Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[CH2:21]([SH:27])[CH2:22][CH2:23][CH2:24][CH2:25][SH:26]>>[SH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][S:27][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: SCCCCCS
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SCCCCCS)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 1,5-pentanedithiol to provide 5-[2-[(5-mercaptopentyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCL3) δ1.32 (m, 1H), 1.40-1.75 (m, 6H) and 1.65 and 1.68 (singlets, 3H), 2.33-2.45 (m, 2H), 2.45-2.60 (m, 2H), 3.06-3.25 (m, 2H), 4.40 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.18 (m, 2H), 7.25-7.43 (m, 6H); MS (HR-FAB) m/z 419.1180 (M+H calcd. for C22H27O2S3 419.1173).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C@H:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[N:14]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:13]=1)=[O:11])[CH3:8])=O.CCN(S(F)(F)F)CC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:1]1[CH2:2][CH2:3][N:4]=[C:5]1[C@H:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[N:14]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[CH:13]=1)=[O:11])[CH3:8]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(=O)NCCO
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1=NCCO1
Temperature: -76 °C
Reaction time: 6 h
Yield: 69.5 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(2-hydroxy-ethylcarbamoyl)-ethyl]-amide (126 mg, 0.23 mmol) was dissolved in dichloromethane (2.2 ml). The solution was cooled to −76° C. and DAST (45 μl, 0.34 mmol) was added. The pale yellow reaction mixture was stirred at −76° C. for 6 h then anhydrous potassium carbonate (64 mg, 0.46 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature, quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-90% EtOAc) to afford 86 mg (71%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4,5-dihydro-oxazol-2-yl)-ethyl]-amide as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:7]=1.[ClH:21]>C(Cl)Cl>[ClH:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(F)ccc1O
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc(F)cc1[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.6 %

Procedure:
To a solution of (R)-tert-butyl 2-(5-fluoro-2-hydroxyphenyl)pyrrolidine-1-carboxylate (3.2 g, 11.4 mmol) in DCM (20 mL) was added HCl (4 N dioxane, 5.69 mL, 22.7 mmol), and the mixture was stirred at ambient temperature for 15 hours. The reaction was concentrated, and the resulting precipitate was taken up in DCM (15 mL) and filtered to afford (R)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride (1.85 g, 90% yield) as a beige solid. MS (apci) m/z=182.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].[C:22]([O:26][C:27](=[O:39])[NH:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36](Br)[CH:37]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:39])[NH:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH:37]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)NCCOc1cncc(Br)c1
Product: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)OC(C)(C)C)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [C], 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to [2-(5-bromo-pyridin-3-yloxy)-ethyl]-carbamic acid tert-butyl ester (intermediate A-7) to give the title compound as a white solid. MS: 398.1 (M+H+).
Reaction SMILES: NCC[N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.C([NH:31][CH2:32][CH2:33][CH2:34]Br)(OC(C)(C)C)=O>>[NH2:31][CH2:32][CH2:33][CH2:34][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCCN)c2)c1

Procedure:
The title compound was synthesized according to above mentioned procedure for N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide, using 3-(Boc-amino)propyl bromide. LC-MS conditions B: tR=0.56 min, [M+H]+=326.19.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:28]O.Cl>CO.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:28][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenyl)piperidine-1-carboxylate (1.26 g, 3.59 mmol) (from example 25, step 1) was dissolved in MeOH (50 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.143 g, 3.59 mmol) dissolved in water (5.00 mL) was added during 5 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.220 mL, 3.59 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (17.93 mL, 107.58 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield trans-methyl 2-(4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.1 g, 95%) as a brown solid, 1.1 g. MS m/z 321 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:28])=[CH:22][C:20]=2[N:21]=1.O1CCOCC1>CN(C)C=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:19]3[S:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)=[N:21][C:20]=3[CH:22]=2)=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: Nc1nc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3nc4cc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)ccc4s3)c2cc1OC

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-5-yl]urea was prepared from 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 29 mg, 0.13 mmol) and 1-(2-aminobenzothiazol-5-yl)-3-(4-chloro-3-trifluoromethylphenyl)urea (Intermediate 5, 50 mg, 0.13 mmol) according to GP 1. Dimethylformamide was used as a solvent instead of dioxane. After removal of the solvent in vacuo, the residue was subjected to silica gel chromatography applying a dichloromethane-methanol gradient. The crude product was dissolved in dimethylformamide (2 mL) and water was added (2 mL). After storing in the fridge overnight, the resulting precipitate was filtered off, washed with water and dried (yellow solid, 7 mg, 12 μmol, 9%). LC/ESI-MS: m/z=575 [M(35Cl)+H]+; m/z=573 [M(35Cl)−H]−; Rt=4.17 min.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:10]=O.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:12]([NH:19][CH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Br:1])[C:6]#[N:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(Br)c(C=O)c1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(Br)c(CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromo-3-formyl-benzonitrile (2.42 g, 11.5 mmol) in MeOH (450 mL) was added benzylamine (1.88 mL, 17.3 mmol) and sodium cyanoborohydride (1.09 g, 17.3 mmol). Acetic acid (0.99 mL, 17.3 mmol) was added dropwise, and the reaction was stirred at room temperature overnight. The mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were dried, concentrated, and purified by silica gel chromatography (0-30% EtOAc in hexanes) to give 3-(benzylamino-methyl)-4-bromo-benzonitrile.
Reaction SMILES: [Br:1][CH2:2][CH:3]=[CH:4][CH2:5]Br.[Na].[CH2:8]1[O:18][C:17]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=2[O:9]1>COCCOC>[Br:1][CH2:2][CH:3]=[CH:4][CH2:5][O:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]2[O:18][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: BrCC=CCBr
Agent: [Na]
Solvent: COCCOC
Product: BrCC=CCOCc1ccc2c(c1)OCO2
Reaction time: 0.25 h

Procedure:
11.8 g (0.055 mol) of 1,4-dibromo-2-butene and 8.7 g (0.05 mol) of sodium salt of 3,4-methylendioxy-benzylalcohol are covered with a layer of 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 20°-25° for 16 hours and at 50° for 15 minutes. The solvent is subsequently distilled off at reduced pressure, the residue is taken up in ether and the ether solution is extracted with water. The organic phase is dried with sodium sulphate and the ether is then distilled off and the residue is chromatographed on silica gel with hexane/ethyl acetate 9 : 1. The chromatographically uniform 5-[(4-bromo-2-butenyloxy)-methyl]-1,3-benzodioxol is obtained as slightly yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[N+:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 35.6 %

Procedure:
To a solution of 1-bromo-4-(nitromethyl)benzene (5.00 g, 20 mmol) in toluene (40 mL) was added palladium tetrakis(triphenylphosphine) (2.67 g, 2.31 mmol), 4-(trifluoromethyl)phenylboronic acid (5.28 g, 27.8 mmol) and potassium fluoride (4.0 g, 69 mmol). The reaction mixture was purged with nitrogen and heated to reflux. Water (10 mL) was added and the mixture was refluxed overnight. The mixture was diluted with saturated aqueous NH4Cl and the phases separated. The aqueous layer was extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with water (50 mL*3), brine, dried over Na2SO4 and concentrated. The crude residue was purified by silica gel chromatography to give 4-(nitromethyl)-4′-(trifluoromethyl)biphenyl (2.0 g) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.75-7.66 (m, 6H), 7.57 (d, J=8.0 Hz, 2H), 5.51 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C@@H:21]([OH:23])[CH3:22])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1>>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C@@H:21]([OH:23])[CH3:22])=[O:18])[CH:14]=[N:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: C[C@H](O)CNC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: C[C@H](O)CNC(=O)c1cncc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with (S)-(+)-1-amino-2-propanol via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 7.6 mg of 342. MS (Q1) 516.5. (M)+.
Reaction SMILES: C([C:3]1[C:8]([Br:9])=[CH:7][C:6]([Br:10])=C[N:4]=1)#N.[C:11]([OH:14])(=[O:13])[CH3:12].S(=O)(=O)(O)O>O>[Br:10][C:6]1[C:12]([C:11]([OH:14])=[O:13])=[N:4][CH:3]=[C:8]([Br:9])[CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(Br)cc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ncc(Br)cc1Br
Temperature: 140 °C

Procedure:
2-Cyano-3,5-dibromopyridine (prepared in the above (2)) 3.27 g is added to a mixture of acetic acid 14 ml, sulfuric acid 14 ml and water 14 ml, and the mixture is refluxed at 140° C. for 4 hours. The reaction mixture is cooled and water is added thereto. The resulting precipitate is filtered and washed with water. The precipitate is dissolved in ether, washed and dried. The solvent is removed in vacuo and crystallized from a mixture of ether and hexane to give 3,5-dibromopyridine-2-carboxylic acid. mp 170-171° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[CH3:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>CO>[CH3:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7]
Reactant: COC(=O)C(C)(C)CN
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Solvent: CO
Product: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Temperature: 150 °C
Yield: 81.3 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (50 mg, 0.13 mmol) and 3-amino-2,2-dimethyl-propionic acid methyl ester (52 mg, 0.40 mmol) in MeOH (2 mL) was heated at 150° C. in a microwave reactor for 3 h. The solvent was evaporated, and the residue was purified by column chromatography (0-40% EtOAc/hexanes+2% AcOH) to give 46 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ ppm=14.0 (s, 1H), 8.20-8.35 (m, 2H), 7.87 (d, 1H, J=1.2 Hz), 6.40-6.70 (m, 6H), 3.79 (s, 3H), 3.61 (d, 2H, J=7.0 Hz), 1.30 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]=2[C:19]([O:21]CC)=[O:20])=[CH:5][CH:4]=1.[OH-].[Li+].Cl>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]=2[C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nc(-c2cccs2)oc1-c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2oc(-c3cccs3)nc2C(=O)O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxylate in MeOH (2 mL) and DCM (0.5 mL) was added 1M aqueous lithium hydroxide solution (2 mL, 2 mmol). The reaction mixture was stirred at 50° C. overnight and then 2M aqueous HCl (0.125 mL) was added and the solvent removed in vacuo to afford 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxylic acid which was used without further purification. LCMS (1) Rt: 1.34 min; m/z (ES+) 302.
Reaction SMILES: [NH2:1][C@H:2](C(N)=O)[CH2:3][C:4]1C=CC(O)=C[CH:5]=1.Cl.C([N:17]([CH2:20]C)[CH2:18][CH3:19])C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>>[N:17]1[C:18]2[CH:19]=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH:20]=1
Reactant: CCN(CC)CC
Reactant: NC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Yield: 193.1 %

Procedure:
To a 0° C. crude solution of compound 2 (4.1 g, 15.34 mmol), triethylamine (6.4 mL, 46.02 mmol) in dicholoromethane (200 ml) was added pentafluorophenyl trifluoroacetate (6.35 mL, 36.82 mmol) via syringe over 3 mins. After 5 mins the ice bath was removed and the reaction mixture was stirred while warming to room temperature for another 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate=1:0, 50:1) to give compound 3 (3.5 g, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.CC#N.OO.NC(N)=[O:19].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N+:3]=1[O-:19]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)[n+]([O-])c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 500 mL round bottom flask containing methyl 6-chloronicotinate (4.50 g, 26.2 mmol) was added MeCN (100 mL). The resulting mixture was then stirred at 0° C. for 10 min. At this time, urea hydrogen peroxide (4.93 g, 52.5 mmol) solid was added before the dropwise addition of trifluoroacetic anhydride (7.41 mL, 52.5 mmol). The reaction was stirred for 30 min and then the ice bath was removed. The reaction was then stirred for 3 h and then the bulk of MeCN was removed by rotary evaporation. The residue was dissolved in EtOAc (150 mL) and washed with sodium thiosulfate (aqueous, 0.5 M, 2×100 mL), water (100 mL), brine (100 mL), dried with sodium sulfate and concentrated to a tan solid. The solid thus obtained was dissolved in DCM (150 mL) and MeOH (30 mL). The solid residue was removed by filtration, and the filtrate was concentrated affording 2-chloro-5-(methoxycarbonyl)pyridine 1-oxide as a tan solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:11])([CH3:10])[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].[H-].[Na+].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>C1COCC1>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH2:2][C:3]([CH3:10])([CH3:11])[C:4]([NH:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)NC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)C(C)(C)COc1cccc(N)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a solution of 3-hydroxy-N-isopropyl-2,2-dimethylpropanamide (Example 134c, 5.12 g, 32.15 mmol) in dry THF (100 mL) was added portion-wise NaH (60% in mineral oil, 1.41 g, 35.37 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for about 30 minutes until bubbling ceased. 2-Amino-6-fluorobenzonitrile (4.38 g, 32.15 mmol) was added and the solution stirred at 80° C. overnight. The reaction mixture was quenched slowly with water at 0° C., and concentrated under reduced pressure. The residue was taken up in EtOAc and washed consecutively with brine and water, dried over Na2SO4 and concentrated. The residue was purified by re-crystallization from EtOAc/hexane to give the title compound as a white crystalline solid (4.4 g, 50%). 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J=6.8 Hz, 6H), 1.32 (s, 6H), 3.94 (s, 2H), 4.04-4.12 (m, 1H), 4.43 (s, 2H), 5.98 (d, J=6.8 Hz, 1H), 6.21 (d, J=8.0 Hz, 1H), 6.32 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H). MS 276 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:33]#[N:34]>CN(C=O)C.N1C=CC=CC=1>[C:33]([C:32]1[CH:35]=[CH:36][C:37]2[NH:38][C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[N:29][C:30]=2[CH:31]=1)#[N:34]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(C#N)ccc3[nH]2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
To the solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (15 g, 65.5 mmol) in DMF (50 mL) and pyridine (50 mL) was added CDI (10.6 g, 65.5 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 3,4-diamino-benzonitrile (8.7 g, 65.5 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (20 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound tert-butyl 4-(5-cyano-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (8 g, 65%) as pale solid.
Reaction SMILES: [CH2:1]([C:4]1[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]2[C:6](=[CH:7][C:8]3[C:9](=[O:30])[C:10]4[C:19]([C:20](=[O:29])[C:21]=3[CH:22]=2)=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=4)[CH:5]=1)[CH2:2][CH3:3].C([BH-](CC)CC)C.[Li+].Cl>C1COCC1>[OH:29][CH:20]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]([OH:30])[C:8]2[CH:7]=[C:6]3[C:23]([CH:24]=[C:25]([CH2:26][CH2:27][CH3:28])[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5]3)=[CH:22][C:21]1=2
Reactant: CCCc1cc2cc3c(cc2cc1CCC)C(=O)c1cc2ccccc2cc1C3=O
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1cc2cc3c(cc2cc1CCC)C(O)c1cc2ccccc2cc1C3O

Procedure:
A solution of 314 mg of 2,3-dipropyl-6,13-pentacenequinone dissolved in 60 mL of THF was added to 6 mL of a 1 mol/1000 mL THF solution of lithium triethylborohydride, and the mixture was heated for 20 hours under reflux in a nitrogen atmosphere. The resulting solution was neutralized with diluted aqueous hydrochloric acid, and the organic phase was separated, concentrated and dried under a vacuum to produce 6,13-dihydro-6,13-dihydroxy-2,3-dipropylpentacene almost stoichiometrically.