Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>ClCCCl>[F:31][C:27]1[CH:26]=[C:25]([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:10]3[CH:15]([CH2:16][N:8]([C:33]([O:35][CH:36]=[CH2:37])=[O:34])[CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:30]=[CH:29][CH:28]=1
Reactant: C=COC(=O)Cl
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CN(Cc3ccccc3)CC12
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C2C1

Procedure:
A solution of (3aRS,7aRS)-2-benzyl-7,7-bis-(3-fluorophenyl)-4-perhydroisoindolone (92.2 g) in 1,2-dichloroethane (860 cc) is treated with vinyl chloroformate (26.3 cc) and the mixture is refluxed for 3 hours and then concentrated under reduced pressure (2.7 kPa). The residue is chromatographed (in two passes) on silica gel (particle size 0.04-0.063 mm, columns 8 cm in diameter and 35 cm high), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (75/25). The meringue obtained is crystallized from isopropyl ether to give (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-vinyloxycarbonyl-4-perhydroisoindolone (50.3 g). m.p.=152° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[N:16]([C:17](=[O:27])[C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])[N:15]=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[S:13]2)[C:7]=1[O:35][CH3:36].C1COCC1.CO.[Li+].[OH-]>C(OCC)(=O)C.O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:14]2[S:13][CH:12]([C:8]3[C:7]([O:35][CH3:36])=[C:6]([CH:11]=[CH:10][CH:9]=3)[O:5][CH2:4][C:3]([OH:37])=[O:2])[N:16]([C:17](=[O:27])[C:18]3[C:19]([F:26])=[CH:20][C:21]([F:25])=[CH:22][C:23]=3[F:24])[N:15]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(OCC(=O)O)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 12 h

Procedure:
To a solution of {3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetic acid methyl ester (2.47 mmol) in 30 mL of a mixture of THF and MeOH (3:2), is added LiOH (1 M) (25 mL). After stirring for 12 hours the reaction is complete as determined by LC/MS. The reaction is diluted with ethyl acetate and water, washed with brine and dried over MgSO4 and the solvent is removed from the reaction mixture to yield {3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetic acid: LC/MS (ES+): 521.1 (M+1)+.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN(CCN(C)C)C.[CH2:36](Br)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CCCCCC.C1CCCCC1>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCCCCBr
Reactant: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CCCCCCC(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
Following the procedure which is described in Example 4, 2.91 parts of 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane in 40 parts by volume of cyclohexane, 5.1 parts by volume of a 2.17 M solution of butyl lithium in hexane are reacted with 1.5 parts of TMEDA and 1.81 parts of n-hexyl bromide to provide 2-(2,2-diphenyloctyl)-1-azabicyclo[2.2.2]octane. This compound is then treated with 0.730 parts of maleic acid to give 2-(2,2-diphenyloctyl)-1-azabicyclo[2.2.2]octane maleate, melting at about 180°-181° C. This compound is represented by the following structural formula ##STR10##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:11]([CH3:23])=[C:10]([C:24](=[O:27])[CH2:25][CH3:26])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:35]([NH:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][C:10]([C:24](=[O:27])[CH2:25][CH3:26])=[C:11]2[CH3:23])=[CH:18][CH:17]=1)(=[O:20])=[O:21])(=[O:37])[CH3:36]
Reactant: CCC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(=O)(=O)NC(C)=O)cc2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[5-(4-chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulfonamide (Example 31, 0.12 g, 0.31 mmol) in dry THF (5 mL) was added triethylamine (0.4 mmol, 0.06 mL) and DMAP (0.031 mmol, 4 mg) at room temperature. 10 Minutes later acetic anhydride (0.62 mmol, 0.06 mL) was added drop wise and the mixture stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (100 mL), washed with sodium bicarbonate (saturated solution, 50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified over silica using CH2Cl2:MeOH (95:5) as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 1.18 (3H), 2.05 (3H), 2.16 (3H), 2.45 (2H), 3.39 (2H), 6.90 (1H), 7.33-7.90 (8H), 8.50 (1H); MS (ESI) m/z 445 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3(Cl)[CH:23]([Cl:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3[Cl:24])=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)C(Cl)(C2CCC(c3ccc(Cl)cc3)CC2)C1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
115.8 g of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-1,4-naphthoquinone (Formula III) obtained in Example 6 was suspended in glacial acetic acid (926 ml). 33.77 g anhydrous sodium acetate was then added to the mixture and heated to reflux for 1 hour. After which, the mixture was cooled. Water was then added. The precipitated product was filtered of and recrystallized from acetonitrile to obtain 94.5 g (89.34% yield) of the trans-isomer of the compound of Formula IV.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[C:30]([C:36](O)=[O:37])=[N:31][C:32]([Cl:35])=[CH:33][CH:34]=1.CCN(C(C)C)C(C)C.[BH4-].[Na+]>C1COCC1>[Cl:28][C:29]1[C:30]([CH2:36][OH:37])=[N:31][C:32]([Cl:35])=[CH:33][CH:34]=1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: OCc1nc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
BOP (1.27 g, 2.9 mmol) was added to a THF (10 mL) solution containing 3,6-dichloropyridine-2-carboxylic acid (0.5 g, 2.6 mmol) and DIEA (0.55 mL, 3.2 mmol). After 5 minutes sodium borohydride (103 mg, 2.7 mmol) was added and the solution stirred at room temperature for 20 minutes. The solution was partitioned between ethyl ether and aqueous 1N HCl. The organic phase was washed with water, brine and dried over MgSO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS2 1.32 min. (M+H)=178
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.I[C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][C@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:24]12[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25]1)[C@H:22]([NH:21][C:19]([C:18]1[CH:30]=[CH:31][C:15]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)=[CH:16][CH:17]=1)=[O:20])[CH2:23]2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 65.4 %

Procedure:
4-(trifluoromethyl)phenylboronic acid (20.9 mg, 0.11 mmol) was added to a flask charged with (S)-4-iodo-N-(quinuclidin-3-yl)benzamide (35.6 mg, 0.1 mmol), cesium carbonate (81.5 mg, 0.25 mmol) in 2 ml of Acetonitrile and 2 ml of water. The mixture was degassed by sonication for 20 minutes followed by charging catalytic amount of Palladium (II) acetate and place under nitrogen to stirred for 3 hours. The reaction mixture was filtered through pad of celite and washed with acetone, solution was concentrated under vacuum to oil. Preparative HPLC instrument was used to obtain pure (S)—N-(quinuclidin-3-yl)-4′-(trifluoromethyl)biphenyl-4-carboxamide (24.5 mg, 65% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.80 (d, J=8 Hz, 2H), 7.63 (m, 4H), 7.58 (d, J=8 Hz, 2H), 6.33 (d, 1H), 4.11 (m, 1H), 3.38 (m, 1H), 2.80 (m, 4H), 2.56 (ddd, J=6, 14, 6 Hz, 1H), 2.00 (m, 1H), 1.65 (m, 3H), 1.47 (m, 1H). C21H21F3N2O=374.16 LCMS (M+H): m/z 375
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][CH:10]=O)=[CH:7][CH:6]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:4]=1.CS(C1[N:23]=[CH:24][C:25]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]=2[N:27]=1)(=O)=O>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]2[N:23]=[CH:24][C:25]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]=3[N:27]=2)=[CH:7][CH:6]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:4]=1
Reactant: COc1nc(N2CCOCC2)ccc1NC=O
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Product: COc1nc(N2CCOCC2)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 14 %

Procedure:
The title compound was prepared according to Example 40 using N-(2-methoxy-6-morpholinopyridin-3-yl)formamide (Preparation 71) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 0-5% MeOH EtOAc followed by a second chromatography eluting with 50-100% EtOAc in cyclohexane. The residue was dissolved in EtOAc and washed with HCl (0.5 M, 10 mL), dried (MgSO4) and concentrated in vacuo. The residue was further purified by passage through a SCX-2 cartridge eluting with 100% MeOH—1 M NH3 in MeOH, to afford the title compound (10 mg, 14%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][C:11]#[N:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:22][OH:23]>O.CCO>[OH:23][NH:22][C:11](=[NH:12])[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=1
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(OCC#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(OCC(=N)NO)cc1

Procedure:
To a mixture of (4-methanesulfonyl-phenoxy)-acetonitrile (2 g, 9.5 mmol), K2CO3 (1.3 g, 9.5 mmol) in H2O (30 mL) and EtOH (15 mL) was added hydroxylamine hydrogenchloride (1.32 g, 19 mmol). The mixture was heated under reflux overnight, cooled and ethanol was removed in vacuo and the residue was extracted with EtOAc (150 mL). The organic layer was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed to afford the desired product.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:31]=[CH:30][CH:29]=[CH:28]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:11]=2)[O:8][CH:9]=1)=[O:4].[OH:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][OH:39]>>[OH:33][CH2:34][CH2:35][N:36]([CH2:37][CH2:38][OH:39])[C:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:28]=[CH:29][CH:30]=[CH:31]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:11]=2)[O:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Reactant: OCCNCCO
Product: O=C1CC(c2cccc(-c3nc(C(=O)N(CCO)CCO)co3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
A solution of 2-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-oxazole-4-carboxylic acid methyl ester (Example 25)(88 mg) in 2-(2-hydroxy-ethylamino)-ethanol (2 mL) was stirred at 50° C. for 6 h. The mixture was partitioned between H2O and EtOAc. The organic layer was dried and evaporated in vacuum, and the residue was triturated with EtOAc to give the title compound (32 mg) as light-yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[O:4].C(=O)(O)[O-].[Na+].ClCCl.C(OCC)(=O)C.O>CN(C=O)C.ClCCl.CO>[C:9]1([C:7]2[O:8][CH2:2][C:3](=[O:4])[NH:5][N:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CCl)NNC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1COC(c2ccccc2)=NN1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
812 g (3.82 mol) of N′-(2-chloroacetyl)benzenecarbohydrazide were dissolved in 13 liters of dry DMF, and 384.95 g (4.58 mol) of sodium bicarbonate were added. The reaction solution was then heated to 100° C. and stirred at this temperature overnight. After the reaction had gone to completion (monitored by TLC, mobile phase dichloromethane/ethyl acetate 9:1), the reaction solution was cooled to room temperature, poured into 65 liters of water and extracted three times with in each case 17.5 liters of ethyl acetate. The combined organic phases were washed with 13.8 liters of saturated aqueous sodium bicarbonate solution, dried and concentrated to dryness under reduced pressure. The solid obtained was dissolved in a 9:1 mixture of dichloromethane and methanol and applied to 17 kg of silica gel. Using two portions of silica gel (8 kg each), the product was chromatographed using 260 liters of dichloromethane/ethyl acetate 9:1 as mobile phase. The combined product fractions were concentrated, and the resulting solid was triturated with 3 liters of diethyl ether. Filtration gave 247 g (1.40 mol, 35% of theory) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[O:28][C:29]=1[CH3:30].[Na+].[I-].[NH4+].[Cl-]>CN(C=O)C.CCOCC>[F:1][C:2]([F:21])([F:22])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[O:28][C:29]=2[CH3:30])[CH2:16][C:17]([F:19])([F:18])[F:20])=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: Cc1oc(-c2cccc(C(F)(F)F)c2)nc1CCl
Reactant: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1oc(-c2cccc(C(F)(F)F)c2)nc1CN(CC(F)(F)F)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 1.2 %

Procedure:
A mixture of 100 mg (0.29 mmol) of 1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol (example 11.2), of 81 mg (0.29 mmol) 4-chloromethyl-5-methyl-2-(3-trifluoromethyl-phenyl)-oxazole and ca 10 mg of NaI in DMF was stirred for 1 week at 125° C. and then distributed between a saturated aqueous solution of NH4Cl and Et2O. Drying of the combined organic phases over Na2SO4 and column chromatography on silica gel with a gradient of n-heptane/EtOAc gave 2 mg (ca. 1%) of 1,1,1,3,3,3-hexafluoro-2-{4-[[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-propan-2-ol, yellow solid, MS: 581 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:26]=[CH:25][C:14]2[C:15]([CH2:18][CH2:19]OS(C)(=O)=O)=[CH:16][O:17][C:13]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].[NH:33]1[CH2:43][CH2:42][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35][CH2:34]1>CC#N>[CH2:40]([O:39][C:37]([CH:36]1[CH2:42][CH2:43][N:33]([CH2:19][CH2:18][C:15]2[C:14]3[CH:25]=[CH:26][C:11]([O:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:12][C:13]=3[O:17][CH:16]=2)[CH2:34][CH2:35]1)=[O:38])[CH3:41]
Reactant: CS(=O)(=O)OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(CCc2coc3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 70 °C
Yield: 47.9 %

Procedure:
To a suspension of methanesulfonic acid 2-[6-(benzothiazol-2-yloxy)-benzofuran-3-yl]-ethyl ester (200 mg, 0.5 mmol) and K2CO3 (78 mg, 0.6 mmol) in MeCN (5.2 mL) was added ethyl isonipecotate (0.08 mL, 0.5 mmol) and the reaction mixture was heated (70° C., 48 h). The reaction mixture was filtered, concentrated in vacuo and the resulting residue was partitioned between EtOAc and brine (20 mL each). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (20-80%) to provide the title compound as a clear oil (108 mg, 47%). MS (ESI): mass calcd. for C25H26N2O4S, 450.6; m/z found, 451.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.43 (d, J=8.5, 1H), 7.65 (d, J=8.0, 1H), 7.58 (d, J=8.5, 1H), 7.54 (s, 1H), 7.51 (d, J=1.5, 1H), 7.39-7.36 (m, 1H), 7.27-7.24 (m, 2H), 4.14 (q, J=7.0, 2H), 2.98 (d, J=11.5, 2H), 2.89-2.85 (m, 2H), 2.69-2.66 (m, 2H), 2.34-2.29 (m, 1H), 2.14-2.10 (m, 2H), 1.96-2.94 (m, 2H), 1.85-1.77 (m, 2H), 1.26 (t, J=7.0, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO.C(OCC)(=O)C>[ClH:24].[F:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(F)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
1-tert-Butoxycarbonyl-4-(4-fluorophenylsulfonyl)piperidine (1.76 g, 5.1 mmol) was suspended in methanol (10 mL). To the suspension was added 4N-hydrogen chloride in ethyl acetate (20 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added ethyl acetate. The precipitates were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the titled compound (1.39 g, 5.0 mmol, Yield 97%) as white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19]C)=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[OH-].[Na+].Cl>C(OCC)(=O)C>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccsc2C(=O)O)cc1
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A mixture of methyl 3-(4-t-butylbenzoylamino)thiophene-2-carboxylate (9.67 g, 30 mmol), dioxane (75 mL) and 2 M sodium hydroxide (75 mL) was stirred for 16 h. The reaction was acidified to pH, 2 with 5 M hydrochloric acid. The mixture was diluted with ethyl acetate and the aqueous layer was extracted with ethyl acetate (3 times). The combined organic layers was magnesium sulfate dried, filtered, and concentrated to afford the title compound as a solid (8.09 g, 89%); NMR(CDCl3) d 1.36(s, 9H), 7.54(d, 2H, J=8.4 Hz), 7.61(d, 1H, J=5.1 Hz), 7.92(d, 2H, J=8.4 Hz), 8.34(d, 1H, J=5.1 Hz), 11.04(s, 1H); MS(FD): 303.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].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>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1)([CH3:14])[CH3:13]
Reactant: Ic1cnc2[nH]ccc2c1
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
Product: C[Si](C)(C)C#Cc1cnc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
5-Iodo-1H-pyrrolo[2,3-b]pyridine (24, 0.303 g, 1.22 mmol), (trimethylsilyl)acetylene (25, 0.210 mL, 1.46 mmol), bis(triphenylphosphine)palladium(II) chloride (0.039 g, 0.055 mmol), and copper(I) iodide (0.0019 g, 0.010 mmol) were dissolved in triethylamine (19 mL, 0.14 mol) under an atmosphere of nitrogen. The resulting mixture was heated to 60° C. and stirred under an atmosphere of nitrogen for 16 hours. The triethylamine was removed under vacuum, 30 mL of water was added to the residue, and it was extracted with 2×20 mL with ether. The combined organic layers were washed with brine and dried over sodium sulfate. Solids were filtered out and the filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography, eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a solid (26, 0.237 g). MS (ESI) [M+H+]+=215.3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][S:10]([CH3:12])=[O:11].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([N:20]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH2:9][S:10]([CH3:12])=[O:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: CS(=O)CC(=O)c1ccccc1O
Product: CS(=O)CC(=NC1CCCCC1)c1ccccc1O
Yield: 96 %

Procedure:
A solution of 2'-hydroxy-2-(methylsulfinyl)acetophenone (15 g, 0.076 mole) in cyclohexylamine (75 ml) was stirred at 90° for 6 hrs. The reaction mixture was cooled and poured into petroleum ether (1 l.). The product was filtered off and washed with hexane to give yellow crystals (20.2 g, 96%), mp 133°-134°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[N:30][C:29](Cl)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-]>CC(N(C)C)=O>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCN(C)C2=O)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (265 mg, 1.0 mmol), azetidin-1-yl-(5-chloropyrazin-2-yl)methanone (Intermediate 32) (198 mg, 1.0 mmol) and polymer supported-carbonate (690 mg, 2.0 mmol) in DMA (5 mL) was stirred at 100° C. for 1 hr. The mixture was filtered and the DMA was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (10 mL), water (20 mL) and brine (20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by chromatography on silica eluting with 20-100% ethyl acetate in isohexane then 10% Methanol in DCM to give afford the product (304 mg, 71%). 1H NMR δ (300 MHz, CDCl3) 2.13-2.27 (m, 1H), 2.31-2.44 (m, 2H), 2.53-2.66 (m, 1H), 2.94 (s, 3H), 3.35-3.58 (m, 2H), 3.90 (s, 3H), 4.26 (t, 2H), 4.68 (t, 2H), 4.93 (t, 1H), 7.14 (s, 1H), 7.46 (s, 1H), 7.60 (s, 1H), 8.31 (s, 1H), 8.84 (s, 1H); m/z 427 (M+H)+