Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=1)#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Product: N#CNC(=NCc1ccc(Cl)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.1 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 4-chlorobenzylamine (0.48 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.13 g, 0.5 mmol, yield: 16%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[C:14]([O:21]C(=O)C)[CH:13]=1.Cl>CN(C)C1C=CC=CC=1.CC(C)=O.[OH-].[Na+]>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([Cl:10])[C:5]=1[OH:9])[NH:1][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH3:11])=[CH:13][C:14]=1[OH:21]
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)Cl
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(C(=O)Nc2cc(Cl)c(O)c(Cl)c2)c(O)c1
Yield: 72.5 %

Procedure:
4-Amino-2,6-dichlorophenol (16 g.) was put into solution in N,N-dimethylaniline (15 ml.) and acetone (200 ml.), to which the acetone solution of 4-methyl-2-acetoxybenzoyl chloride was added dropwise. After reaction for several hours, by condensing and then acidifying the solution with 4 N hydrochloric acid a precipitate was obtained, which was redissolved in 2 N sodium hydroxide solution. The solution was made acidic with dilute hydrochloric acid, thereby precipitating the product which was recrystallized from aqueous acetone to give white crystals (20.3 g.) of 3',5'-dichloro-2,4'-dihydroxy-4-methylbenzanilide. Yield: 72.5%. The melting point was 246°-247° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>>[ClH:23].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[S:31]([N:18]1[C:19]2[C:15](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: Cl
Product: O=S(=O)(c1cc(Cl)ccc1Cl)n1ccc2c(N3CCNCC3)cccc21

Procedure:
The title compound was prepared according from 4-(4-boc-piperazinyl)-indole and 2,5-dichlorophenylsulfonyl chloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.09 (br, 1 H), 8.25 (d, J=3 Hz, 1 H), 7.91–7.81 (m, 2 H), 7.72 (d, J=8 Hz, 1 H), 7.36 (d, J 8 Hz, 1 H), 7.23 (t, J=8 Hz, 1 H), 6.98 (d, J 3 Hz, 1 H), 6.82 (d, J=8 Hz, H), 3.26(m,8 H).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])C=1.C(I)C.[Li+].CC([N-]C(C)C)C>CCCCCC.C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:7]=1[CH2:5][CH3:6]
Reactant: Brc1cccc(Br)c1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c(Br)cccc1Br
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a three litre neck round flask charged with 19.30 g of diisopropylamine and 110 mL of THF was added 76 mL of n-BuLi in hexane (2.5 M) in dropwise at −70° C. After addition was finished, the resulting mixture was stirred at the same temp. for 10 min. In another 500 mL three neck round flask, 25 g of 1,3-dibromobenzene and 49.6 g of ethyl iodide was mixed well and cooled to −70° C. The freshly prepared LDA was introduced dropwise to above mixture below −65° C. After the addition was finished, the resulting mixture was stirred for 4 h at the same temp. GCMS showed that the desired product was formed. The reaction was warmed to 0° C. in 30 mins. To the reaction mixture was added 100 mL of sat. ammonium chloride solution to quench the reaction.
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2Cl)=[N:14][C:13]([Cl:18])=[CH:12][CH:11]=3)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]2)=[N:24][CH:25]=1>>[Cl:18][C:13]1[N:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])=[C:16]2[NH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27]2)=[N:24][CH:25]=1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CCC4)cnc4ccc(Cl)nc34)cn2)C1
Yield: 91.8 %

Procedure:
Following general procedure I, cyclobutyl(4,6-dichloro-1,5-naphthyridin-3-yl)methanone (200 mg, 0.71 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (311 mg, 1.1 mmol) to afford the desired product (350 mg, 78%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 11.52 (s, 1H), 8.88 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 7.31 (dd, J=9.0, 2.7 Hz, 1H), 6.72 (d, J=9.0 Hz, 1H), 4.81 (br s, 1H), 4.15-3.97 (m, 1H), 3.91-3.60 (m, 3H), 3.58-3.31 (m, 2H), 2.54-2.21 (m, 4H), 2.20-2.00 (m, 1H), 2.00-1.85 (m, 2H), 1.82-1.63 (m, 2H), 1.51 (s, 9H); ESI MS m/z 537 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Li+].CCC[CH2-].[Cl-].[CH:17]([SiH:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18].O>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: CC(C)[SiH](C(C)C)C(C)C
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(F)cc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
To a solution of 400 mg (2.96 mmol) of 6-fluoroindole dissolved in 6 ml of anhydrous tetrahydrofuran are added dropwise at −78° C. under argon 1.18 ml of a N-butyllithium solution (2.5M in hexane, 2.96 mmol). The reaction mixture is stirred for 5 min at −78° C., then 634 μL (2.96 mmol) of triisopropylsilane chloride are added dropwise at −78° C. to the reaction mixture. This mixture is stirred for 20 min at room temperature then water is added. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 99:1) to yield 760 mg (89%) of 6-fluoro-1-triisopropylsilylindole as a colourless oil.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][N:2]=2)=[O:13])[CH2:30][CH2:29]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1nccc2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](NC(=O)c2nccc3ccccc23)CC1
Temperature: 50 °C

Procedure:
A solution of isoquinoline-1-carboxylic acid (346 mg, 2 mmol), and 1,1′-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.523 mL, 3 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with ethyl acetate (20 mL). The organic solution was washed with water (3×15 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 429 mg (80%) of 405:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:22]1([C:26]([C:28]2[CH:29]=[C:30]([Cl:35])[C:31](Cl)=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:22]1([C:26]([C:28]2[CH:29]=[C:30]([Cl:35])[C:31]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1
Reactant: CC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
A solution of 3-hydroxy-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (116 mg, 0.4 mmol) and the 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (111 mg, 0.48 mmol) in acetonitrile (2 mL) containing potassium carbonate (111 mg, 0.8 mmol) was heated with stirring in the microwave reactor for 6 hours at 160° C. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane, to give the required product (177 mg).
Reaction SMILES: [Br:1]Br.Cl.[S:4]1[C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=[CH:5]1>C(O)(=O)C>[BrH:1].[Br:1][C:5]1[S:4][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1
Reactant: c1cc2c(s1)CNCC2
Reactant: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: Br
Product: Brc1cc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 176.8 %

Procedure:
A solution of bromine (139 mg, 0.87 mmol) in acetic acid (0.5 mL) was added to a solution of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride (150 mg, 0.85 mmol) in acetic acid (3 mL) and the mixture left to stir at ambient temperature for 1.5 h. The resultant precipitate was collected by filtration, washed with diethyl ether and left to air dry to afford the title compound as an off-white solid (230 mg, 90%). 1H NMR (DMSO-D6, 300 MHz): 9.19 (s, 2H), 7.09 (s, 1H), 4.29-4.26 (m, 2H), 2.86-2.78 (m, 2H), 2.52-2.48 (m, 2H). LCMS (Method B): RT=1.65 min, M+H+=218/220.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C.O>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][O:8][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[O:3][C:2]=1[CH3:1])=[O:9]
Reactant: Cc1cc(C(=O)O)c(C)o1
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOC(=O)c1cc(C)oc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
A 2 L round-bottomed flask equipped with a mechanical stirrer was charged with 2,5-dimethyl-3-furoic acid (81.0 g, 0.58 mol) and potassium carbonate (95.9 g, 0.69 mol) in DMF (500 mL). An ice bath was used to cool the reaction as 2-methoxyethoxymethyl chloride (72.2 g, 0.58 mol) was added portionwise. The reaction was stirred for 5 h at rt. The mixture was then diluted with water (1.5 L) and extracted with EtOAc (2×600 mL). The combined organics were washed with water (2×900 mL) and saturated sodium chloride solution (1 L), dried over MgSO4, filtered and concentrated to afford compound 803A (103 g, 82%) as a yellow oil. 1H NMR (CDCl3): δ=6.23 (s, 1H), 5.47 (s, 1H), 3.84 (m, 2H), 3.56 (m, 2H), 3.38 (s, 3H), 2.51 (s, 3H) and 2.20 ppm (s, 3H).
Reaction SMILES: O.[ClH:2].Cl.C([O:11][C:12]1[CH:29]=[CH:28][C:15]([O:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].CO>[ClH:2].[ClH:2].[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][O:16][C:15]2[CH:14]=[CH:13][C:12]([OH:11])=[CH:29][CH:28]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1ccc(COc2ccc(OCCNCCCn3ccnc3)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1ccc(OCCNCCCn2ccnc2)cc1

Procedure:
N-[2-(4-Benzyloxyphenoxy)ethyl]-3-(imidazol-1-yl)propylamine dihydrochloride hydrate (4.24 g) was suspended in IMS (200 ml) and methanol (10 ml) and hydrogenated at atmospheric pressure using 10% palladium/charcoal as a catalyst (0.44 g). The mixture was filtered and the filtrate evaporated to give a residue which was triturated with warm ether and filtered to give a solid which was recrystallised from methanol/ether to give 4-{2-[3-(imidazol-1-yl)propylamino]ethoxy}phenol dihydrochloride, m.p. 195-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Br:15]Br>C(OC(=O)C)C>[Br:15][CH:10]([CH:11]([CH3:12])[CH3:13])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: COc1ccc(C(=O)CC(C)C)cc1
Reactant: BrBr
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)C(Br)C(C)C)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
While 56.9 g of 1-(4-methoxy-phenyl)-3-methyl-butan-1-one (3) prepared in Example 1 were added to 200 ml of ethylacetate and stirred, 18.2 ml of bromine were added at room temperature and stirring was continued at the same temperature for 1 hr. After the reaction was completed, the resultant reaction mixture was washed with brine and water, in that order, after which the ethylacetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, thus obtaining 77.0 g (yield: 96.0%) of a title compound as light yellow liquid.
Reaction SMILES: [SH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC.CN(C)[CH:22]=[O:23]>C(OCC)(=O)C>[CH3:11][C:3]1[C:2]([S:1][CH3:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:23][CH3:22])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: Cc1c(S)cccc1C(=O)O
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(SC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A mixture of 3-mercapto-2-methylbenzoic acid (180 mg, 1.05 mmol), cesium carbonate (690 mg, 2.1 mmol) and iodomethane (132 L1, 2.10 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate then washed with 5% aqueous lithium chloride, 1N aqueous sodium hydroxide, and brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded 138 mg, 0.62 mmol (58%) of methyl 2-methyl-3-(methylthio)benzoate. 1H NMR (400 MHz, CDCl3): 7.58 (d, 1H), 7.41 (d, 1H), 7.21-7.16 (m, 1H), 4.09 (s, 3H), 2.83 (s, 3H), 2.58 (s, 3H). MS (EI) for C10H12SO2: 197 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH:25]([S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28])=[CH2:26]>CC(O)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[C:6]2[C:5]3[C:13](=[CH:14][C:2]([N:1]4[CH2:31][CH2:30][S:27](=[O:29])(=[O:28])[CH2:25][CH2:26]4)=[CH:3][CH:4]=3)[NH:12][C:11]=2[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Reactant: C=CS(=O)(=O)C=C
Solvent: CC(C)O
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 100 °C
Yield: 28.3 %

Procedure:
A suspension of 7-amino-4-(2-fluorophenyl)-9H-carbazole-1-carboxamide (Example 54-1, 36 mg, 0.113 mmol) in 2-propanol (1.0 mL) was treated with vinylsulfonylethene (20 μL, 0.199 mmol) at rt. The reaction mixture was heated at 100° C. for 26 h. The mixture was cooled to rt, concentrated and the residue was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-(1,1-dioxothiomorpholino)-9H-carbazole-1-carboxamide as a yellow solid (14 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 11.26 (1 H, s), 8.17 (1 H, br. s.), 7.90 (1 H, d, J=7.9 Hz), 7.47-7.62 (3H, m), 7.37-7.46 (2 H, m), 7.35 (1 H, d, J=1.8 Hz), 7.01 (1 H, d, J=7.9 Hz), 6.93 (1H, d, J=8.3 Hz), 6.74 (1 H, dd, J=9.0, 2.4 Hz), 3.77-3.81 (4 H, m), 3.08-3.19 (4 H, m). Mass spectrum m/z 438.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N([CH2:32][CH3:33])CC)C.O1C[CH2:37][CH2:36][CH2:35]1>O>[CH:33]1([O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:32][CH2:37][CH2:36][CH2:35]1
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccccc1
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Solvent: O
Product: NC(=O)OC(CCN1CCN(c2ccc(OC3CCCC3)cc2)CC1)c1ccccc1
Reaction time: 10 h

Procedure:
The compound ‘carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-1-phenyl-propyl ester (2 mmol) prepared in Example 84 was dissolved in tetrahydrofuran (25 mL), and triethylamine (2.4 mmol) and bromopentyl (2.4 mmol) were added thereto, and the resulting mixture was stirred at 80? for 10 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N:18][CH:19]=[CH:20][CH:21]=2.[OH:23]O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N+:18]([O-:23])[CH:19]=[CH:20][CH:21]=2
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ncccc2[nH]1
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2c(ccc[n+]2[O-])[nH]1

Procedure:
3.19 g of 2-(2-methoxy-4-methanesulfonyloxy-phenyl)imidazo[4,5-b]pyridine were dissolved in 25 ml of trifluoroacetic acid, and then 5 ml of 30% hydrogen peroxide were added dropwise thereto. The mixture was refluxed for one hour and concentrated to about one-tenth of its volume. The residue was poured onto ice and digested until it had crystallized throughout.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.[Br:23]Br>C(O)(=O)C.ClCCl>[Br:23][C:17]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[C:6]([F:18])=[CH:5][C:4]([NH:19][C:20](=[O:22])[CH3:21])=[CH:3][C:2]=2[F:1])[NH:15][CH:16]=1
Reactant: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]cc(Br)c23)c(F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1.05 g (3.45 mmol) of N-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]acetamide are dissolved in 35 ml of glacial acetic acid and, using an ice bath, cooled to about 10° C. 4.8 ml (4.8 mmol) of a 1M solution of bromine in dichloromethane are added, and the mixture is stirred at 20° C. for about 30 min, resulting in the precipitation of a solid. The solid is filtered off with suction and washed with ethyl acetate. The mother liquor is neutralized using conc. aqueous sodium hydroxide solution and extracted with ethyl acetate. The crystals that were filtered off with suction are dissolved in 3 ml of DMF. The mixture is diluted with ethyl acetate and extracted three times with 1N sodium hydroxide solution. The combined organic phases are dried over magnesium sulfate. The solvent is removed under reduced pressure. The product is reacted without further purification.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)=[CH2:2].[CH2:8]([O:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][C:17]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:8]([O:15][C:16]1[CH:21]=[C:20](/[CH:2]=[CH:1]/[N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH:19]=[CH:18][C:17]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=Cn1cncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CN(c2ccc(/C=C/n3cncn3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 110 °C

Procedure:
A mixture of 1-vinyl-1,2,4-triazole (0.100 g, 1.06 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.236 g, 0.531 mmol), palladium acetate (0.024 g, 0.107 mmol), triethylamine (0.295 mL, 2.09 mmol) in acetonitrile is heated in a microwave apparatus at 110° C. for 30 min. The mixture is filtered over Celite, washed with acetonitrile, and concentrated. The residue is purified by column chromatography using a gradient of 10-60% EtOH/water as eluent to afford the title compound: (M−1)−=410.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CCCCC.S(O[CH2:33][CH2:34][C:35]1[O:36][CH:37]=[CH:38][CH:39]=1)(=O)(=O)C>CN(C)C=O>[O:36]1[CH:37]=[CH:38][CH:39]=[C:35]1[CH2:34][CH2:33][N:12]1[C:11](=[O:20])[CH2:10][C@@:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19]
Reactant: CS(=O)(=O)OCCc1ccco1
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CCc2ccco2)C(=O)C3)c1
Temperature: 0 °C

Procedure:
A solution of 5.0 g (18.5 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 100 ml of anhydrous dimethylformamide was added to a stirred suspension of 1.4 g (28 mmoles) of 50% sodium hydride in mineral oil (washed with pentane) in 75 ml of anhydrous dimethylformamide heated at 50° under nitrogen. The mixture was heated at 90° for 2 hours, then cooled to 35°. A solution of 7.1 g (37 mmoles) of freshly prepared 2-furylethyl mesylate (prepared according ot the procedure of Crossland and Servis, J. Org. Chem., 35, 3195 (1970)) in 10 ml of anhydrous dimethylformamide was added and the reaction mixture heated at 90° overnight. It was the cooled and poured into ice-water, and extracted with ether. Evaporation of the ether gave an oil which was purified by column chromatography (Silicar CC-7, eluting with acetone-benzene). The major fraction was identified as N-(2-furylethyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]>CC(O)=O.C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1C#N
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CN
Yield: 68.9 %

Procedure:
A clear solution of tert-butyl (5-cyano-6-methoxy-4-methylpyridin-2-yl)carbamate (0.60 g, 2.279 mmol) in HOAc (5 mL) and ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min., Raney Nickel cartridge) for 18 hr. LCMS showed that the reaction was complete (86% pure). The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 12% (5% NH4OH/MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum to give the product tert-butyl (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.42 g, 1.571 mmol, 68.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1 H), 7.16 (s, 1 H), 3.80 (s, 3 H), 3.57 (s, 2 H), 2.28 (s, 3 H), 1.46 (s, 9 H). MS(ES)+m/e 268.1 [M+H]+.