Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][C:25](O)=[C:24]([CH2:29][CH:30]=[CH2:31])[CH:23]=2)[N:18]=1>N1C=CC=CC=1.Cl>[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:24]([CH2:29][CH:30]=[CH2:31])[CH:23]=2)[N:18]=1
Reactant: C=CCc1cc(-c2noc(C)n2)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: C=CCc1cc(-c2noc(C)n2)ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 0.75 h

Procedure:
Triflic anhydride (1.4 ml) was added dropwise to a stirred solution of 5-methyl-3-(3-allyl-4-hydroxyphenyl)1,2,4-oxadiazole (1.2 g) in pyridine (10 ml) cooled in an ice-bath. The mixture was stirred for 45 minutes. The mixture was diluted with 1M aqueous hydrochloric acid (200 ml) and extracted with ethyl acetate (200 ml). The organic extract was washed with 1M aqueous hydrochloric acid, aqueous sodium bicarbonate solution, and brine, then dried (MgSO4), and evaporated to give 5-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-1,2,4-oxadiazole (1.37 g) as a solid, NMR: 8.1(2H,m), 7.6(1H,d), 6.1-5.9(1H,m), 5.3-5.1(2H,m), 3.55(2H,d) and 2.7(3H,s); m/z 351 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:10]=1)[C:5](O)=[O:6].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]([F:13])([F:14])[F:15])[CH:10]=1)[CH2:5][OH:6]
Reactant: O=C(O)c1cc(Cl)cc(OC(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 3-chloro-5-trifluoromethoxybenzoic acid (22.5 g, 93.5 mmol; see step (iv) above) in anhydrous THF (1200 mL) under a N2 atmosphere at room temperature was added a solution of BH3.THF complex (140 mL of 1M in THF; 140.3 mmol). The solution was refluxed for 2 h, cooled to room temperature and stirred for 18 hours, quenched cautiously with H2O and concentrated in vacuo to remove most of the THF. The residue was diluted with EtOAc and the organics were washed with brine (3×), dried (Na2SO4), filtered and concentrated in vacuo to give the crude sub-title compound (21.2 g, 100%) as an oil that was used without further purification.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:15]=[C:14](Cl)[S:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18]>>[NH2:10][C:11]1[CH:15]=[C:14]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: OB(O)c1ccccc1
Product: Nc1cc(-c2ccccc2)sc1S(N)(=O)=O

Procedure:
The title compound was prepared from phenylboronic acid and 3b by following the procedure in example 3c. This compound is a white solid: MS (ES) 255 (M+H)+; 1H NMR (400 MHz, CD3OD)δ7.61 (m, 2 H), 7.42–7.37 (m, 3 H), 6.89 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH:14]=[CH2:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH2:14][CH3:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: C=Cc1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Yield: 95.8 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6 vinyl-1,3-benzoxazole-4-carbonitrile (I-180) (114 mg, 0.47 mmol) was dissolved in ethyl acetate (2.5 ml), then at room temperature, 10% palladium-carbon (23 mg) was added. The suspension was stirred at the same temperature under atmospheric pressure of hydrogen for 16 hours. The catalyst was separated by filtration with washing with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent, ethyl acetate:hexane=1:2) to obtain the entitled compound (110 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2s1
Yield: 42 %

Procedure:
Prepared from VII and 3,4-dichloroaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 42%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2851, 2225, 1644, 1612, 1579, 1456, 1378, 1355, 1308, 1270, 1241, 1168, 1122, 1026, 971, 879, 834, 816; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, 1H, J=8.7 Hz), 8.30 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.63-7.53 (m, 2H), 7.30 (m, 2H); HRMS calcd for C16H8N5SCl2 (M+H+): 371.9877, found 371.9882.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=O)(C)(C)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].NC[C@@H]1CCCN1CC.C(=O)C>>[CH3:15][S:16]([N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH2:8])[CH2:11]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Agent: CC=O
Agent: CCN1CCC[C@H]1CN
Product: CS(=O)(=O)N1CCC(CN)C1

Procedure:
By using 3-(t-butoxycarbonylaminomethyl)pyrrolidine (1.0 g) and methanesulfonyl chloride (0.48 ml) as starting materials, the title compound (0.78 g) was obtained in the same manners as those of Reference Example 58, (1) and Reference Example 39, (2).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[C:6]1([C@H:12]([NH:14][CH:15]2[CH2:19][O:18][CH2:17][CH:16]2[OH:20])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[OH-].[K+]>ClCCl.O>[C:6]1([C@H:12]([N:14]2[CH:15]3[CH:16]([CH2:17][O:18][CH2:19]3)[O:20][CH2:2][C:3]2=[O:4])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](NC1COCC1O)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C(=O)COC2COCC21
Reaction time: 2 h
Yield: 64.1 %

Procedure:
Chloroacetyl chloride (0.88 ml, 11 mmol) was added to a solution of (3RS,4SR)-4-((1R)-1-phenyl-ethylamino)-tetrahydro-furan-3-ol (1.9 g, 9.2 mmol) and triethylamine (1.8 ml, 13 mmol) in dichloromethane (30 ml) at 0° C. and the solution was stirred for 2 hours at that temperature. The resulting mixture was poured into water and extracted with chloroform. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude material was dissolved into 2-propanol (30 ml) at room temperature and 85% potassium hydroxide (1.3 g, 20 mmol) was added to the resulting solution with vigorous stirring at room temperature. After 15 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=100/0 to 3/1) to yield (3aRS,7aSR)-7-((1R)-1-Phenyl-ethyl)-tetrahydro-2,4-dioxa-7-aza-inden-6-one (1.46 g, 5.9 mmol, 64%) as colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[Cl-].[Na+].O.O>N1C=CC=CC=1>[O:8]=[C:6]1[NH:5][CH2:4][C@H:3]([CH2:2][O:1][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[O:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1NC[C@H](CO)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CNC(=O)O2)cc1
Reaction time: 2 h

Procedure:
A solution of (5R)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (10.0 g), prepared as described in Tetrahedron: Asymmetry 1995, 6, 1181-1190, in pyridine (60 mL) at −10° C. was treated with para-toluenesulfonyl chloride (21.2 g), stirred for 2 hours, poured into 1:1 brine/water (100 mL), and extracted with ethyl acetate. The extract was washed with 1:1 saturated sodium bicarbonate/water and 1:1 brine/water, and the washes were back extracted with ethyl acetate. The combined extracts was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 272 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 2H), 7.39 (d, 2H), 4.80 (m, 1H), 4.18 (d, 2H), 3.70 (t, 1H), 3.50 (dd, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH:7]=1.[CH2:12]([OH:16])[CH:13](O)[CH3:14].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:14][CH:13]1[CH2:12][O:16][C:6]2([CH2:5][C:4]([CH3:10])([CH3:9])[C:3](=[O:11])[C:2]([CH3:1])=[CH:7]2)[O:8]1
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1=CC2(CC(C)(C)C1=O)OCC(C)O2
Yield: 70.2 %

Procedure:
To a 2-liter flask fitted with a reflux condenser, a water separator and a stirrer is charged 265 g of 2,6,6-trimethylcyclohex-2-en-1,4-dione (prepared by the method described in Helv. Chim. Acta, 39:2041 [1956]), 266 g of propylene glycol, 500 ml of benzene and 1 g of p-toluenesulfonic acid. The reactants are stirred and refluxed until no additional water is collected in the water separator. The product is washed with water to a pH of 6, and the solvent is stripped off. The residue is vacuum distilled through a 9" Goodloe column to yield 257 g of product, boiling point 92° C. at 1 mm Hg (80% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])=[CH:11][C:10]([Cl:18])=[CH:9][CH:8]=2)=[O:4].[OH-].[K+]>>[Cl:18][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([C:3]([OH:4])=[O:2])=[C:13]2[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: COC(=O)c1c(OC(C)C)c2cc(Cl)ccc2n1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)Oc1c(C(=O)O)n(-c2ccccc2)c2ccc(Cl)cc12
Yield: 71.9 %

Procedure:
The crude 5-chloro-3-(1-methylethoxy)-1-phenyl-1H-indole-2-carboxylic acid methyl ester intermediate (14.8 g; 0.043 mole) was saponified with 6.4 g (0.11 mole) of potassium hydroxide as described in Example 1 to yield 10.2 g (72% yield) of the crude carboxylic acid product, mp 120° -dec. This material was used for further synthesis without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:20]O.C=O>C(O)=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:20])[CH2:7][CH:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CO
Reactant: CCOC(=O)C1CNCCN1Cc1ccccc1Cl
Agent: C=O
Solvent: O=CO
Product: CCOC(=O)C1CN(C)CCN1Cc1ccccc1Cl
Yield: 86.5 %

Procedure:
A mixture of 28 g (0.1 mol) of the compound obtained in Step b, 120 ml of methanol, 12 ml of 37% formaldehyde and 12 ml of formic acid is heated under reflux for 20 hours. The solvent is evaporated off in vacuo and the resulting residue is taken up in ether and a saturated sodium hydrogen carbonate solution. The organic phase is washed, neutralised and then extracted with ether. After drying over magnesium sulfate and evaporation of the solvent, the residue is dissolved in 200 ml of absolute ethanol and saturated with gaseous hydrochloric acid. The dihydrochloride precipitates by the addition of ether. 32 g of white crystals are isolated.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1C(OCC1C=CC=CC=1)=O>CCO.[Ni]>[CH3:1][O:2][CH:3]([O:19][CH3:20])[CH:4]1[CH2:8][CH2:7][CH2:6][NH:5]1
Reactant: COC(OC)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: COC(OC)C1CCCN1

Procedure:
A solution of acetal 15 (5.8 9, 0.02 mol) in EtOH (50 mL) was allowed to stir for 16 hours at room temperature over Raney nickel (0.2 g), in order to remove the trace amounts of sulphur impurities prior to hydrogenation. Excess nickel was removed by filtration through Celite.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][C:22](C(OC(C)(C)C)=O)=[CH:21][CH:20]=1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)=[O:37].[C:43](=[O:46])([O-])[O-:44].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:30][CH:31]=1)[C:43]([O:44][C:6]([CH3:11])([CH3:7])[CH3:2])=[O:46]
Reactant: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Reactant: O=C(CCCI)c1cccs1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4cccs4)CC3)C2=O)c1
Yield: 170.5 %

Procedure:
tert-Butyl 4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 4-iodo-1-(thiophen-2-yl)butan-1-one (0.17 g, 0.593 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in N,N-dimethylformamide (8 mL) were heated at 65° C. for 4 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.29 g, 84%); NMR (DMSO-d6); δ1.52 (s, 9H); 1.57 (m, 2H); 1.85 (m, 2H); 2.33-2.49 (m, 4H); 2.73 (m, 4H); 3.00 (m, 2H); 4.58 (s, 2H); 4.61 (m, 2H); 6.78 (m, 2H); 7.18-7.26 (m, 4H); 7.48-7.55 (m, 2H); 7.80-7.84 (m, 2H); 7.96-8.00 (m, 2H); MS for C33H39N3O4S m/z 574 (M+H)+.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]([CH3:33])=[CH:26][C:25]=1[N:34]=[C:35]=[S:36]>>[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]([CH3:33])=[CH:26][C:25]=1[N:34]=[C:35]1[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:36]1
Reactant: CCC(C)[C@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1N=C=S
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2cc(C)c([N+](=O)[O-])cc2C)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride an described in Method B7a. 2,5-methylaniline was converted to 2,5-dimethyl-4-nitrophenyl isothiocyanate according to Method A2a. 2,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(2,5-dimethyl-4-nitrophenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(2,5dimethyl-4-nitrophenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: C[C@H](O)CN1C2C=C(C)C=CC=2N=C1.[Cl:15][C:16]1[N:21]=[C:20]2[N:22]([CH2:25][C@@H:26]([CH3:51])[O:27]C3C=C(NC(=O)C)C=CC=3S(=O)(=O)NC3CC(=O)OC3OCC)[CH:23]=[N:24][C:19]2=[CH:18][CH:17]=1>>[Cl:15][C:16]1[N:21]=[C:20]2[N:22]([CH2:25][C@H:26]([CH3:51])[OH:27])[CH:23]=[N:24][C:19]2=[CH:18][CH:17]=1
Reactant: CCOC1OC(=O)CC1NS(=O)(=O)c1ccc(NC(C)=O)cc1O[C@H](C)Cn1cnc2ccc(Cl)nc21
Agent: Cc1ccc2ncn(C[C@H](C)O)c2c1
Product: C[C@H](O)Cn1cnc2ccc(Cl)nc21

Procedure:
(S)-2-(5-Chloro-imidazo[4,5-b]pyridin-3-yl)-1-methyl-ethanol was synthesized via the method used for (S)-1-Methyl-2-(6-methyl-benzimidazol-1-yl)-ethanol giving a tan solid. MS (APCI) m/z 212 (M). This fragment was used in the synthesis of N-[3-[(R)-2-(5-Chloro-imidazo[4,5-b]pyridin-3-yl)-1-methyl-ethoxy]-4-(2-ethoxy-5-oxo-tetrahydro-furan-3-ylsulfamoyl)-phenyl]-acetamide, which was synthesized via route J; a white solid, MS (APCI) m/z 552 (M). Analysis calculated for C23H26N5O7SCl (552.010): C, 50.05; H, 4.75; N, 12.69. Found: C, 50.40; H, 4.87; N, 11.99.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:30][CH:29]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 160 °C
Yield: 69.9 %

Procedure:
A mixture of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.525 mmol), (4-morpholin-4-ylphenyl)amine (0.094 g, 0.525 mmol) and TEA (0.070 ml, 0.525 mmol) in MeCN (2 ml) was heated in a microwave reactor at 150° C. for 15 mins and 160° C. for 30 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography using 35% EtOAc in hexane as eluent, to give the title compound (0.157 g, 70%). 1H NMR (500 MHz CDCl3): δ 7.24-7.18 (m, 1H), 7.15-7.10 (m, 5H), 6.64 (d, 2H), 6.59 (bs, 2H), 4.54-4.45 (m 1H), 3.85 (bs, 4H), 3.03 (bs, 4H), 1.65 (d, 6H); 13C NMR (125 MHz CDCl3): δ 159.1, 131.3, 129.5, 128.9, 128.2, 125.2, 123.6, 15.9, 66.8, 50.0, 47.9, 20.5; Mass spectrum: M+H+ 428.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[O+]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.C(=O)([O-])[NH2:30].[NH4+]>O>[C:12]1([C:9]2[CH:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]3[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:11]=3[N:30]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCc2c(-c3ccccc3)cc(-c3ccccc3)[o+]c21
Reactant: NC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [NH4+]
Solvent: O
Product: O=C1CCCc2c(-c3ccccc3)cc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5,6,7,8-tetrahydro-8-oxo-2,4-diphenyl-1-benzopyrylium-tetrafluoroborate (2) and ammonium carbamate (63.1 g, 808 mmol) in 600 mL water is agitated for 24 hours at room temperature. The medium turned cacao after a while and the precipitate gets thicker as the reaction proceeds.
Reaction SMILES: N#N.[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[CH:7][CH:6]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:36])C=CC=CC=1>O1CCCC1>[OH:36][CH:13]1[CH2:14][CH2:15][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:17])[F:18])=[CH:10][CH:9]=2)[C:12]1=[O:16]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: O=C1CCCN1c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(O)CCN1c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
(Referring to Scheme 1) To a 100 mL round-bottomed flask equipped with septum and N2 inlet were added 600 mg (2.62 mmol) 1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one and 25 mL dry tetrahydrofuran. The solution was cooled to −78° C., and 5.24 mL (5.24 mmol) of a 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran was added, and the reaction was stirred at −78° C. for 45 minutes. Then a solution of 856 mg (3.27 mmol) of N-(benzenesulfonyl)phenyloxaziridine in 5 mL dry tetrahydrofuran was added, and the reaction allowed to warm to room temperature and stirred overnight. The reaction was quenched with aqueous ammonium chloride solution and diluted with ethyl acetate, and the layers were separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phase dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with hexane/ethyl acetate to afford 241 mg (38%) of a while solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([C:14]1[CH:19]=[CH:18][C:17](Br)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)([CH3:13])[C:11]#[N:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:13][C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)([CH3:9])[C:11]#[N:12]
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(C)(C#N)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C#N)c1ccc(Sc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 87.2 %

Procedure:
A mixture of 4-chlorothiophenol (6.5 g, 0.045 m), 2-methyl-2-(3-nitro-4-bromophenyl)propionitrile (11.0 g, 0.041 m), sodium carbonate (8.67 g, 0.082 m) and absolute ethanol (150 ml) as stirred and heated at reflux for 4 hours. The mixture was cooled and poured into ice-water and the resultant yellow solid was filtered off. This solid was then slurried in a mixture of water and SVM (1:1, 150 ml) and refiltered and washed with water/SVM (1:1, 150 ml). The solid was crystallised from ethanol to give yellow crystals (11.86 g, 87%) mpt. 159°-160°.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8](=[O:19])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18].[CH3:20][O:21][N:22]1[CH2:27][CH2:26][C:25]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>C(NC(C)C)(C)C.O1CCCC1>[CH3:6][O:7][C:8](=[O:19])[CH:9]([C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=1[CH3:16])[C:28]([C:25]1([S:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[CH2:24][CH2:23][N:22]([O:21][CH3:20])[CH2:27][CH2:26]1)=[O:29]
Reactant: COc1ccc(CSC2(C(=O)Cl)CCN(OC)CC2)cc1
Reactant: COC(=O)Cc1c(C)cc(C)cc1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)C1(SCc2ccc(OC)cc2)CCN(OC)CC1)c1c(C)cc(C)cc1C
Temperature: -5 °C
Reaction time: 1 h

Procedure:
In a separate flask, 512 mg diisopropylamine was dissolved in 15 ml tetrahydrofuran, cooled to −5° C., and 2.86 ml n-butyllithium (1.6M in hexane) was added, then stirred at 0° C. for 1 hour. Then 864 mg (2,4,6-trimethyl-phenyl)-acetic acid methyl ester was added, and the mixture stirred for additional 30 minutes at 0° C. The crude 1-methoxy-4-(4-methoxybenzylsulfanyl)-piperidine-4-carbonyl chloride was dissolved in 5 ml tetrahydrofuran and added to the reaction mixture, which was then allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, the residue partitioned between half saturated aqueous ammonium chloride and t-butylmethyl ether, the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel with ethyl acetate/cyclohexane (1:9, then 1:5, then 1:2) as a solvent. Thus, 508 mg 3-[1-methoxy-4-(4-methoxy-benzylsulfanyl)-piperidin-4-yl]-3-oxo-2-(2,4,6-trimethylphenyl)-propionic acid methyl ester was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][NH2:19])[CH2:11][CH2:10]1.ClC/C=C/CN1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].COC1C=CC=CC=1N1CCNCC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][N:19]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(C/C=C/CN)CC1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Agent: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C/C=C/CN2C(=O)c3ccccc3C2=O)CC1
Yield: 85.6 %

Procedure:
Trans-4-[4-(2-methyloxyphenyl)piperazinyl]-2-buten-1-yl-amine: according to the method of Example 5, N-(trans-4-chloro-2-buten-1-yl)phthalimide was reacted with 1-(2-methyloxyphenyl)piperazine to obtain N-{4-[4-(2-methyloxy-phenyl)piperazinyl]-trans-2-buten-1-yl}phthalimide, which was then reacted with hydrazine hydrate. Yield: 85.6%, hydrochloride mp: 178-180° C.