, Rt 1.10 min (acidic).