Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[N:17]=[CH:16][C:15]=2Br)=[C:10]([CH3:28])[N:9]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:8]1=[O:39])(=O)C.[C:40](B1OC(C)(C)C(C)(C)O1)([CH3:42])=[CH2:41].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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.C(OCC)(=O)C>[OH:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[N:17]=[CH:16][C:15]=2[CH:40]([CH3:42])[CH3:41])=[C:10]([CH3:28])[N:9]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=2)[C:8]1=[O:39]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)OCCn1c(=O)c(-c2c(Br)cnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1c(-c2c(C(C)C)cnn2-c2ccc(C#N)cc2)c(=O)n(CCO)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
To a solution of 2-(5-(4-bromo-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)ethyl acetate (prepared in Example 98) (220.3 mg) in dimethoxyethane (4.0 ml) were added isopropenyl boronic acid pinacol ester (69.0 μl), tetrakis(triphenylphosphine)palladium (85.2 mg), sodium carbonate (194.3 mg) and water (0.4 ml) and the resulting mixture was stirred at 100° C. for seven hours. To the reaction mixture was added ethyl acetate (100 ml) and the mixture was washed with water (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a solution of the residue in methanol (4 ml) was added palladium carbon (28.7 mg) and the resulting mixture was stirred at room temperature under hydrogen atmosphere for six hours. The reaction mixture was filtered through Celite (trade mark) and then concentrated under reduced pressure. To a solution of the residue in methanol (5 ml) was added under ice-cooling 1M aqueous potassium carbonate solution (392 μl) and the resulting mixture was stirred under ice-cooling for one hour. To the reaction mixture was added 1M hydrochloric acid (329 μl) and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate) to afford 4-(5-(3-(2-hydroxyethyl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-isopropyl-1H-pyrazol-1-yl)benzonitrile (62.6 mg) as white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH2:18][CH2:19][CH2:20][CH3:21])=O)C.[BH4-].[Li+]>>[OH:3][CH2:4][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]([C:16]#[N:17])[CH:9]2[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1c(C#N)cnc2ccc(C(=O)OCC)cc12
Agent: [BH4-]
Agent: [Li+]
Product: CCCCC1C(C#N)=CNc2ccc(CO)cc21

Procedure:
Similar procedure as described in example 46e was used, starting from 3-cyano-4-butyl-quinoline-6-carboxylic acid ethyl ester (example 49a) and lithium borohydride to give 6-hydroxymethyl-4-butyl-1,4-dihydro-quinoline-3-carbonitrile as a yellow solid. LC-MS m/e 243 (MH+).
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[Cl:8][C:9]1[CH:10]=[C:11]([O:33][CH2:34][CH:35]=[O:36])[CH:12]=[N:13][C:14]=1[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:26][C:27]1[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=1>O>[Cl:8][C:9]1[CH:10]=[C:11]([O:33][CH2:34][CH2:35][OH:36])[CH:12]=[N:13][C:14]=1[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:26][C:27]1[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(OCC=O)cc4Cl)cc23)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(OCCO)cc4Cl)cc23)n1
Reaction time: 0.25 h

Procedure:
With cooling with ice, sodium borohydride (9 mg, 0.25 mmol) was added to a tetrahydrofuran (3 ml)/water (0.3 ml) mixed solution containing {[5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}acetaldehyde obtained in Example 1, and the reaction solution was stirred for 15 minutes. Saturated saline water was added to the reaction solution, extracted with chloroform/methanol (9:1), the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:4 to 100:5) and reversed-phase liquid chromatography (YMC CombiPrep Pro C18 AS-360-CC), and the obtained solid was recrystallized from ethyl acetate to obtain the entitled compound (19 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([B:9]2[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C(OCC)(=O)C>[CH3:15][C:12]1([CH3:16])[CH2:13][O:14][B:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])[O:10][CH2:11]1
Reactant: CC1(C)COB(c2cccc(CBr)c2)OC1
Reactant: CCNCC
Solvent: CCOC(C)=O
Product: CCN(CC)Cc1cccc(B2OCC(C)(C)CO2)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
2-(3-Bromomethyl-phenyl)-5,5-dimethyl-[1,3,2]dioxaborinane (0.21 mmol, 60 mg) and diethyl-amine (1 mL, >10 equiv) were combined and left to stir at 70° C. for 4 hours. The reaction mixture was then diluted with ethyl acetate, concentrated in vacuo and dried on high vacuum for 1 hour. The residue was then dissolved in dichloromethane, washed with water, followed by brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the final product as yellow oil (37.7 mg, 65%). 1H NMR (300 MHz, CDCl3): δ (ppm)=7.71 (m, 2H), 7.44 (m, 1H), 7.33 (m, 1H), 3.79 (s, 4H), 3.59 (s, 2H), 2.54 (q, 4H), 1.06 (t, 6H), 1.04 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:20][S:21]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCc1cccc(OCc2ccccc2)c1
Product: CS(=O)(=O)OCCCCc1cccc(OCc2ccccc2)c1

Procedure:
In substantially the same manner as in Reference Example 85, 4-(3-benzyloxyphenyl)butanol was allowed to react with methanesulfonylchloride to give 4-(3-benzyloxyphenyl)butyl methanesulfonate. The yield was quantative. Oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH:7]([C:17]([OH:19])=[O:18])[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH:7]([C:17]([O:19][CH3:27])=[O:18])[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1
Reactant: CO
Reactant: Cc1ccc2c(c1)Cc1cc(C)ccc1OC(C(=O)O)O2
Agent: O=S(=O)(O)O
Product: COC(=O)C1Oc2ccc(C)cc2Cc2cc(C)ccc2O1

Procedure:
The carboxylic acid was dissolved in 300 ml of methanol and 2 ml of concentrated sulfuric acid was added. The mixture was refluxed for 1 hour, cooled, the resulting crystals collected and recrystallized from methanol-acetone to give methyl 2,10-dimethyl-12H-dibenzo[d,g][1,3]dioxocin-6-carboxylate, m.p. 158°-160°C. The methyl ester and excess diethylamine are refluxed for 16 hours. The remaining diethylamine is removed, and N,N-diethyl-2,10-dimethyl-12H-dibenzo[d,g][1,3]dioxocin-6-carboxamide is obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH:10]=[CH:11][CH:12]=1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:1](=[O:3])[CH3:2])[CH2:15]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)Cl
Reactant: Fc1cccc(C=C2CCCNC2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)N1CCCC(=Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (0.515 mL) was added to a mixture of 3-[1-(3-fluorophenyl)methylidene]-piperidine hydrochloride (Intermediate 226, 1.5 g) and N,N-di-isopropyl-N-ethylamine (2.52 mL) in anhydrous THF (50 mL) at 0° C. under nitrogen. The mixture was allowed to warm to room temperature and was stirred for 2 hours. The mixture was diluted with water (100 mL) and extracted with ether, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 75-100% to give 1-{3-[1-(3-fluorophenyl)-methylidene]piperidin-1-yl}ethanone (1.38 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])=[CH:11][CH:10]=1.[F:27][C:28]1[C:35]([F:36])=[CH:34][C:33]([CH2:37][CH2:38][OH:39])=[CH:32][C:29]=1[CH:30]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:27][C:28]1[C:35]([F:36])=[CH:34][C:33]([CH2:37][CH2:38][OH:39])=[CH:32][C:29]=1[CH2:30][N:24]1[CH2:25][CH2:26][C:20]2([O:19][CH2:18][CH2:17][N:16]([C:14]([C:12]3[S:13][C:9]([CH3:8])=[CH:10][CH:11]=3)=[O:15])[CH2:21]2)[CH2:22][CH2:23]1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reactant: O=Cc1cc(CCO)cc(F)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)cc(F)c4F)CC3)C2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(5-Methylthiophen-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 9, step b) (0.53 g) was added to a solution of 2,3-difluoro-5-(2-hydroxyethyl)benzaldehyde (example 32, step b) (0.25 g) and acetic acid (0.08 mL) in methanol (5 mL). The reaction was stirred for 30 min and cooled in an ice bath. Sodium cyanoborohydride (0.13 g) was then added, the mixture allowed to warm to RT and stirred for 18 h. The reaction was concentrated in vacuo. Purification was by silica gel chromatography eluting with 99:1:0.1 to 97:3:0.3 DCM:methanol:‘880’ aqueous ammonia gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a gum. Yield 0.08 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29]Cl)=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:14][CH:13]=3)[C:6]=2[CH:28]=1.[C:31]([OH:35])(=[O:34])[CH2:32][CH3:33].C([O-])(O)=O.[Na+].O>CN(C)C=O>[C:31]([O:35][CH2:29][C:3]1[C:2]([Cl:1])=[CH:28][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])=[CH:14][CH:13]=3)[C:8]([CH2:10][CH3:11])=[N:9][C:5]=2[CH:4]=1)(=[O:34])[CH2:32][CH3:33]
Reactant: CCc1nc2cc(CCl)c(Cl)cc2n1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Reactant: CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)OCc1cc2nc(CC)n(-c3ccc(CCO[Si](C)(C)C(C)(C)C)cc3)c2cc1Cl
Temperature: 60 °C
Reaction time: 7 h
Yield: 54.5 %

Procedure:
To a solution of 6-chloro-5-(chloromethyl)-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole (step 2, 403 mg, 0.86 mmol) in N, N-dimethylformamide (10 ml) was added propionic acid (0.06 ml, 0.86 mmol) and NaHCO3 (144 mg, 1.72 mmol) at room temperature. The mixture was stirred at 60° C. for 7 h. The mixture was added water (50 ml) and extracted with ethyl acetate(100 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (8:1/4:1) to afford 235 mg (53%) of the title compound as pale yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: COC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
To a stirred solution of 4-fluoro nitrobenzene (1a, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxy-late (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4-nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8a, 323 mg, 81%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@@H:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[N:12]=1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@@H:27]([OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: CC1(C)OC[C@@H](COc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1cc(OC[C@@H](O)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step ii) (0.48 g) in methanol (5 mL)/H2O (0.1 mL) was added pyridinium p-toluenesulfonate (0.12 g) and the mixture was stirred at reflux for 2 h. The reaction mixture was evaporated, suspended in H2O and extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was triturated with DCM to give the title compound as a white solid. Yield: 0.30 g
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:24].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH2:21][Br:24])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(OCCNC(=O)OCc2ccccc2)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: O=C(NCCOc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Yield: 90 %

Procedure:
Benzyl-[2-(4-acetyl-phenoxy)-ethyl]-carbamate (10.2 g, 32.5 mmol) was dissolved in methylene chloride (100 ml) and methanol (50 ml), and tetrabutylamonium tribromide (15.7 g, 32.5 mmol) was added in one portion. The reaction mixture was stirred for about sixteen hours, and then quenched with water. The aqueous phase was extracted with ethyl acetate and then washed with saturated aqeous sodium bicarbonate, and saturated Na2S2O3. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo, and the resulting crude material was purified by column chromatography (silica gel; hexanes to 2:1 hexanes/ethyl acetate) to afford a colorless oil which solidified upon standing. (11.5 g, 90% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:12]2[CH:16]=[C:15]([CH2:17]O)[N:14]=[CH:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl.CN(C=O)C.CCCCCC>[Cl:3][CH2:17][C:15]1[N:14]=[CH:13][N:12]([C:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
Thionyl chloride (0.82 g) was added over 1 min. to a stirred suspension of 1-(triphenylmethyl)-1H-imidazole-4-methanol (1.3 g) in a mixture of dichloromethane (50 ml) and DMF (1.0 ml) at 23°. The solution so obtained was stirred for 15 min. and extracted with 8% sodium bicarbonate solution (80 ml). The organic phase was washed with water (50 ml), dried and evaporated to give an oil which solidified. The solid was slurried in hexane and filtered to give the title compound (1.28 g), m.p. 139°-141°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:28][CH:27]=2)=[O:24])[CH:17]=[CH:18][C:19]=1[OH:20]>C(O)(=O)C>[OH:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:34][N:35]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:33])=[CH:28][CH:27]=2)=[O:24])[CH:17]=[CH:18][C:19]=1[OH:20]
Reactant: NNC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(CCc1ccc(O)c(O)c1)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-(3,4-dihydroxyphenyl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 161 mg of the title compound (87%) as a yellow solid in 96% purity by HPLC (Rt: 3.56, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[CH:18]=[N:17][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[C:9]([CH2:15][CH3:16])[C:8]=3[C:4]=2[CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:15]([C:9]1[C:8]2[C:4]3[CH:3]=[C:2]([C:29]4[CH:28]=[CH:27][C:26]([CH2:25][N:19]5[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]5)=[CH:31][CH:30]=4)[CH:18]=[N:17][C:5]=3[NH:6][C:7]=2[CH:12]=[N:11][C:10]=1[C:13]#[N:14])[CH3:16]
Reactant: CCc1c(C#N)ncc2[nH]c3ncc(Br)cc3c12
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCc1c(C#N)ncc2[nH]c3ncc(-c4ccc(CN5CCCCC5)cc4)cc3c12
Temperature: 140 °C
Yield: 45.8 %

Procedure:
A mixture of 3-bromo-5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (48 mg, 0.16 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (56 mg, 0.26 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg, 0.016 mmol) in 2N aqueous sodium carbonate (0.5 mL) and acetonitrile (0.63 mL) was heated under microwave irradiation at 140° C. for 35 minutes. The reaction mixture was allowed to cool to ambient temperature, diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 2 g column, ISCO, 0-5% methanol in DCM) and trituration with diethyl ether (2×1 mL) to afford the title compound as a beige solid (29 mg, 46%). 1H NMR (DMSO-D6, 400 MHz): 12.93 (br. s, 1H), 8.99 (d, J=2.2 Hz, 1H), 8.91 (s, 1H), 8.79 (d, J=2.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 3.53-3.43 (m, 4H), 2.42-2.33 (m, 4H), 1.55-1.47 (m, 4H), 1.46-1.37 (m, 5H). LCMS (Method A): RT=6.23 min, M+H+=396.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=1
Reactant: CCOC(=O)c1csc(-c2cccs2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1csc(-c2cccs2)n1
Yield: 94 %

Procedure:
In substantially the same manner as in Reference Example 72, ethyl 2-(2-thienyl)-4-thiazolecarboxylate was reduced with lithium aluminum hydride to give crystals of 2-(2-thienyl)-4-thiazolylmethanol. The yield was 94%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 54-55° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=O)[CH2:9]2)=[CH:4][C:3]=1[F:13].[BH3-]C#[N:16].[Na+]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH2:16])[CH2:9]2)=[CH:4][C:3]=1[F:13]
Reactant: O=C1CCc2cc(F)c(Br)cc2C1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: NC1CCc2cc(F)c(Br)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-Bromo-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine XVI was prepared from commercial available 7-bromo-6-fluoro-3,4-dihydro-1H-naphthalen-2-one XV. To a stirred solution of XV (0.10 g, 0.41 mmol) in 3 mL of MeOH was added NH4OAc, followed by NaCNBH3 (0.018 g) in one portion at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h. Removal of solvent under vacuum gave the crude product, which was partitioned between 2N Na2CO3 and CH2Cl2. The organic layer was separated and dried over MgSO4. The solvent was removed under vacuum and the so-obtained crude product was dissolved in 2 mL of CH2Cl2. To this solution was added TEA (0.12 mL) and (Boc)2O (90 mg, 0.41 mmol). The reaction mixture was stirred at rt overnight. Removal of the solvent under vacuum gave the crude product, which was purified by column to give the pure product XVII (119 mg, 84% over 2 steps). MS: calc'd (MH+) 344, exp (MH+) 344.