Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2sccc2c1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2sccc2c1O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-bromo-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (example 43 a, 165 mg, 0.5 mmol), ethynyl-trimethyl-silane (87 μl, 0.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.015 mmol), CuI (5 mg, 0.025 mmol), and triethylamine (1.5 ml) was heated in a microwave oven at 100° C. with stirring for 15 min. After cooling to ambient temperature water (20 ml) was added and the mixture was extracted with diethylether (1×30 ml). The organic phase was dried over MgSO4. Then silica gel was added and the mixture concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with ethyl acetate:hexanes=9:1 and in vacuo concentration gave the title compound as a dark oil (75 mg); MS-(+)-ion: MS-(+)-ion: M+1=348.4.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([CH:14]1[CH2:16][CH2:15]1)([OH:13])[CH3:12])=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][CH2:10][C:11]([CH:14]2[CH2:16][CH2:15]2)([OH:13])[CH3:12])=[O:8])[CH:32]=[CH:33][CH:34]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Product: CC(O)(CNC(=O)c1cc(-c2cccc(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-(2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 3-chlorophenylboronic acid as starting materials, MS (ISP) 531.0, 497.1 (M)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[NH2:13].[Br:14]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:14][C:10]1[CH:9]=[C:8]([CH3:12])[C:7]([NH2:13])=[C:6]([C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)[CH:11]=1
Reactant: Cc1cccc(C2=NCCN2)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C2=NCCN2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
To a solution of the title compound of Step B (0.38 g, 2.17 mmol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (0.38 g, 2.13 mmol) and the mixture was stirred at ambient temperature for 1 hour. Additional N-bromosuccinimide (0.06 g, 0.34 mmol) was added and the mixture stirred for an additional 0.5 hour before being diluted with ethyl acetate and washed three times with water. The combined aqueous fractions were extracted with ethyl acetate and the organic layer was washed with water. The combined organic fractions were dried (magnesium sulfate), concentrated and purified by flash column chromatography (silica gel, 2% then 5% methanol in dichloromethane) to give the title compound of Step C (94 mg) as a light brown oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[NH:12][C:11]=2[C:10](=[O:27])[N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:8]1=[O:36].[BH4-].[Li+]>O1CCCC1>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:9]1[C:10](=[O:27])[C:11]2[NH:12][C:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=3)=[N:14][C:15]=2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[C:8]1=[O:36]
Reactant: COC(=O)CCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCCO)cc1

Procedure:
Prepared by the reduction of 4-[8-(4-acetylamino-benzyl)-1-(2-fluorobenzyl)-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-yl]-butyric acid methyl ester with lithium borohydride in tetrahydrofuran. The product was purified by chromatography on silica gel eluted with 9:1 chloroform/methanol. MS, m/z(M+)=479.1967.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=1.C(=O)(O)[O-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2cccnc2)cc1
Temperature: 0 °C
Yield: 77 %

Procedure:
A stirred solution of 4-nitrophenyl 3-pyridyl sulfone (1.60 g, 6.1 mmol) and stannous chloride dihydrate (6.83 g, 30.2 mmol) in absolute ethanol (20 mL) was heated at reflux for 45 min. The reaction mixture was poured into ice water, and the aqueous solution basified with sodium bicarbonate (pH=8-9) and extracted with ethyl acetate (2×200 mL). The organics were combined, dried (MgSO4), filtered, and the solvent distilled to yield the title benzenamine (1.10 g, 79%) as a pale yellow solid; mp 182°-184° C. 1H-NMR (300 MHz, d6 -DMSO): 6.29 (broad s, 2H, NH2), 6.64 (d, 2H, J=11.2 Hz, aromatic), 7.58 (m, 1H, aromatic), 7.61 (d, 2H, J=11.1 Hz, aromatic), 8.21 (dd, 1H, J=9.8, 2.4 Hz, aromatic), 8.78 (dd, 1H, J=9.9, 1.4 Hz, aromatic), 9.01 (d, 1H, J=2.4 Hz). MS (CI, CH4): 235(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:17]([CH3:19])[CH3:18])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].CCN(CC)CC.ClC(OCC(C)C)=O.[N+:35](=[CH2:37])=[N-:36]>O1CCCC1.CCOCC>[N+:35](=[CH:37][C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:17]([CH3:19])[CH3:18])=[O:16])=[N-:36]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-])C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A mixture of Example 37B (100 mg, 0.367 mmol) and Et3N (154 μL, 1.102 mmol) in tetrahydrofuran (4 mL) at 0° C. was added Isobutyl chloroformate (50 μL, 0.386 mmol). Mixture was then stirred at 0° C. for 30 minutes followed by addition of excess diazomethane in Et2O. Mixture was allowed to slowly come to ambient temperature over 3 hours. Mixture was then concentrated and diluted with EtOAc. Organic was then washed with saturated aqueous NaHCO3 and brine. Organic was dried (MgSO4), filtered and concentrated. Purification by chromatography (silica gel, 100% EtOAc) afforded 82 mg (75%) of the title compound. MS (ESI) m/z 297 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:24](=O)[C:25]([N:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:43]=[C:44]=[N:45][Si](C)(C)C)(C)C.Cl.C(=O)(O)[O-]>C(#N)C>[NH2:43][C:44]1[N:45]=[C:24]([C:25]([N:27]2[CH2:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:35]2)=[O:26])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([C:15]3([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]3)[CH:11]=2)[N:8]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N3Cc4ccccc4C3)c2)CCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C1(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.2 g of ethyl 1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclobutanecarboxylate are dissolved in 50 ml of acetonitrile under argon. 370 mg of caesium fluoride and 679 μl of bis(trimethylsilyl)carbodiimide are added to the solution. The mixture is stirred at room temperature for 15 min, and 6 ml of hydrochloric acid (1N) are then added, and the mixture is neutralised using bicarbonate. The aqueous phase is washed 3 times with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo. Yield: 1 g (99%) of ethyl 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylate (oil);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:18](OCC)[CH2:19][Br:20])C.FC(F)(F)C(O)=O>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[CH:18]([CH2:19][Br:20])[O:14][CH2:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCCO)cc1OC
Reactant: CCOC(CBr)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: COc1cc2c(cc1OC)C(CBr)OCCC2

Procedure:
A solution of 5.00 g. of 3-(3,4-dimethoxyphenyl)-1-propanol, 9.76 ml of bromoacetaldehyde diethyl acetal, 2.0 ml of trifluoroacetic acid, and 125 ml of nitromethane is heated at 65° under a nitrogen atmosphere for 2 hours. After cooling, the reaction mixture is extracted with methylene chloride and aqueous sodium bicarbonate. The organic layer is taken to dryness in vacuo and the residue is chromatographed first with 100% CH2Cl2 and a second time with 10% ethyl acetate:SSB to give 300 g of 7,8-dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin, m.p., 44°-45°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19][CH2:20]Br>CC(=O)CC>[Cl:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1ccc(OCCCCl)cc1
Yield: 87.2 %

Procedure:
A mixture of 4-hydroxybenzamide (5 g, 36.5 mmol, 1 eq), potassium carbonate (10.08 g, 72.9 mmol, 2 eq), 3-chloro-1-bromopropane (4.7 ml, 47.4 mmol, 1.3 eq) in butanone is stirred at reflux for 48 h. The solvent is then removed under vacuum and the residue is triturated in hexane and filtered. The solid is taken up in ethyl acetate and washed with a saturated solution of sodium hydrogencarbonate. The organic layer is dried over magnesium sulfate and concentrated to give 4-(3-chloropropoxy)benzamide ax54 (6.8 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[OH:8].Br[C:13]1[CH:14]=[C:15]([C:33]([O:35][CH3:36])=[O:34])[C:16]2[NH:17][C:18]3[CH:19]=[C:20]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:21]=[CH:22][C:23]=3[C:24]=2[N:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([C:33]([O:35][CH3:36])=[O:34])[C:16]3[NH:17][C:18]4[CH:19]=[C:20]([N:26]5[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]5)[CH:21]=[CH:22][C:23]=4[C:24]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCN(C)CC3)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COC(=O)c1cc(-c2ccc(O)c(Cl)c2)nc2c1[nH]c1cc(N3CCN(C)CC3)ccc12
Temperature: 80 °C
Yield: 34.9 %

Procedure:
A microwave vial containing a mixture of 3-chloro-4-hydroxyphenylboronic acid (64 mg, 0.37 mmol), methyl 2-bromo-7-(4-methylpiperazin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (50 mg, 0.12 mmol), powdered potassium phosphate tribasic (116 mg, 0.546 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (12 mg, 0.025 mmol), and Pd(OAc)2 (2.8 mg, 0.012 mmol) was flushed with nitrogen. THF (0.5 mL) was added, the vial was sealed, and the reaction was heated at 80° C. for 3 hr. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA; 10-60% B at 42 mL/min over 20 min) of the reaction mixture followed by SCX capture and release with 2 N NH3 in MeOH gave methyl 2-(3-chloro-4-hydroxyphenyl)-7-(4-methylpiperazin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (30 mg, 0.043 mmol, 34.9% yield. MS (ESI) m/z 451.10 (M+H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11]2[C:16](=[O:20])[O:17][CH2:18][CH2:19][C:10]3=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl.CS(O)(=O)=O.[CH3:27][OH:28]>>[CH3:27][O:28][C:16]([C:11]1[NH:12][C:13]2[C:9]([C:10]=1[CH2:19][CH2:18][OH:17])=[CH:8][C:7]([CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[CH:15][CH:14]=2)=[O:20]
Reactant: CO
Reactant: O=C1OCCc2c1[nH]c1ccc(Cn3cncn3)cc21
Agent: CS(=O)(=O)O
Agent: Cl
Product: COC(=O)c1[nH]c2ccc(Cn3cncn3)cc2c1CCO
Reaction time: 4 h
Yield: 94 %

Procedure:
To a suspension of 2.5 g (8.2 mmoles) of the 6-(1,2,4-triazol-1-ylmethyl)-4,9-dihydro-3H-pyrano[3,4-b]indol-1-on a hydrochloride in 50 ml of methanol were added 0.66 ml (10.2 mmoles) of methanesulphonic acid. The mixture was left under stirring at the reflux temperature for 4 hours. The solvent was evaporated to dryness under reduced pressure, the residue dissolved with 10 ml of a saturated bicarbonate solution and extracted 3 times with ethyl acetate. The combined organic phases were dried and evaporated to dryness and the evaporated solid recrystallised from isopropyl alcohol/heptane to give 2.3 g (94%) of the title ester as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][C:23]([F:31])([F:30])[CH:24]([F:29])[C:25]([F:28])([F:27])[F:26])=[N:4][N:5]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[C:6]=1[NH2:7].ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[NH2:7][C:6]1[N:5]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:40])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:4]=[C:3]([O:22][C:23]([F:30])([F:31])[CH:24]([F:29])[C:25]([F:26])([F:27])[F:28])[C:2]=1[Cl:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)c(Cl)c2N)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 77.5 %

Procedure:
0.3 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-aminopyrazole was dissolved in 10 mL of chloroform, and 140 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.24 g of 5-amino-4-chloro 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NS(=O)(=O)c4ccc(F)cc4)cc3c2C1

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 13.1 mg (0.067 mMol) 4-fluorobenzenesulfonyl chloride, the title compound was recovered as a light beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:14])=O)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O>O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=3)[C:12]#[N:14])[O:8][C:4]=2[CH:3]=1
Reactant: NC(=O)c1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 92.3 %

Procedure:
To a mixture of 3-(6-bromobenzoxazol-2-yl)benzamide (Compound of Example 253) (1.09 g), pyridine (0.41 g) and N,N-dimethyl formamide (20 ml) was added dropwise oxalyl chloride (0.52 g) at 0° C., and the mixture was stirred at 0° C. for 50 minutes. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, successively, and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain 3-(6-bromobenzoxazol-2-yl)benzonitrile (949 mg, 92%).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[S:7](=[O:9])=[O:8]>CO>[S:1]([S:7]([O-:9])=[O:8])([O-:4])(=[O:3])=[O:2].[Na+:5].[Na+:5]
Reactant: O=S=O
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=S([O-])S(=O)(=O)[O-]
Reaction time: 1 h

Procedure:
To 16.6 g. (132 mm.) of sodium sulfite was added 100 ml. of methanol, and then a solution of sulfur dioxide (8.3 g., 130 mm.) in methanol with stirring at room temperature. After stirring for one hour, the reaction mixture was allowed to stand still and after 24 hours, the supernatant portion was removed and thereby, a methanol suspension containing 0.89 moles/l. of sodium pyrosulfite was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:19](I)([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[CH:19]([NH:1][C:2]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Nc1cc2c(cc1C(=O)c1ccccc1)OCO2
Temperature: 25 °C

Procedure:
To a flask equipped with a stirrer and condenser are charged 80 g. of 2-amino-4,5-methylenedioxybenzophenone, 600 ml. of isopropyliodide and 80 g. anhydrous potassium carbonate. The mixture is stirred and refluxed for ca. 48 hours, cooled to room temperature, filtered and concentrated in vacuo on a rotary evaporator. The residue is dissolved in 1:1 chloroform-hexane and chromatographed through a silica gel (500 g.) column with the same solvent system. There is obtained 2-isopropylamino-4,5-methylenedioxybenzophenone, which, when recrystallized from ethanol, has a melting point of 77-78°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: Clc1ccc2cc[nH]c2c1
Product: Clc1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and iodobenzene: ESMS m/e: 228.0 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22]([C:24]1[CH:25]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:26]([CH3:36])[C:27](=[O:35])[N:28](COCCC)[CH:29]=1)=[O:23])[CH3:20].Cl>>[CH2:19]([O:21][C:22]([C:24]1[CH:25]([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)[N:26]([CH3:36])[C:27](=[O:35])[NH:28][CH:29]=1)=[O:23])[CH3:20]
Reactant: CCCOCN1C=C(C(=O)OCC)C(c2ccc(F)cc2)N(C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: CCOC(=O)C1=CNC(=O)N(C)C1c1ccc(F)cc1
Temperature: 65 °C
Yield: 97.2 %

Procedure:
Tetrabutylammonium fluoride (2.1 mL of 1M solution in THF, 2.1 mmol) was added to 4-(4-fluoro-phenyl)-3-methyl-2-oxo-1-propoxymethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (140 mg, 0.34 mmol) under Ar. The mixture was heated at 65° C. overnight, then cooled. HCl (2N aqueous solution) was added and the mixture was extracted with diethyl ether. The combined extracts were washed with water and brine, dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. Purification by flash column (hexane/ethyl acetate gradient) gave 4-(4-fluoro-phenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (92 mg, 97%).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[Cl:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C:22]2[CH:23]=[C:24]([CH2:27]Cl)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH3:29].O>CN(C)C=O>[C:1]1([S:7]([NH:10][CH2:27][C:24]2[CH:25]=[CH:26][C:21]3[N:20]=[C:19]([CH3:29])[N:18]([CH2:17][C:16]4[CH:30]=[CH:31][CH:32]=[CH:33][C:15]=4[Cl:14])[C:22]=3[CH:23]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1nc2ccc(CCl)cc2n1Cc1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(CNS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 0.667 g of benzenesulfonic acid amide in 5 ml of N,N-dimethylformamide were added 0.127 g of 60% sodium hydride at room temperature, and the mixture was stirred for 1 hour. Further, 0.648 g of 1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole hydrochloride were added thereto, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution to stop the reaction, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate and with water. The organic layer was concentrated, and was purified through silica-gel column chromatography (eluent: ethyl acetate) to give 0.240 g of 6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-methyl-benzimidazole (264).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:48])[C:23]([CH3:47])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:48])[C:23]([CH3:47])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
Piperidine (0.054 g, 0.634 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.182 g, 0.950 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.129 g, 0.317 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.060 g, 0.126 mmol, 40%).