Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[CH2:8][N:9](NC(OC(C)(C)C)=O)[CH2:10][CH:11]=1)(=[O:5])=[O:4].FC(F)(F)S(NC1C=CC=CC=1)(=O)=O.Cl>O1CCOCC1>[NH:9]1[CH2:10][CH:11]=[C:7]([O:6][S:3]([C:2]([F:1])([F:20])[F:21])(=[O:4])=[O:5])[CH2:8]1
Reactant: CC(C)(C)OC(=O)NN1CC=C(OS(=O)(=O)C(F)(F)F)C1
Agent: Cl
Agent: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: C1COCCO1
Product: O=S(=O)(OC1=CCNC1)C(F)(F)F
Reaction time: 3 h
Yield: 75 %

Procedure:
10.2 g of tert-butyl 3-trifluoromethanesulfonyloxy-2,5-dihydropyrrole-1-carbamate as a 1/1 mixture with C,C,C-trifluoro-N-phenylmethanesulfonamide in 50 ml of dioxane are placed in a 500 ml round-bottomed flask. 120.5 ml of a 4N solution of hydrochloric acid in dioxane are subsequently added carefully. The reaction mixture is stirred for 3 h. The dioxane is evaporated and the product is purified on silica gel using a dichloromethane/methanol 95/5 mixture as eluent. 5 g of trifluoromethanesulfonic acid 2,5-dihydro-1H-pyrrol-3-yl ester are obtained.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:13]([O:17][CH2:18]C)(=[O:16])[CH2:14][SH:15].C(=O)([O-])[O-].[K+].[K+].CCCCCC.CCOC(C)=O>CCO>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:4]=2[S:15][C:14]=1[C:13]([O:17][CH3:18])=[O:16]
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2cc(Cl)ccc2c1N
Yield: 31 %

Procedure:
2-nitro-4-chlorobenzonitrile (1.94 g, 10.6 mmol) was treated with 1 eq of ethyl thioglycolate and 1 eq potassium carbonate in EtOH as described in Example 41A to give after chromatography (4:1 hexane/EtOAc) the title compound in 31% yield. 1H NMR (300 MHz, CDCl3) d 1.38 (t, J=7 Hz, 3H), 4.36 (q, J=7 Hz, 2H), 5.85 (bs, 2H), 7.33 (dd, J=9,2 Hz, 1H), 7.54 (d, J=9 Hz; 1H), 7.1 (d, J=2 Hz, 1H). MS (DCI/NH3) m/e 256 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]2[C:5]=1[CH:6]1[CH:11]([C:12]2=O)[CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+].O>CO.C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]2[C:5]=1[CH:6]1[CH:11]([CH:12]2[NH:2][CH3:1])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CN
Reactant: Cc1cc(C)c2c(c1O)C(=O)C1CCCCC21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNC1c2c(O)c(C)cc(C)c2C2CCCCC21
Temperature: 25 °C

Procedure:
3.4 Milliliters of a methanol solution of 40% methylamine was added to a methanol solution containing 2 g of 5,7-dimethyl-8-hydroxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 20 ml of methanol and the mixture was refluxed under heating for 4 hours. Then, thereto were further added 10 ml of methanol and 3.4 ml of a methanol solution of 40% methyl amine, followed by refluxing for 6 hours. After left to stand for cooling, 3.66 g of sodium borohydride was gradually added thereto with stirring at room temperature, followed by stirring for 1 hour at the same temperature. Then, water was added to the reaction mixture and extraction was effected with chloroform. The organic layer was dried with magnesium sulfate and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) and then recrystallized from ethanol to obtain 0.70 g of 5,7-dimethyl-8-hydroxy-9-methylamino-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[Si:30]([O:29][CH2:28][CH2:27][CH2:26][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OCCCO[Si](C)(C)C(C)(C)C)cc(C)c21
Temperature: 60 °C

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.5 g, 2 mmol) and cesium carbonate (1.95 g, 6 mmol) in 10 ml DMF was added (3-bromopropoxy)(tert-butyl)dimethylsilane (1.39 ml, 6 mmol). The reaction was heated at 60° C. for six hours. It was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[C:24]([CH3:29])=[N:25][O:26][C:27]=3[CH3:28])=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:36])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[C:24]([CH3:29])=[N:25][O:26][C:27]=3[CH3:28])=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2c(C)noc2C)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1noc(C)c1C(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-(5-chloro-8-{4-[(3,5-dimethylisoxazol-4-yl)carbonyl]piperazin-1-yl}quinolin-7-yl)ethanone (0.044 g, 0.11 mmol) and ammonium acetate (0.0821 g, 1.06 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.26 mL, 0.26 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H23ClN3O2 (M+H)+: m/z=414.2; Found:414.2.
Reaction SMILES: [CH:1]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:11])[CH:2]=1.Cl.[CH3:13][NH:14][CH3:15]>>[I:11][C:3]1[CH:4]=[CH:5][C:6]([S:7]([N:14]([CH3:15])[CH3:13])(=[O:9])=[O:8])=[CH:1][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CNC
Agent: Cl
Product: CN(C)S(=O)(=O)c1ccc(I)cc1

Procedure:
The title compound was prepared from pipsyl chloride and dimethylamine hydrochloride using a similar procedure to that used for Description 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:8][N:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][CH:14]=2)[CH:10]=1)[CH3:2].O1CCCC1>[C].[Pd].C(O)C>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][N:9]2[CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:33])[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:8]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1cn(CCc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)Cc1cn(CCc2ccc(O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
A mixture of ethyl(1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazol-4-yl)acetate (800 mg), 5% palladium-carbon (1.50 g), tetrahydrofuran (20 ml), and ethanol (30 ml) was stirred for 3 hours at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-[2-(4-hydroxyphenyl)ethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (400 mg, yield: 63%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[CH:11][C:10]=2[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:4][C:3]=1[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:51]=[CH:50][C:44]([O:45][CH2:46][C:47](O)=[O:48])=[CH:43][CH:42]=2)[S:35]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:45][CH2:46][C:47]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]([OH:19])=[CH:11][C:10]=4[C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:4][C:3]=3[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:48])=[CH:50][CH:51]=2)[S:35]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)cc2C(C)(C)C)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)cc2C(C)(C)C)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 99.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2,5-di-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.71 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.68 g), diethyl cyanophosphonate (0.39 g), triethylamine (0.24 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.13 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.O>O1CCCC1>[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[NH2:25]
Reactant: Clc1cccc2[nH]ccc12
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nn1ccc2c(Cl)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
Sodium hydride (60 %wt suspension in mineral oil; 0.86 g, 21.5 mmol) is suspended in dry tetrahydrofuran (THF, 20 mL) and is cooled to 0° C. A mixture of 4-chloroindole (2.5 g, 16.5 mmol) and THF (10 mL) is added to the slurry at 4° C. After the addition is completed, the mixture is stirred for 30 min. Then a mixture of O-mesitylenesulfonylhydroxylamine (3.02 g, 14 mmol) and THF (25 mL) is added slowly at a temperature below 5° C. After the addition is completed, the reaction mixture is allowed to reach room temperature and is subsequently stirred for 3 h. Then the mixture is cooled again to 0° C., and a second aliquot of O-mesitylenesulfonylhydroxylamine (3.02 g, 14 mmol) in THF (25 mL) is added slowly. The mixture is allowed to reach ambient temperature and was subsequently stirred overnight. The reaction mixture is worked up by adding it to water, extracting into ethyl acetate, and drying over sodium sulfate. The crude product (4 g) is obtained after filtration of the drying agent and evaporation of the solvent. The aminated indole (2,2 g) is obtained as a black oil (mixture of starting material and product) after flash chromatography, using toluene as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[C:6]([CH2:16][OH:17])([CH2:14]O)[C:5]2=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C1(C)C=CC=CC=1.CN(C)C(=S)[S-].CN(C)C(=S)[S-].[Zn+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[C:6]1([CH2:16][O:17][CH2:14]1)[C:5]2=[O:18]
Reactant: CC1(C)Oc2ccc(Br)cc2C(=O)C1(CO)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CN(C)C(=S)[S-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(Br)cc2C(=O)C12COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To a mixture of 6-bromo-3,3-bis(hydroxymethyl)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (6.76 g, 21.4 mmol), zinc bis(dimethyldithiocarbamate) (26.2 g, 85.8 mmol) and triphenylphosphine (8.44 g, 32.2 mmol) in THF (0.20 L) was added diisopropyl azodicarboxylate (1.9 M solution in toluene, 16.9 mL, 32.2 mmol) in an ice-water bath. The mixture was stirred overnight at ambient temperature. The mixture was diluted with toluene (0.20 L), and the mixture was filtered off. The filtrate was washed with 1 M aqueous NaOH (three times), water and brine, dried over MgSO4 and filtered. The filtrate was evaporated to give a crude product. The crude product was purified with column chromatography on silica gel (Hexane-EtOAc, a linear gradient of EtOAc from 0 to 20%) to afford 6-bromo-2,2-dimethyl-4H-spiro[chromene-3,3′-oxetan]-4-one (2.22 g).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17]>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][O:10][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:6][CH:5]=1
Reactant: OCCc1ccc(F)cc1
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(CCOCCCCl)cc1
Temperature: 25 °C

Procedure:
A solution of 86 g (2.14 mol) of NaOH pellets in 86 g of water is stirred, cooled to 25° C. and then treated with 20 g (0.143 mol) of 4-fluorophenethyl alcohol, 113 ml (1.14 mol) of 1-bromo-3-chloropropane and then with 4.85 g (14 mmol) of tetrabutylammonium hydrogen sulfate. Vigorous stirring is maintained for 4 h at 25° C., extraction is then carried out with ether and the extract is washed with water and with aqueous saline solution and dried over anhydrous sodium sulfate. After removing the inorganic salt, the filtrate is evaporated to dryness and the residual oil is rectified under vacuum to give 20.3 g (Yd: 65%) of product of formula 22.1:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:28]([CH3:27])[CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:30])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(C)c1ccccc1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)C(C)c3ccccc3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with methyl-(1-phenyl-ethyl)-amine to give 112 mg of {6,8-dimethoxy-4-[methyl-(1-phenyl-ethyl)-carbamoyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C27H33N3O5+H 480.6; found 480.0.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5](OS(C(F)(F)F)(=O)=O)[CH2:6]2.[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1B(O)O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+].[C:38]([OH:47])(=[O:46])[C@H:39]([C@@H:41]([C:43]([OH:45])=[O:44])[OH:42])[OH:40]>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(O)C.O.COCCOC>[C:38]([OH:47])(=[O:46])[C@H:39]([C@@H:41]([C:43]([OH:45])=[O:44])[OH:42])[OH:40].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:5]1[CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]([CH2:9][CH2:8]2)[CH:4]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CN1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CN1C2C=C(c3cc4ccccc4s3)CC1CC2
Temperature: 25 °C

Procedure:
A mixture of (−)-8-methyl-3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene, (4.64 g, 17.1 mmol), 1,2-dimethoxyethane (100 ml), 2-benzothienyl boronic acid (4.5 g, 25 mmol), potassium carbonate (9.2 g, 66.6 mmol), lithium chloride (2.0 g, 47.2 mmol) and water (50 ml) was bubbled through with argon for 10 min. Pd(PPh3)4 (0.17 g, 0.13 mmol) was added followed by reflux for 45 min. The mixture was allowed to cool to room temperature. Water (100 ml) was added followed by extraction with diethyl ether (2×50 ml). The organic phase was washed with water (2×50 ml). The organic phase was dried and evaporated. The hydrochloric acid salt was precipitated by addition of hydrochloric acid (4 M) solved in ethanol (5 ml, 96%). Addition water (50 ml) and concentrated ammonia (50 ml) followed by extraction with dichloromethane (2×50 ml) gave the free base. (4.09 g, 100% from the salt) [α]D25=(−)-46.3°. The tartaric acid salt was prepared by adding D-tartaric acid (2.4 g, 16 mmol) to a mixture of the free base and ethanol (96%) at reflux. The mixture was allowed to cool overnight and was isolated by filtration. Yield 5.06 g (12.47 mmol), chiral HPLC (−) 94.9% and (+) 5.1%. Recrystallization of 4.85 g (11.9 mmol) from ethanol (150 ml, 96%) yielded (3.26 g, 8.0 mmol), chiral HPLC (−) 97.9% and (+) 2.1%. Mp 67.6-76.0° C.
Reaction SMILES: C[N:2]([CH3:19])/[CH:3]=[C:4](/[C:10](=[O:18])[C:11]1[C:16](F)=[CH:15][CH:14]=[CH:13][N:12]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:28][C:29]([F:45])([F:44])[C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2CN)[CH:33]=[CH:34][CH:35]=1.O>CC(N(C)C)=O>[O:18]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][N:12]=2)[N:2]([CH2:19][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:45])[F:44])[CH:31]=2)[CH:3]=[C:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1F
Reactant: NCc1ccccc1-c1cccc(C(F)(F)F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cn(Cc2ccccc2-c2cccc(C(F)(F)F)c2)c2cccnc2c1=O
Temperature: 74 °C
Reaction time: 15 h
Yield: 37.1 %

Procedure:
To a brown solution of (Z)-ethyl 3-(dimethylamino)-2-(3-fluoropicolinoyl)acrylate (31) (200 mg, 0.751 mmol) in DMA (dimethylacetamide) (8 mL) in a 20 mL vial were added a solid powder of tribasic potassium phosphate (399 mg, 1.88 mmol) and (3′-(trifluoromethyl)biphenyl-2-yl)methanamine (208 mg, 0.826 mmol) at room temperature under a nitrogen atmosphere. The resulting brown suspension was heated to 74° C. and stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, it was cooled to room temperature and poured slowly into water (100 mL), but no solids precipitated. Then, the organic compound was extracted with dichloromethane and the combined extracts were washed with water and brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave the crude brown oil which was purified using ISCO (120 g) column chromatography, eluting with ethyl acetate in hexanes (0 to 100%) and then 5 to 10% methanol in dichloromethane. The desired fractions were combined and the solvent was removed under vacuum to obtain ethyl 4-oxo-1-((3′-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate (32) (126 mg, 37% yield) as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:42]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:21]=[C:22]([N:26]6[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]6)[CH:23]=[CH:24][CH:25]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=5[F:19])[N:11]=4)=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, R and C stepwise) (56 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{3-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2CN2C3C=CC=CC=3COC3C=CC=CC2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N1CC[C@H]([OH:41])C1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:41][C@H:13]1[CH2:14][CH2:15][N:11]([CH2:10][CH2:9][C:8]2[CH:32]=[CH:33][CH:34]=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH2:12]1
Reactant: c1cc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc(N2CCCC2)c1
Reactant: O[C@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@H]1CCN(CCc2cccc(N3CCCC3)c2)C1
Temperature: 100 °C

Procedure:
3-Pyrrolidinophenethyl mesylate (1.80 g, 4.00 mmol) synthesized in Example 21, (S)-3-pyrrolidinol hydrochloride (0.50 g, 4.05 mmol) and potassium carbonate (1.70 g, 12.3 mmol) were added to acetonitrile (20 ml), and they were heated at 100° C. for 12 hours. Acetonitrile was evaporated under reduced pressure, and the residue was distributed into water and ethyl acetate. The intended product was extracted from the ethyl acetate layer with 1 M hydrochloric acid. The extract was neutralized and then the product was extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure to obtain (S)-3-hydroxy-1-(3-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow solid (1.04 g, 100%).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH:6]=1)C.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][O:14][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH3:13])[C:4]([OH:25])=[O:3]
Reactant: CCOC(=O)c1ccc(OCC)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
0.300 g (0.78 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-ethoxy-benzoic acid ethyl ester was dissolved in 10 ml of dioxan. 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 10 h. 5 ml water was added, followed by concentrated hydrochloric acid to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, and then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: N#Cc1ccc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 417 [M+1]+.