Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[C:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](C(OCCC(C)(C)C)=O)[C:11]([C:25]([O-:27])=[O:26])=[CH:10]2)(=[O:5])[CH3:4].CO.O>C1COCC1>[C:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:25]([OH:27])=[O:26])=[CH:10]2)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc2c(c1)cc(C(=O)[O-])n2C(=O)OCCC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Yield: 42.7 %

Procedure:
Lithium hydroxide (0.028 g, 1.184 mmol) was added to a solution of 1-(1,1-dimethylethyl)2-ethyl 5-(acetylamino)-1H-indole-1,2-dicarboxylate (0.041 g, 0.118 mmol) in THF:MeOH:water/3:1:1. The reaction mixture was heated at 50° C. for 1 h. The solvent was evaporated. The residue was dissolved in water, acidified with 6N aqueous HCl and extracted with dichloromethane. A solid formed in the aqueous layer which was collected by filtration and dried to give the title compound (0.011 g, 43%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.85 (s, 1H), 11.63 (s, 1H), 9.79 (s, 1H), 7.97 (s, 1H), 7.22-7.38 (m, 2H), 7.01 (s, 1H), 2.01 (s, 3H). MS: m/z 219 (M+1).
Reaction SMILES: [CH:1]([S:4]([NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]1)(=[O:6])=[O:5])([CH3:3])[CH3:2].NC1CCC(C(OC)=O)CC1.CC(S(Cl)(=O)=O)C.[NH2:35][C:36]1[C:41]([NH2:42])=[CH:40][CH:39]=[C:38]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[F:50])[N:37]=1>>[F:50][C:44]1[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=1[C:38]1[N:37]=[C:36]2[N:35]=[C:14]([C@H:11]3[CH2:12][CH2:13][C@H:8]([NH:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:9][CH2:10]3)[NH:42][C:41]2=[CH:40][CH:39]=1
Reactant: CC(C)S(=O)(=O)NC1CCC(C(=O)O)CC1
Reactant: Nc1ccc(-c2ccc(F)cc2F)nc1N
Agent: CC(C)S(=O)(=O)Cl
Agent: COC(=O)C1CCC(N)CC1
Product: CC(C)S(=O)(=O)N[C@H]1CC[C@H](c2nc3nc(-c4ccc(F)cc4F)ccc3[nH]2)CC1

Procedure:
4-isopropylsulfonylaminocyclohexanecarboxylic acid as prepared easily from methyl 4-aminocyclohexanecarboxylate with 2-propanesulfonyl chloride, and 2,3-diamino-6-(2,4-difluorophenyl)pyridine were allowed to undergo ring-closure condensation under the same conditions as described in Example 1-3), followed by separatory purification on a collective thin-layer chromatograph (chloroform:methanol=20:1) to give the title compounds.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)OCc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 2-chloro-6-methylnicotinic acid (3.0 g), benzyl alcohol (2.27 g), 4-dimethylaminopyridine (2.56 g) in DMF (10 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide (WSC) hydrochloride (4.02 g). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1, v/v) to give the title compound (3.6 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:34][CH:33]=[CH:32][N:31]=2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C.CO>ClCCl>[OH:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[C:35]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:33]=[CH:32][N:31]=2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(CCO)C(=O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Yield: 85.1 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (166) (140 mg, 85.93%) as a light yellow sticky solid was synthesized from 5-benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (165) (200 mg, 0.33 mmol) following the procedure as described for 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (132). Silica thin layer chromatography was performed (5% methanol in dichloromethane, Rf=0.4).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O.O=[CH:20][C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:10][C:11]1([F:17])[CH2:16][CH2:15][N:14]([CH:20]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]([OH:23])=[O:22])[CH2:13][CH2:12]1
Reactant: OB(O)c1ccccc1
Reactant: O=CC(=O)O
Reactant: FC1(F)CCNCC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)C(c1ccccc1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of phenylboronic acid (400 mg, 3.28 mmol), 4,4-difluoropiperidine (397 mg, 3.28 mmol) and 2-oxoacetic acid hydrate (302 mg, 3.28 mmol) in DCM (30 ml) was stirred at room temperature overnight. DCM was evaporated and crude was purified by flash-chromatography (DCM/MeOH=8/2) to obtain the title compound (512 mg, 61.1% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][NH2:19].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.CCCCCC>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:11])[N:19]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: Cc1ccccc1NN
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Yield: 92.5 %

Procedure:
4,4-Dimethyl-3-oxopentanenitrile (36.7 g, 0.29 mol), (2-methylphenyl)hydrazine hydrochloride (47.7 g, 0.29 mol), and glacial acetic acid (7.03 g, 6.7 mL, 0.12 mol) were dissolved in abs ethanol (585 mL) and heated under reflux for 18 h. After removal of the solvent under reduced pressure, EtOAc and water (500 mL each) were added, then sodium bicarbonate (42 g, 0.50 mol) was carefully added. After addition of hexane (500 mL), the organic phase was separated, washed with brine (500 mL), and dried over Na2SO4. The mixture was then filtered through a pad of silica gel (500 g) on a sintered glass funnel. The pad was eluted with hexanes/EtOAc (1:1, v/v), and the filtrate was concentrated under reduced pressure. The resulting solid was triturated with hexanes/EtOAc (9:1, v/v), filtered, washed and dried in vacuo to afford a colorless solid (61.5 g, 93%). 1H NMR (400 MHz, CD2Cl2) δ 1.29 (s, 9H), 2.12 (s, 3H), 3.56 (br, 2H), 5.48 (s, 1H), 7.28 (m, 2H), 7.31 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([O:23][CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2c(cc1OCC1CC1)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 1 intermediate d), from (4R,9aR)-7-hydroxy-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 7, intermediate), sodium hydride and (bromomethyl)cyclopropane.
Reaction SMILES: Br[C:2]1[C:3]2[C:4](=[N:15][S:16][N:17]=2)[C:5](Br)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH3:13])=[N:7]2.C1C=CC([As](C2C=CC=[CH:35][CH:36]=2)C2C=CC=CC=2)=CC=1.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39].CCN(CC)CC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:12][C:9]1[C:8]([CH3:13])=[N:7][C:6]2[C:11](=[C:2]([C:35]#[C:36][Si:38]([CH3:40])([CH3:39])[CH3:37])[C:3]3[C:4](=[N:15][S:16][N:17]=3)[C:5]=2[C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[N:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Reactant: Cc1nc2c(Br)c3nsnc3c(Br)c2nc1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2c(C#C[Si](C)(C)C)c3nsnc3c(C#C[Si](C)(C)C)c2nc1C
Temperature: 45 °C
Reaction time: 18.5 h

Procedure:
4,9-Dibromo-6,7-dimethyl[1,2,5]thiadiazolo[3,4-g]quinoxaline (68.0 mg, 1.82×10−4 mol), Pd2dba3 (36.0 mg, 3.93×10−5 mol), AsPh3 (62.2 mg, 2.03×10−4 mol), (trimethylsilyl)acetylene (0.60 ml, 4.2×10−3 mol), Et3N (2.0 ml), and THF (15 ml) were added to a 100-ml Schlenk tube. The reaction mixture was stirred at 45° C. for 18.5 h under N2. After the solvent was evaporated, the residue was chromatographed on silica gel using 8:1 hexanes:THF as the eluant. Yield=0.051 g (69% based on 68.0 mg of 4,9-dibromo-6,7-dimethyl[1,2,5]thiadiazolo[3,4-g]quinoxaline). 1H NMR (360 MHz, CDCl3): δ 2.83 (s, 6H, —CH3), 0.42 (s, 18H, —Si—CH3). Chemical Ionization MS m/z: 408.1264 (M+) (calcd 408.126).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].[CH2:12]1[CH2:16][O:15][CH2:14][CH2:13]1>>[CH:14]12[O:15][CH:16]1[CH2:12][CH2:2][CH2:6][CH2:13]2.[NH:4]1[CH:3]=[C:8]([C@@H:9]2[CH2:10][CH2:16][CH2:12][CH2:13][C@H:14]2[OH:15])[CH:7]=[N:5]1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: Ic1cn[nH]c1
Product: C1CCC2OC2C1
Product: O[C@@H]1CCCC[C@H]1c1cn[nH]c1
Yield: 10 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 155b by using 4-iodo-1H-pyrazole (5.82 g, 30.0 mmol), butyl lithium (2.69 M solution in hexane; 22.3 mL, 60.0 mmol), a boron trifluoride-diethyl ether complex (7.54 mL, 60.0 mmol), cyclohexene oxide (3.24 g, 33.0 mmol) and THF (120 mL), to yield the title compound (0.48 g, 10%) as a colorless solid.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:22]1([O:21][NH:20][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(NOC1CCCCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NOC1CCCCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 85.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-N-(cyclohexyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 22 (0.24 g, 0.64 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)—N-(cyclohexyloxy)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 23 (0.155 g, 85%) as a colorless foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].O[CH2:11][CH:12]([CH2:14]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O>O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:7]([CH:11]=[CH:12][CH:14]=[N:6]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCc1cccc(N)c1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: CCc1ccc2cccnc2c1
Yield: 93.3 %

Procedure:
In a similar fashion using route 10 general procedure 20, 3-ethylaniline (1 g, 8.25 mmol), glycerol (2.35 g, 25.6 mmol), 3-nitro benzenesulfonic acid sodium salt (2.42 g, 10.7 mmol), H2SO4:H2O (3.5 ml:2.5 ml) gave the title compound (1.21 g, 93%) which was used in the next step without purification. The structure was confirmed by 1H NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:12]([OH:13])[CH2:11][N:10]([CH3:14])[C:9]2=[O:15])=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17].[OH-].[NH4+].[H][H]>[Pd].C(O)C>[CH3:19][C:16]([C:3]1[CH:4]=[C:5]([N:8]2[CH:12]([OH:13])[CH2:11][N:10]([CH3:14])[C:9]2=[O:15])[N:6]=[N:7][CH:2]=1)([CH3:17])[CH3:18]
Reactant: CN1CC(O)N(c2cc(C(C)(C)C)c(Cl)nn2)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CN1CC(O)N(c2cc(C(C)(C)C)cnn2)C1=O
Reaction time: 1 h
Yield: 122.4 %

Procedure:
A mixture of 2.0 g (0.00702 mole) of 3-[6-chloro-5-(1,1-dimethylethyl)-3-pyridazinyl]-4-hydroxy-1-methyl-2-imidazolidinone, 2.0 ml of concentrated ammonium hydroxide, 300 milligrams (mg) of 10% palladium on carbon, and 100 ml of 2B ethanol was placed on a Parr shaker apparatus at 50 pounds of hydrogen. After one hour, when the consumption of hydrogen exceeded the theoretical amount, the mixture was filtered and concentrated, giving 2.15 g of a white solid, which was partitioned between 400 ml of methylene chloride and 40 ml of water. The layers were separated and the organic layer was dried with magnesium sulfate.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:23])[CH:3]=1.[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+].Cl>CCOC(C)=O.CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37][C:3]1[C:4](=[O:23])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(c2ccccc2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(c3ccccc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-phenyl-5,6-dihydro-pyran-2-one (0.2 g, 0.64 mmol) from Example TT, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.26 g, 0.71 mmol), K2CO3 (0.35 g, 2.5 mmol), and DMF (3 mL). The solution was stirred overnight at room temperature and then poured into 1N HCl and EtOAc. The organic phase was dried (MgSO4), and concentrated. Purification by silica gel chromatography, eluting with MeOH:CH2Cl2 :hexane (5:80:20 to 5:95:0) gave the title compound, m.p. 196-199° C. 1H NMR (DMSO-d6) δ 1.44 (s, 9 H), 1.76 (s, 3 H), 2.08-2.21 (m, 3 H), 2.42 (m, 1 H), 3.41 (dd, 2 H), 4.32 (s, 2 H), 4.91 (br s, 1 H), 6.16 (s, 1 H), 6.61 (d, 2 H), 6.86 (d, 2 H), 7.21 (s, 1 H), 7.34-7.46 (m, 5 H), 9.14 (s, 1 H), 12.15 (bs, 1 H).
Reaction SMILES: [Br:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[C:14]=1[CH3:21].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:38]([F:42])([F:41])([F:40])[F:39]>C(OCC)C>[F:39][B-:38]([F:42])([F:41])[F:40].[Br:1][CH2:2][S+:3]([C:18]1[CH:17]=[C:16]([CH3:19])[C:15]([CH3:20])=[C:14]([CH3:21])[C:13]=1[CH3:12])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C)c(C)c1C
Reactant: Cc1ccc(S(=O)CBr)cc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CBr)c2cc(C)c(C)c(C)c2C)cc1
Reaction time: 0.5 h

Procedure:
1-((Bromomethyl)sulfinyl)-4-methylbenzene (200 mg, 0.86 mmol) of example 35 was dissolved in dry diethyl ether (6 mL) under an argon atmosphere. 1,2,3,4-tetramethylbenzene (0.127 g, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.145 mL, 1 eq) was slowly added maintaining the same temperature. After 30 minutes, HBF4 in diethyl ether was added (54%, 0.209 mL, 1.5eq). The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and dried under vacuum. 0.309 g (82%) of the desired product was obtained as a white solid. mp: 238° C. 1H NMR (DMSO-d6, 400 MHz): δ 7.98 (2H, d, J=8.4 Hz), 7.78 (1H, s), 7.58 (2H, d, J=8.2 Hz), 6.8 (2H, ABQ, J=9.08 Hz), 2.51 (3H, s), 2.42 (3H, s), 2.36 (3H, s), 2.26 (3H, s), 2.25 (3H, s). 13C NMR (DMSO-d6, 100 MHz): δ 145.7, 142.8, 138.4, 137.3, 136.8, 131.6, 130.6, 126.2, 121.4, 120.5, 35.0, 20.9, 20.4, 17.1, 16.4. FT-IR (KBr): 3048, 2967, 1494, 1446, 1392, 1284, 1261, 1218, 1195, 1085, 1051, 1031, 862 cm−1.
Reaction SMILES: COC([N:5]1[CH:10]=[C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH2:8][C:7]([CH:17]=[O:18])=[CH:6]1)=O.C(N(CC)CC)C>CO>[CH3:16][N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]1[CH2:8][C:7]([CH:17]=[O:18])=[CH:6][NH:5][CH:10]=1
Reactant: COC(=O)N1C=C(C=O)CC([C@@H]2CCCN2C)=C1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1C1=CNC=C(C=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104 %

Procedure:
To a solution of (S)-3-formyl-5-(1-methyl-pyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester III (0.0124 g, 0.05 mmol) in 2 mL of anhydrous MeOH was slowly added triethylamine (0.02 mL, 0.15 mmol), and the reaction mixture was stirred at RT for 1 day. Evaporation of the solvent afforded a quantitative yield (0.010 g) of (S)-5-(1-methylpyrrolidin-2-yl)-1,4-dihydro-pyridine-3-carbaldehyde IV as a yellow oil. The product was used without further purification. IR (thin film, neat, NaCl): 3416-3244, 2957, 1595, 1509, 1377, 1228 cm−1. 1H NMR (CDCl3, 300 MHz) δ 9.14 (s, 1 H), 6.85 (d, 1 H, J=6 Hz), 6.48 (s, 1 H), 6.00-5.99 (m, 1 H), 3.05-3.00 (m, 3 H), 2.45 (m, 1 H), 2.19-2.11 (m, 4 H), 1.83-1.67 (m, 4 H); 13C NMR (CDCl3, 75 MHz) δ 189.59, 146.95, 119.91, 119.01, 112.67, 70.03, 57.03, 40.69, 28.96, 22.80, 20.37. HRMS Calcd for C11H16N2O: 193.1341 [M+H]+. Found: 193.1334 [M+H]+. [α]28D −80.7 (c=0.55, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[C:8](O)=[CH:9][C:10]([F:17])=[C:11]([CH:16]=1)[C:12](OC)=[O:13].CC1(C)CCC[C@@H]1C1[C:27](O)=[CH:28][C:29]([F:36])=C(C=1)C(OC)=O.CC1(C)C(C2C(O)=CC(F)=C(C=2)C(OC)=O)=CCC1.[CH2:58]1[CH2:62][O:61][CH2:60][CH2:59]1>>[CH3:19][C:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:16]=[C:11]([CH2:12][OH:13])[C:10]([F:17])=[CH:9][C:8]=1[C:59]1[CH:58]=[C:62]([O:61][CH3:60])[CH:27]=[CH:28][C:29]=1[F:36]
Reactant: COC(=O)c1cc([C@@H]2CCCC2(C)C)c(O)cc1F
Reactant: COC(=O)c1cc([C@H]2CCCC2(C)C)c(O)cc1F
Reactant: C1CCOC1
Agent: COC(=O)c1cc(C2=CCCC2(C)C)c(O)cc1F
Product: COc1ccc(F)c(-c2cc(F)c(CO)cc2C2CCCC2(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
(R)-Methyl 5-(2,2-dimethylcyclopentyl)-2-fluoro-4-hydroxybenzoate or (S)-methyl 5-(2,2-dimethylcyclopentyl)-2-fluoro-4-hydroxybenzoate (66.44AA or 66.44AB). A mixture of Rh(COD)2BF4 (Stem Chemical) 35138-22-8, 36.95 mg, 0.091 mmol) and (R)-1-[(S)-2-(R)-(Ditertbutylphosphino)ferrocenyl]ethyl-bis-(3,5-bistrifluoromethylphenyl)phosphine (Solvias, SL-J210-1, 81.5 mg, 0.100 mmol), was stirred in THF (75 mL) under N2 for 60 minutes and a dark red solution formed. To the resulting solution was added 66.43E (8.2 g, 45.4 mmol) and TEA (10 mol %, 0.63 mL, 4.54 mmol). The resulting solution was filled with H2 (200 psi) three times and stirred at room temperature under 200 psi H2 for 2 hours. The resulting mixture was passed through a short plug of silica gel, eluting with 1:1 hexane/EtOAc and then concentrated affording the desired product as a white solid (83% yield (6.8 g), 99.3% ee). The other enantiomer may be obtained as the majority product using the enantiomer of the ferrocenyl compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:22]([C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:23]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1cccc(C(=O)O)c1
Reaction time: 65 h
Yield: 39.1 %

Procedure:
3-Hydroxybenzoic acid (27.6 g), 4-chloro-3-cyanobenzotrifluoride (41.1 g) and anhydrous potassium carbonate (55.2 g) were stirred together for 71/2 hours at 100° C. in dry dimethylformamide (500 ml) and then left at room temperature for 65 hours. The solvent was then removed under reduced pressure and the residue taken up in water and acidified with dilute hydrochloric acid. The solid which separated was washed with water, dissolved in ether and the solution dried and concentrated. The colourless solid which separated was recrystallized to give the benzoic acid derivative (24.0 g) with a melting point of 224°-226° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]1([C:18]2([C:24]#[N:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>ClCCl>[C:12]1([C:18]2([C:24]#[N:25])[CH2:19][CH2:20][N:21]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1(c2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC(C#N)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
17.2 g (89.8 mmol) of 4-methylbenzenesulfonyl chloride dissolved in 150 mL of dichloromethane are added to a solution of 20 g (89.8 mmol) of 4-phenylpiperidine-4-carbonitrile and 28 mL of triethylamine in 200 mL of dichloromethane. The reaction mixture is stirred for 1 hour at room temperature. The reaction is stopped by adding 200 mL of water, and is then extracted with dichloromethane. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then taken up in diethyl ether and filtered off. 30.3 g of 4-phenyl-1-(toluene-4-sulfonyl)piperidin-4-carbonitrile in the form of a white powder are obtained in a yield of 99%.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:30][CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)[CH3:31]
Reactant: CCN1CCC[C@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 28.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 107 mg, 2.68 mmol) in DMF (2.00 mL) was added Intermediate A (110 mg, 0.67 mmol) and the reaction stirred for 20 min. Intermediate 61b (150 mg, 0.67 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave the title compound (72.0 mg, 28%). LCMS (Method 4): Rt 0.29 min, m/z 378.2 [MH+].