Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([Cl:28])=[C:26]4[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]4[C@@H:29]4[CH2:31][C@@H:30]4[F:32])=[CH:20][C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.Cl>>[ClH:28].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]4[C@@H:29]4[CH2:31][C@@H:30]4[F:32])=[CH:20][C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC(C)(C)OC(=O)NCC12CN(c3c(F)cc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3Cl)CC1CCO2
Agent: Cl
Product: NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4[C@@H]3C[C@@H]3F)CC1CCO2

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-6-fluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 180°-185° C. (with decomposition).
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10].Br[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][C:2]1([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]#[N:25])=[CH:19][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10]
Reactant: N#CCBr
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
[2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine (3.40 g, 10.9 mmol), bromoacetonitrile (1.44 g, 1.1 eq) and potassium carbonate (1.80 g, 1.2 eq) were combined in acetone (20 mL) and stirred overnight at room temperature under a nitrogen atmosphere. The solution was then filtered and the filtrate was concentrated under reduced vacuum to yield 3.71 g as a brown oil. This material was purified via silica gel chromatography employing the Water's Prep. 200 while eluting with a solvent of hexane/ethyl acetate 3:2 to yield the intermediate title compound (2.52 g, 67%) as a tan solid. Ion spray M.S. 351.2 (M*−1). Calculated for C17H24N2O4S: Theory: C 57.93, H 6.86, N 7.95. Found: C 57.61, H 6.84, N 8.12.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([C:27]([F:26])([F:38])[F:37])=[CH:36][CH:35]=4)[CH:31]=[N:32]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: FC(F)(F)c1ccc2[nH]ncc2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(C(F)(F)F)ccc43)nc12
Temperature: 125 °C
Yield: 44.1 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (200 mg, 468 μmol), 5-(trifluoromethyl)-1H-indazole (87.1 mg, 468 μmol) in dioxane (3.5 mL) was added sodium tert-butoxide (98.9 mg, 1.03 mmol) and bis(tri-tert-butylphosphine)palladium(0) (23.9 mg, 46.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-30% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-(trifluoromethyl)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (110 mg, 44%). 1H NMR (CDCl3) δ: 9.20 (s, 1H), 8.69-8.74 (m, 2H), 8.42 (s, 2H), 8.39 (d, J=0.8 Hz, 1H), 8.33-8.36 (m, 1H), 8.18 (s, 2H), 7.70-7.74 (m, 1H), 5.73 (s, 2H), 3.59 (dd, J=8.9, 7.7 Hz, 2H), 1.63 (s, 9H), 0.92-0.98 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11])([CH3:4])([CH3:3])[CH3:2].[CH:17](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>CO.C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:13][CH3:17])=[C:9]([CH:12]=1)[C:10]#[N:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(C#N)c(O)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: COc1c(C#N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Yield: 99.9 %

Procedure:
The above nitrile (0.5 g, 2.27 mmol) was taken up in 1:9 methanol/acetonitrile (20 mL). N,N-diisopropylethylamine (1.1 mL, 6.35 mmol) was added dropwise followed by (trimethylsilyl)diazomethane (3.2 mL, 6.35 mmol). The reaction was stirred until the bubbling stopped (20 min) and the reaction was quenched with water. The water was extracted 3× with methylene chloride, dried over Na2SO4, filtered, and concentrated in vacuo to give 5-tert-butyl-2-methoxy-3-nitro-benzonitrile (0.531 g, 99%) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=O>C(O)C>[CH3:11][C:9]1([C:8]([OH:13])=[O:12])[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(=O)C(=O)O
Solvent: CCO
Product: CC1(C(=O)O)NC(C(=O)O)CS1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Under an argon atmosphere, L-cysteine (15 g) was dissolved in dry ethanol (35 mL), pyruvic acid (18.6 mL) was added thereto at room temperature, and the mixture was stirred for 3 hours. The resulting solid was collected by filtration under reduced pressure, and washed with ice-cooled ethanol to give 2-methylthiazolidine-2,4-dicarboxylic acid (diastereomer mixture) (23 g, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[O:24])=[CH:12][CH:13]=1)=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:40](OC(C)=C)(=[O:42])[CH3:41]>>[C:40]([O:24][C:19]1[C:20]2[C:16](=[C:15]([O:14][C:11]3[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)=[CH:13][CH:12]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:17][CH:18]=1)(=[O:42])[CH3:41]
Reactant: C=C(C)OC(C)=O
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=O)nc1)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1=CCc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 1.00 g of 3,4-dichloro-N1-[6-(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl]benzamide obtained in Example 1, 50 mg of p-toluenesulfonic acid and 5 ml of isopropenyl acetate was stirred overnight at 70° C. The reaction mixture was concentrated and the resulting residue was extracted with ethyl acetate. This extracted solution was washed in turn with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (2:1)) to obtain the titled compound (230 mg, white powder). Melting point: 161-164° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:14]([C:18]([O:20]CC)=[O:19])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[C:10]([C:12]#[CH:13])[CH:11]=1.[OH-].[Li+].Cl>O1CCCC1.CO>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:14]([C:18]([OH:20])=[O:19])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[C:10]([C:12]#[CH:13])[CH:11]=1
Reactant: C#Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)OCC)n2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.2 %

Procedure:
580 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-6-ethynyl-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 38A; contained 35% of the methyl ester) were initially charged in 30 ml of tetrahydrofuran and 5 ml of methanol, and 7.8 ml of 1N aqueous lithium hydroxide solution were added. The resulting reaction mixture was stirred at room temperature for 6 h and then kept at 0° C. for 16 h. The mixture was then acidified with 6 N hydrochloric acid and concentrated. The solid which formed was filtered off, triturated with a little water and filtered off again. Drying under reduced pressure gave 521 mg of the desired product (quantitative yield).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH2:22][CH3:23])[CH:20]=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].C[N:35](C)C1C=CC=CC=1>>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH2:22][CH3:23])[C:20]([NH2:35])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCn1cnc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Reactant: CN(C)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Product: CCn1c(N)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 135 °C
Reaction time: 3 h

Procedure:
A mixture of 4.1 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-ethyl-1H-benzimidazole, 1.2 parts of sodium amide and 20 parts of N,N-dimethylbenzenamine is stirred and heated slowly to 135° C. Stirring at 135° C. is continued for 3 hours. The reaction mixture is cooled and poured onto water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) and a small amount of ammonium hydroxide as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 1.5 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-ethyl-1H-benzimidazol-2-amine; mp. 214.3° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].O.[NH3:16].O.Cl>O1CCCC1>[F:14][C:8]1[CH:7]=[CH:6][C:5]([S:2](=[O:4])(=[O:3])[NH2:16])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: N
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1

Procedure:
A solution of 5-chlorosulfonyl-2-fluorobenzoic acid (7.0 g) and 28% ammonia water (20 ml) in tetrahydrofuran (70 ml) is stirred at 0° C. for 1.5 hours. The reaction mixture is poured into water (200 ml), acidified with concentrated hydrochloric acid, and extracted with chloroform. The extracts are washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is washed with diethyl ether to give the title compound (5.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C>[Br:15][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:14])([CH3:13])[CH2:9][CH2:8][CH2:7]2
Reactant: BrBr
Reactant: COc1ccc2c(c1)C(C)(C)CCC2
Solvent: CC(=O)O
Product: COc1cc2c(cc1Br)CCCC2(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.7 %

Procedure:
To a solution of 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (0.99 g, 5.2 mmol) in glacial acetic acid (30 mL) at 0° C. was added slowly bromine (0.5 mL, 10.4 mmol), and the resulting solution was allowed to slowly warm to room temperature while being stirred. After 48 h, the reaction mixture was quenched with a saturated solution of Na2S2O3 and extracted with ethyl acetate, and the combined extracts were dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash column (hexane:ethyl acetate=95:5) to afford 0.5556 g (40%) of the title compound as a clear oil.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CN(C)CCN(C)C.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23](B(O)O)[CH:24]=1>CO.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][CH:9]=3)[CH:24]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: c1ncc2[nH]cnc2n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: CO
Solvent: O
Product: Oc1ccc(Cl)cc1-n1cnc2cncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a mixture of purine (0.24 g, 2.0 mmol), copper(II) acetate (0.36 g, 2.0 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.6 mL, 4 mmol) in a mixture of methanol (160 mL) and water (40 mL) was added (5-chloro-2-hydroxyphenyl)boronic acid (0.69 g, 4.0 mmol). The reaction mixture was stirred vigorously open to the atmosphere at ambient temperature for 2 h. The mixture was filtered over a pad of diatomaceous earth and the pad was washed with a mixture of dichloromethane (50 mL) and methanol (50 mL). The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in dichloromethane, followed by trituration in a mixture of ethyl acetate and hexanes, to afford 4-chloro-2-(9H-purin-9-yl)phenol as a tan solid in 20% yield (0.098 g): 1H NMR (300 MHz, DMSO-d6) δ10.65 (s, 1H), 9.26 (s, 1H), 8.95 (s, 1H), 8.76 (s, 1H), 7.73-7.67 (m, 1H), 7.49-7.41 (m, 1H), 7.17-7.09 (m, 1H); MS (ES+) m/z 247.0 (M+1), 248.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Yield: 103.5 %

Procedure:
A mixture of 4-methoxyphenol (6.2 g, 50 mmol), K2CO3 (10 g, 72 mmol) and acetic anhydride (6.12 g, 60 mmol) in acetone (150 ml) was stirred at RT. over night. The solid was filtered off and washed with acetone (50 ml). After removal of acetone, 8.6 g of product was obtained. Yield: 100%.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:24].[H-].[Na+].I[CH3:28]>CN(C)C=O>[CH3:28][N:4]1[CH2:5][CH2:6][N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH:2]([CH3:1])[C:3]1=[O:24]
Reactant: CC1C(=O)NCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1C(=O)N(C)CCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone (100 mg, 0.294 mmol, Compound 32), in N,N-Dimethylformamide (DMF) (1.5 mL) was added sodium hydride (25.9 mg, 0.646 mmol). After stirring for 1 hour under argon, iodomethane (0.020 mL, 0.323 mmol) was added. The resulting reaction mixture was stirred under argon for 1 hour.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([CH3:16])=[C:14](Br)[CH:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])[S:5][CH:6]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([CH3:16])=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=3)[CH:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)cc(Br)c2C)n1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: Cc1csc(NC(=O)c2nc(C)cc(-c3ccc(F)c(Cl)c3)c2C)n1

Procedure:
The title compound, was prepared from 4-Bromo-3,6-dimethyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide and 3-Chloro-4-fluorophenylboronic acid in accordance with the general method of example 1, step 6 to yield the final compound as a light yellow solid, MS (ISP): m/e=376.2, 378.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:15][S:16]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17].S(Cl)(Cl)(=O)=O.N12CCN(CC1)CC2>CC(C)=O>[F:15][S:16]([C:19]1[CH:20]=[C:21]([S:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: O=S(=O)(F)c1cccc(S(=O)(=O)Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CC(C)=O
Solvent: O=S(=O)(Cl)Cl
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2cccc(S(=O)(=O)F)c2)cc1
Temperature: 25 °C

Procedure:
To an acetone solution of 10.4 g (0.05 mol) 2-cyanovinyl 4-aminophenyl sulfone is added 12.8 g (0.05 mol of 3-fluorosulfonylbenzenesulfonyl chloride at room temperature, with agitation. The sulfonyl chloride dissolves immediately, giving a clear yellow solution. To this mixture is added over a ten minute period an acetone solution of 1,4-diazabicyclo[2.2.2]-octane (11.2 g, 0.05 mol). A light yellow precipitate forms almost at once; the reaction mixture is maintained at about 25° C for 30 minutes with stirring. Precipitation in water and workup affords a bright yellow powder, 2-cyanovinyl 4-(3-fluorosulfonylbenzenesulfonamido)phenyl sulfone: ##SPC44##
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.C(Cl)Cl>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:13]4[CH:12]=[CH:11][C:10]([CH2:9][N:3]5[C@H:4]([CH3:8])[CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[CH:15][CH:14]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Reactant: C[C@@H]1CCC[C@H](C)N1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)cc1
Yield: 38.7 %

Procedure:
A degassed mixture of (2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]piperidine (685 mg, 2.08 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (389 mg, 1.04 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (127 mg, 0.16 mmol) in saturated sodium carbonate solution (1 mL) and THF (10 mL) was heated under reflux for 18 h. The cooled reaction mixture was diluted with DCM (50 mL) and washed with water (25 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g column, ISCO, 0-15% methanol in DCM) to afford the title compound as an off-white solid (181 mg, 39%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=2.2 Hz, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.69 (d, J=0.9 Hz, 1H), 8.29 (d, J=0.9 Hz, 1H), 7.68-7.63 (d, J=8.1 Hz, 2H), 7.56-7.50 (m, 2H), 4.00 (s, 2H), 2.65-2.51 (m, 2H), 1.72-1.56 (m, 4H), 1.46-1.30 (m, 2H), 1.25 (d, J=6.2 Hz, 6H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC(CC(C)C)[C:13]#[N:14].OS([O-])=O.[Na+].[C-]#N.[Na+]>O>[OH:10][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]#[N:14]
Reactant: CC(C)CC(O)C#N
Reactant: O=CCCc1ccccc1
Agent: O=S([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CC(O)CCc1ccccc1

Procedure:
2-Hydroxy-4-phenylbutanenitrile is prepared from 3-phenylpropionaldehyde according to the protocol described for 2-Hydroxy-4-methylpentanenitrile; (11.14 g, 83.2 mmol) 3-phenylpropionaldehyde, NaHSO3 (17.7 ml of solution at 37%, 83 mmol), (4.08 g, 83.2 mmol) of NaCN in H2O (18 ml). The product, a yellow oil, is used with no other purification (12.4 g, 93%); 1H NMR (100 MHz, CDCl3) δ: 2.02-2.25 (m, 2H), 2.76-2.91 (m, 2H), 3.98 (s, 1H), 4.39 (t, J=8 Hz, 1H), 7.26 (d, J=3 Hz, 5H); 13C NMR (25 MHz, CDCl3) δ: 30.49, 36.37, 59.92, 120.04, 126.28, 128.28, 128.49, 139.60. Analysis calculated for C10H11NO: C, 74.51; H, 6.88; N, 8.69. Experimental: C, 74.38; H, 6.97; N, 8.42.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:26]2=[O:40])[CH2:12][CH2:13][CH2:14][N:15]([CH3:24])[S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(=O)C.C(O[C:48]1(O[Si](C)(C)C)[CH2:50][CH2:49]1)C.C([BH3-])#N.[Na+]>CO>[CH:48]1([N:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:32]=3[CH2:33][N:25]([C@@H:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:12][CH2:13][CH2:14][N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[C:26]4=[O:40])[CH2:39][CH2:38]2)[CH2:50][CH2:49]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: COc1ccc([C@@H](CCCN(C)S(=O)(=O)c2cccs2)N2Cc3c(cccc3N3CCNCC3)C2=O)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc([C@@H](CCCN(C)S(=O)(=O)c2cccs2)N2Cc3c(cccc3N3CCN(C4CC4)CC3)C2=O)cc1OC
Temperature: 25 °C
Yield: 22.6 %

Procedure:
According to the method of M. L. Gillaspy, B. A. Lefke, W. A. Hada, D. J. Hoover, Tetrahedron Letters 1995, 7399-7402, Cpd 30 (50 mg, 0.085 mmol), acetic acid (0.050 mL, 0.87 mmol), 3 Å molecular sieves (230 mg), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.102 mL, 0.51 mmol) were combined in methanol (4 mL) at rt. Sodium cyanoborohydride (24 mg, 0.38 mmol) was added and the reaction mixture was heated at reflux overnight, cooled to RT, filtered, and concentrated. The residue was dissolved in EtOAc (25 mL), washed with 2 N sodium hydroxide solution (2×10 mL) and brine (2×10 mL), dried (Na2SO4), concentrated, and purified by reversed phase HPLC [Phenomenex, Kromasil C18, 10μ, 110 Å, 250×50 mm, gradient elution with 20-90% acetonitrile (0.16% TFA) in water (0.2% TFA)] to yield Cpd 7 (12 mg, 19%) as a TFA salt. 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=7.4 Hz, 1H), 7.59 (d, J=4 Hz, 1H), 7.52 (d, J=4 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.13 (t, J=4 Hz, 1H), 6.99 (br d, J=8.2 Hz, 1H), 6.92 (br s, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.56 (br t, J=7.5 Hz, 1H), 4.34 (d, J=17 Hz, 1H), 3.93 (buried d, J=17 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.7-2.9 (m, 11H), 2.66 (s, 3H), 2.5-2.0 (m, 6H), 1.7 (m, 2H); LC/MS (ES+) m/z 625.3 (M+1).
Reaction SMILES: C([O-])(=O)C.[Na+].[NH:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>O.CC(C)=O>[Cl:19][CH2:20][C:21]([N:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: C1CNCC2(C1)CC1CCC2CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCl)N1CCCC2(CC3CCC2CC3)C1

Procedure:
An amount of 20 g (0.244 mole) of sodium acetate and 18 g (0.100 mole) of spiro[bicyclo[2.2.2]octane2,3'-piperidine] is dissolved in 100 ml of water and 300 ml of acetone. A two-phase system is formed, to which is added dropwise at 0° to 5° an amount of 10.2 ml (14.4 g, 0.13 mole) of chloroacetyl chloride. An addition is then made to the mixture, at 0° to 5°, of 700 ml of water, whereupon the reaction product precipitates in flake form. Stirring is maintained for a further hour and the reaction product subsequently filtered off. After washing and then drying of the product over phosphorus pentoxide in a desiccator, there is obtained 1'-chloroacetyl-spiro [bicyclo[2.2.2]octane-2,3'-piperidine], M.P. 63° (with decomposition).