Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)#N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22]([NH:24][CH2:25][CH2:26][NH2:27])[CH3:23].[O-]CC.[Na+]>C(O)C>[CH2:22]([N:24]1[CH2:25][CH2:26][N:27]=[C:1]1[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:23]
Reactant: N#CCCc1ccncc1
Reactant: CCNCCN
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN=C1CCc1ccncc1
Temperature: 190 °C
Yield: 59.1 %

Procedure:
A mixture of 4-(2-cyanoethyl)pyridine (1.32 g, 0.01 M) and N-ethyl-1,2-diaminoethane mono-p-toluenesulfonate (5.5 g, 0.02 M) were heated at 190° C. for 4 hrs under nitrogen. The reaction mixture was dissolved in ethanol (30 ml) and sodium ethoxide (0.02 M) in ethanol (50 ml) was added. The mixture was filtered and the filtrate was stripped to dryness and distilled at 130° C./0.2 mmHg to yield 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine (1.2 g, 60% yield).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]([N+:25]([O-:27])=[O:26])=[CH:11][CH:10]=1>CO.C(Cl)Cl>[CH3:1][O:16][C:15](=[O:17])[C:14]1[C:9]([F:8])=[CH:10][CH:11]=[C:12]([N+:25]([O-:27])=[O:26])[C:13]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
Trimethylsilyldiazomethane (2M in hexane, 7.24 mL, 14.5 mmol) was added dropwise to a solution of 6-fluoro-3-nitro-2-phenylaminobenzoic acid (2.0 g, 7.24 mmol) in MeOH (5 mL) and DCM (40 mL) at RT. The solution was stirred at RT for 45 min then the volatiles were removed under reduced pressure to afford the title compound (2.1 g, quantitative). 1H NMR (CDCl3, 400 MHz): δ 9.67 (1H, br s), 8.32 (1H, dd, J=9.47, 5.75 Hz), 7.36-7.30 (2H, m), 7.23-7.07 (3H, m), 6.64 (1H, dd, J=9.47, 8.33 Hz), 3.27 (3H, s)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](N)=[O:10])=[C:4]([F:12])[CH:3]=1.[OH-:13].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:13])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: NC(=O)Cc1ccc(Br)cc1F
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)Cc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 38 %

Procedure:
4-Bromo-2-fluoro-phenylacetamide (1.3 gm) was suspended in 100 ml of 30% NaOH, heating at reflux temperature for 24 hrs, cooled to room temperature, washed with DCM and ethyl acetate. The aqueous layer was acidified with conc. HCl, extracted with ethyl acetate, evaporated; the residue was crystallized from isopropanol-water to give needle crystals (0.5 gm, 38%) H1-NMR INOVA-500 (DMSO d6) δ 3.619 (s, 2H), 7.316 (t, J=8.0 Hz, 1H), 7.379 (dd, J=8.0, 1.5 Hz, 1H), 7.516 (dd, J=8.0, 1.5 Hz, 1H), 12.555 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[O-].[Na+:30].N1C=CC=CC=1.[S:37](=[O:40])(=[O:39])=[O:38]>C1COCC1>[S:37]([O-:40])([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([OH:15])[CH3:14])=[N:20][N:19]=2)=[CH:26][CH:25]=1)(=[O:39])=[O:38].[Na+:30]
Reactant: O=S(=O)=O
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(OS(=O)(=O)[O-])cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reaction time: 0.67 h
Yield: 68.6 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 8) (257 mg, 0.67 mmol) in THF (2.0 mL) was added a solution of sodium methoxide (36 mg, 0.67 mmol) in THF (1.5 mL) at room temperature. After 20 minutes sulfur trioxide-pyridine (85 mg, 0.53 mmol) was added and the mixture was stirred for 40 minutes, then partitioned between H2O (25 mL) and Et2O (20 mL). The aqueous layer was concentrated under reduced pressure to provide a colourless solid (177 mg, 68%): 1H NMR (400 MHz, d6-DMSO, δ in ppm) 7.88 (dm, J=9.0 Hz, 2H), 7.56 (d, J=8.6 Hz, 1H), 7.36 (dm, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 1H), 5.86 (d, J=8.6 Hz, 1H), 5.49 (d, J=6.1 Hz, 1H), 5.08 (dd, J=4.3, 8.4 Hz, 1H), 4.40 (tq, J=3.9, 5.9 Hz, 1H), 2.33 (s, 3H), 1.25 (d, J=6.3 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][OH:3].[Na].N[OH:6].[C:7](#[N:16])[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>C(O)C>[C:7](=[N:2][OH:3])([NH2:16])[C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:6])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1ccc(C(N)=NO)cc1

Procedure:
A solution of 7 g hydroxylamine hydrochloride (0.10 mol) was dissolved in 15 ml of ethanol and cooled to 0°-5° C. To the mixture was added 2.3 g sodium (0.10 mol) dissolved in 30 ml ethanol. After generating the free hydroxylamine, 3.05 g of terephthalonitrile (23.8 mmol) suspended in 40 ml of ethanol was added dropwise to the ethanol solution. The mixture was then refluxed for 20 hours. The volume of solution was reduced to 5 ml, and upon cooling a precipitate formed which was filtered. The yield was 2.21 g (48%), m.p. 224-225° C (decomp.). The infrared spectrum (KBr pellet) showed formation of peaks at 2.91 μ and 2.98 μ (NH2), 306 μ (OH), and 6.07 and 6.26 μ (C=N).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc(C)c(C)cc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate(200 mg, 0.7 mmol) and 1-(3,5-dimethylphenyl)piperazine(154 mg 0.7 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(106 mg) was added thereto. The mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11](N)=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:30]([NH2:33])=[CH:31][CH:32]=1>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:10]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:33]=1)[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccc(F)cc1Nc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of (S)-Boc-alaninamide (1.5 g, 7.9 mmol) in anhydrous THF (20 mL) was added triethyloxonium tetrafluoroborate (1.6 g, 8.3 mmol) in one portion under a nitrogen atmosphere. The resulting mixture was left to stir at RT for 2 h. The volatiles were removed in vacuo and the resulting residue redissolved in absolute EtOH (20 mL). To the mixture was added 4-fluoro-N2-pyridin-2-yl-benzene-1,2-diamine (1.0 g, 4.9 mmol) and the mixture stirred at 75° C. for 16 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic fractions washed with water, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cHex) to afford the title compound as an orange oil (1.6 g, 92%). LCMS (Method B): RT 3.21 min [M+H]+ 357.0.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([CH2:8][CH2:9][C:10]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:14][CH2:13][CH2:12][O:11]1)=[O:7])#[N:2].C(O)(=O)C>[Pt]=O.C(O)C>[NH2:2][CH2:1][CH2:3][CH2:4][O:5][C:6]([CH2:8][CH2:9][C:10]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:14][CH2:13][CH2:12][O:11]1)=[O:7]
Reactant: N#CCCOC(=O)CCC1(c2ccc(F)cc2)OCCO1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: NCCCOC(=O)CCC1(c2ccc(F)cc2)OCCO1

Procedure:
A Parr apparatus is charged with 450 g of the product obtained in Stage B, 900 ml of acetic acid, 3,000 ml of anhydrous ethanol and 20 g of platinum oxide. The mixture is hydrogenated at 5 bars at 45° C. When the theoretical volume has been absorbed, the catalyst is filtered off and the solvent is evaporated off under vacuum. The residue is taken up in 1 liter of water and the mixture is neutralized with sodium hydroxide and extracted with dichloromethane. The oil obtained is purified by chromatography on 70-230 mesh silica, using a mixture of dichloromethane, methanol and ammonia solution (95:5:0.5 V/V/V) as eluant.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]21[CH2:19][CH2:18][CH2:17][CH2:16]2.O.[NH2:21][CH2:22][C@H:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]3[CH:3]=[CH:2][N:21]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:12]=32)=[CH:7][CH:8]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C21CCCC1
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
A solution of 2.58 g of (RS)-2'-(2-oxoethyl)-5'-methoxy-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1). 1.98 g (67%) of (R)-1-[7'-methoxy-1',4'-dihydro-spiro[cyclopentane-1,4'-indeno[1,2-b]pyrrole]-1'-yl]-propan-2-ol were obtained as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:15]=[CH:14][C:11](C=O)=[CH:10][CH:9]=2)[CH:2]=1.[C:16](NC1C=CC(S(N=[N+]=[N-])(=O)=O)=CC=1)(=O)[CH3:17].C(=O)([O-])[O-].[K+].[K+].N#N>CC#N.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]#[C:15][C:14]2[CH:11]=[CH:10][CH:9]=[CH:17][CH:16]=2)[CH:2]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C(#Cc1ccccc1)Oc1cccnc1

Procedure:
4-(Pyridine-3-yloxy)benzaldehyde (0.500 g, 2.510 mmol), 4-acetamidobenzene sulfonyl azide (0.724 g, 3.01 mmol), dimethyl (2-oxopropyl) phosphonate (0.412 mL, 3.01 mmol), and potassium carbonate (1.041 g, 7.53 mmol) in MeCN (10.5 mL) and MeOH (2.1 mL) was heated to 40° C. for 16 h while under N2. The solvent was removed and residue was redissolved in EtOAc and washed with water (3×) and brine (1×). The organic phase was separated, dried with Na2SO4 and evaporated to afford an oil. This material was chromatographed on silica (0-80% EtOAc in hexanes) to yield 0.238 g as an oil.
Reaction SMILES: [C:1](O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl-].[Ca+2].[Cl-].[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)[OH:19].C(Cl)(Cl)Cl>O.[Cl-].[Zn+2].[Cl-]>[C:1]([C:23]1[CH:24]=[CH:25][C:18]([OH:19])=[CH:20][C:21]=1[OH:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CCCCCCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCC(=O)c1ccc(O)cc1O
Yield: 41.4 %

Procedure:
68 g of granular zinc chloride and 250 g of lauric acid were melted togerther at 125° C., under nitrogen and with protection from moisture by calcium chloride. The mass was stirred and 55 g of resorcinol were added portionwise over 15 minutes. The mixture was stirred a further 2 hours, cooled and drowned in 500 ml of water. 100 ml of chloroform was added to break up the solid mass, and the crystalline solid remaining was filtered, washed with chloroform, then water, to give 60.4 g of a solid with a melting point of from 79°-83° C. This was used without further purification. The analytical sample was recrystallised from light petroleum (b.p. 60°-80° C.). The pure product had a melting point of from 83.5°-85° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:26])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:44]([O:51][C:52]1[CH:59]=[CH:58][C:55]([CH:56]=[O:57])=[CH:54][CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:26])[C@H:15]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=1)[C@@H:56]([C:55]1[CH:58]=[CH:59][C:52]([O:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:53][CH:54]=1)[OH:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(OCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(O[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1
Yield: 75.6 %

Procedure:
In a similar manner to that described in Reference example 29(b), a reaction was carried out using (R)-4-benzyl-3-[(4isopropylphenoxy)acetyl]oxazolidine-2-one (10.0 g), which is the product of Reference example 30(a), solution of dibutylboron triflate in dichloromethane (1M, 34.0 ml), triethylamine (5.11 ml) and 4-benzyloxybenzaldehyde (6.60 g) and the reaction mixture was treated to afford the desired compound (12.1 g) as a mass of foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:38]#[N:39].CO>CN(C=O)C>[C:38]([NH:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][CH:3]=1)#[N:39]
Reactant: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1
Reactant: N#CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#CNc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N-({1-[4-(6-amino-pyridin-2-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (120 mg, 0.25 mmol) in DMF (2 mL) was treated with NaH (95%, 10 mg, 0.40 mmol) at 0° C. The reaction was stirred for 20 min. and BrCN (Aldrich, 32 mg, 0.30 mmol) was slowly added. The reaction was warmed to room temperature over 2 hours. MeOH (˜0.2 mL) was added to quenched extra NaH. The reaction solution was partitioned between DCM and water. The aqueous layer was extracted with a chloroform/IPA “cocktail” (3:1 v/v). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was purified by silica gel column on a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:28]1([N:27]([CH2:26][C@H:13]2[CH2:14][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]2[C:9]2[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:34])[F:35])=[CH:11][CH:10]=2)[S:37]([CH3:36])(=[O:39])=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNc2ccccc2)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN(c2ccccc2)S(C)(=O)=O)cc1)C(F)(F)F
Reaction time: 15 h
Yield: 29.6 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-((phenylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.100 g, 0.190 mmol, Example 203) in CH2Cl2 (3.0 mL) was added 4-dimethylaminopyridine (0.0046 g, 0.038 mmol), methanesulfonyl chloride (0.044 g, 0.381 mmol) and Hünig's base (0.135 mL, 0.774 mmol). After 15 h at room temperature, the solvent was removed and the crude product was purified by column chromatography (24 g of silica gel, 10 to 40% acetone in hexanes) to give N-phenyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide (0.034 g) as a mixture of two isomers.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:33]2([CH3:34])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH2:9]1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>N1C=CC=CC=1.O>[CH3:43][S:44]([O:27][CH:21]([C@H:20]([C@@H:19]1[C@:29]2([CH3:35])[C@H:16]([C:15]3[C@H:32]([CH2:31][CH2:30]2)[C@:33]2([CH3:34])[C:12]([CH2:11][C@@H:10]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[CH2:9][C@@H:8]2[O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:13][CH:14]=3)[CH2:17][CH2:18]1)[CH3:28])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:46])=[O:45]
Reactant: CC(C)CCC(O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)CCC(OS(C)(=O)=O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
In 20 ml of pyridine was dissolved 0.58 g of the 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-ol obtained as above. To this solution was added 0.12 g of methanesulfonyl chloride and the mixture was stirred at 0° C. for 2 hours. Then, at room temperature, the reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The procedure yielded 0.57 g of 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-yl methanesulfonate (yield: 86%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[O:16][N:15]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)no2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A mixture of methyl 4-[3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl]benzoate (1.50 g), 1 M aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (10 ml) and methanol (10 ml) was stirred at 60° C. for 1 hr. and acidified by adding 1 M hydrochloric acid. The crystals were collected by filtration to give 4-[3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (1.31 g, yield 91%). Recrystallization from hexane-tetrahydrofuran gave colorless crystals. melting point: 278–279° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:16](=[O:18])=[O:17]>CN(C)CCN(C)C.CCOCC>[C:11]([O:10][C:9]([NH:8][C:5]1[C:4]([C:16]([OH:18])=[O:17])=[CH:3][C:2]([F:1])=[N:7][CH:6]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)nc1
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Temperature: -15 °C

Procedure:
To 30 g of (6-fluoro-pyridin-3-yl)-carbamic acid, tert-butyl ester in 60 mL of tetramethylethylenediamine and 750 mL of ether at −78° C. under an inert atmosphere was added slowly 180 mL of 2.5 M n-butyllithium/hexanes (3 eq). After the addition was complete, the reaction was allowed to warm to −15° C. for 5 minutes then recooled to −78° C. Dry ice was allowed to sublime in a separate flask and the vapor was passed over the rapidly stirred reaction mixture while the cooling bath was removed and the reaction allowed to warm to 0° C. Sufficient water was added to dissolve the precipitated product and the resultant aqueous phase was washed twice with ether before acidifying with concentrated HCl. The precipitate was filtered, washed with water, and dried in vacuo to give 21.2 g of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid, which was used as is for the next step: melting point 240-245° C. (decomposed); mass spectrum (negative mode, m/e): M−H 255.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[O:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:16]3[O:17][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc(Cl)o1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)o1
Yield: 97.2 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (3.2 g, 19.1 mmol) (Alfa) was reacted with 5-chloro-2-furaldehyde (2.5 g, 19.1 mmol) (Aldrich) and piperidine (1.89 mL, 19.1 mmol) in methanol to give E/Z-6-chloro-3-(5-chloro-furan-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 5.2 g, 97%)